Prostate cancer susceptibility genes - CiteSeerX

Endocrine-Related Cancer (2003) 10 225–259

International Congress on Hormonal Steroids and Hormones and Cancer

Prostate cancer susceptibility genes: lessons learned and challenges posed J Simard 1,2, M Dumont 1,2, D Labuda 3, D Sinnett 3, C Meloche 3, M El-Alfy 2, L Berger 2, E Lees 4, F Labrie2 and S V Tavtigian 5 1

Canada Research Chair in Oncogenetics and Cancer Genomics Laboratory Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Laval University, Quebec City, Canada G1V 4G2 3 Sainte-Justine Hospital Research Center, Pediatrics Department, Montreal University, Montreal, Canada H3T 1C5 4 DNAX Research Institute, Department of Oncology, Palo Alto, California, USA 5 International Agency for Research on Cancer, 69372, Lyon Cedex 08, France 2

(Requests for offprints should be addressed to J Simard; Email: [email protected])

Abstract In most developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal and/or genetic factors remains unknown. A positive family history is among the strongest epidemiological risk factors for prostate cancer. It is now well recognized that the role of candidate genetic markers to this multifactorial malignancy is more difficult to identify than the identification of other cancer susceptibility genes. Indeed, despite the localization of several susceptibility loci, there has been limited success in identifying high-risk susceptibility genes analogous to BRCA1 or BRCA2 for breast and ovarian cancer. Nonetheless, three strong candidate susceptibility genes have been described, namely ELAC2 (chromosome 17p11/HPC2 region), 2′-5′-oligoadenylate-dependent ribonuclease L (RNASEL), a gene in the HPC1 region, and Macrophage Scavenger Receptor 1 (MSR1), a gene within a region of linkage on chromosome 8p. Additional studies using larger cohorts are needed to fully evaluate the role of these susceptibility genes in prostate cancer risk. It is also of interest to mention that a significant percentage of men with early-onset prostate cancer harbor germline mutation in the BRCA2 gene thus confirming its role as a high-risk prostate cancer susceptibility gene. Although initial segregation analyses supported the hypothesis that a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer, current experimental evidence better supports the hypothesis that some of the familial risks may be due to inheritance of multiple moderate-risk genetic variants. In this regard, it is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action led to the observation of a significant association between a susceptibility to prostate cancer and common genetic variants in some of those genes. Endocrine-Related Cancer (2003) 10 225–259

Introduction In most developed countries, prostate cancer is the most frequently diagnosed non-cutaneous malignancy among men. In the United States, one in eight men will develop prostate cancer during his life. The incidence of prostate cancer varies markedly throughout the world, with the United States, Canada, Sweden, Australia and France having the highest rates (ranging from 48.1 to 137.0 cases per 100 000 personyears as estimated between the 1988–1992 period), whereas

most European countries have intermediate rates (23.9 to 31.0 cases per 100 000 person-years). The lowest prevalence is observed in Asian populations (2.3 to 9.8 cases per 100 000 person-years) (Hsing et al. 2000b). The extent to which this racial/ethnic difference is attributable to screening methods, environmental, hormonal and/or genetic factors is unknown. Although early detection using prostate-specific antigen (PSA) and improved treatment have emerged as the most critical strategies to decrease prostate cancer mortality (Labrie 2003), the potential of early detection through

Endocrine-Related Cancer (2003) 10 225–259 1351-0088/03/010–225  2003 Society for Endocrinology Printed in Great Britain

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Simard et al.: Prostate cancer susceptibility genes genetic indicators is also particularly relevant. Nevertheless, scientists involved in cancer genomics acknowledge that obvious heterogeneity exists, making the association of candidate genetic markers to this multifactorial malignancy more difficult than the identification of susceptibility genes for some common cancers such as breast, ovary and colon cancer. A positive family history is among the strongest epidemiological risk factors for prostate cancer. Familial clustering of prostate cancer was first reported by Morganti et al. (1956). Thereafter, various case-control and cohort studies have investigated the role of family history as a risk factor for prostate cancer (for recent reviews see Eeles 1999, Ostrander & Stanford 2000, Singh 2000, Nwosu et al. 2001). Much evidence comes from the study of pedigrees having a large number of cases, as those observed in the Utah population (Cannon et al. 1982, Eeles et al. 1996). The relative risk of prostate cancer increases markedly when the age of the index case decreases or when the number of affected individuals in a cluster increases, thus suggesting that this increased risk has a genetic component. For example, the brother of a proband diagnosed at age 50 has a 1.9-fold relative risk of developing prostate cancer compared with the brother of a case diagnosed at age 70 (Carter et al. 1992). Moreover, having one, two or three affected first-degree relatives increases the relative risk by 2.2-, 4.9- and 10.9-fold respectively (Steinberg et al. 1990). It should be noted that family studies offer the opportunity to estimate risks of siblings and parent-offspring pairs, but cannot distinguish between genetic and non-genetic causes of familial aggregations of cancer. In contrast, comparisons of the concordance of cancer between monozygotic and dizygotic pairs of twins provide valuable information on whether the familial clustering is due to hereditary or environmental influences. Thus, the importance of inherited predisposition to prostate cancer is also supported by the finding that monozygotic twins have a fourfold increased concordance rate of prostate cancer compared with dizygotic twins (Carter et al. 1992). In support of this latter observation, it has recently been estimated, using the combined data from 44 788 pairs of twins listed in Swedish, Danish and Finnish twin registries, that 42% (95% confidence interval (CI) = 29%–50%) of all prostate cancer risk may be explained by inheritable factors (Lichtenstein et al. 2000). The first segregation analysis, which included 691 families affected by prostate cancer ascertained through 740 consecutive probands undergoing radical prostatectomy, suggested that inherited predisposition was due to a rare, highly penetrant autosomal dominant allele(s) with a population frequency of 0.003, and with carriers having an 88% cumulative risk of disease by 85 years of age compared with only 5% in non-carriers (Carter et al. 1992). The gene accounted for approximately 43% of prostate cancer cases diagnosed before age 55 and 9% of cases diagnosed through age 85. In two

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other segregation analyses, similar transmission models were proposed (Gro¨nberg et al. 1997, Schaid et al. 1998); however, the Gro¨nberg model proposed a more common allele (1.67%) and a lower life span penetrance (63%). All these studies thus supported the presence of at least one highly penetrant autosomal dominant prostate cancer predisposition gene. However, consistently higher risks observed in brothers of prostate cancer-affected relatives compared with sons of affected individuals have led to hypotheses of an X-linked, recessive, and/or imprinted component to the genetics of prostate cancer susceptibility (Monroe et al. 1995, Narod et al. 1995). Finally, Cui et al. (2001) recently suggested a model of a dominantly inherited increased risk that was greater at younger ages, whereas a recessive or X-linked risk was greater at older ages.

Mapping putative loci for prostate cancer susceptibility genes Several factors may contribute to the difficulty of identifying prostate cancer susceptibility genes (Eeles et al. 1996, Eeles 1999, Ostrander & Stanford 2000, Singh 2000, Nwosu et al. 2001, Simard et al. 2002a). Prostate cancer is typically diagnosed at a late age, thus often making it difficult to obtain DNA samples from living affected men for more than one generation. Another significant problem is the lack of clear distinguishing features between hereditary and sporadic forms of the disease, making it difficult to distinguish, within high-risk pedigrees, men who have developed a cancer that is sporadic rather than due to an inherited germline mutation (phenocopies). Indeed, the presence within a pedigree of a sporadic case who harbors a meiotic recombinant within a bona fide region of linkage that is not actually relevant to his disease can push a peak of logarithms of the odds (LOD) score away from the true location of an underlying susceptibility gene or lead a positional cloning team to incorrectly narrow a putative region of linkage, thus misleading scientists to focus their analysis of candidate genes in the wrong chromosomal region. A particularly difficult problem is the apparent genetic heterogeneity of the trait; appropriate analysis would require development of statistical transmission models that can take into account multiple susceptibility genes, many of which are apparently of moderate or modest penetrance (Eeles 1999, Ostrander & Stanford 2000, Singh 2000, Nwosu et al. 2001). To date, chromosome by chromosome results of genome scans for prostate cancer susceptibility loci have been published by four independent groups. Three additional independent groups have published focused results derived from at least nearly complete genome scans. Because most of the subsequent replication studies are based on the family sets assembled for these genome scans, we will identify most of the study sets either by the acronym for the underlying family study or by the name of the research center most clearly associated with ascertainment of the family set (Tables 1 and 2).

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Table 1 Group 1 linkages References

Family set assemble for genome scans

HPC1 at 1q23-25 Hypothesis generating linkage analysis Smith et al. Johns-Hopkins pedigree (1996) resource

Ascertainment criteria/analytic methods/covariates

Linkage results

Remarks

Ascertained on the basis of early onset familial prostate cancer

Multipoint hetLOD score = 5.43

Heterogeneity analysis suggested that HPC1 accounts for up to 34% of prostate cancer families with ⱖ 4 cases

LOD score = 5.10

Evidence of linkage was prominent in the subset of 21 families that have an average age at diagnosis < 65 yrs as well as ⱖ 5 members affected More evidence of linkage was observed in a subset of 20 families that fulfilled one or more of the clinical diagnostic criteria for hereditary prostate cancer. However, this study did not exceed the threshold recommended by Lander & Kruglyak (1995)

Confirmatory and/or subsequent supportive studies Gro¨nberg et Johns-Hopkins pedigree Stratification of pedigrees by age al. (1997) resource of onset and the number of afftected individuals Cooney et al. (1997)

59 prostate cancer pedigrees Entire data set (University of Michigan Prostate Cancer Genetics Project)

Hsieh et al. (1997)

Stanford/USC pedigree resource

Neuhausen et Utah high risk pedigrees al. (1999)

NPL Z score = 1.58

The evidence for linkage is strongest in the younger-onset families (< 67 yrs). However, this study did not exceed the threshold recommended by Lander & Kruglyak (1995)

Entire data set 3-point LOD score = 2.43 Stratification of pedigrees into 3-point LOD score = 2.82 quartiles by ascending median age at diagnosis

Stronger evidence of linkage was found in pedigrees with younger ages at diagnosis (mean median age of the youngest quartile = 64.5 yrs (62.0–65.8 yrs))

Xu (2000)

Meta-analysis from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics 2000

Goode et al. (2001)

PROGRESS pedigree resource Stratification of pedigrees by disease aggressiveness Stratification of pedigrees by disease aggressiveness and by age at diagnosis

HPC1 accounted for only a small proportion of all families (앑6%) and played a predominant role in families with several members affected (> 5 cases), at an early age (ⱕ 65 yrs) and with male-to-male disease transmission NPL score = 2.55 NPL score = 3.47

HPC1 linkage may be most common among families with more severe prostate cancer and older-onset families showed stronger suggestion of HPC1 linkage (> 66% of cases with aggressive disease (Gleason score 7–10 or stage C or D) per family and ⱖ 65 yrs). Stratification by age at diagnosis gave a result opposite from that obtained from the Utah high risk pedigrees and contrary to the set of criteria used to ascertain the set of pedigrees from which the linkage was first described.

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Previous studies using the PROGRESS pedigree resource, McIndoe et al. (1997) (49 high-risk families) and Goode et al. (2000) (150 high-risk families) did not confirm the linkage for this region


Stratification of pedigrees by mean 3-point NPL Z score = 1.83 age at onset

References



Xu et al. (2001b)

Johns-Hopkins pedigree resource (expanded pedigree set)

Stratification of pedigrees by LOD score = 2.76 male-to-male disease transmission Stratification of pedigrees by age LOD score = 3.05 of onset

The evidence for linkage mainly came from a subset of families with male-to-male transmission and early age of onset (< 65 yrs)

LOD score = 3.25

A large peak, located 앑30 cM centromeric to the most significant marker described by Smith et al. (1996) was found only when Gleason score was included as a covariate Previous study using the WUSM pedigree resource, Suarez et al. (2000a) did not initially find evidence for HPC1

Goddard et al. WUSM pedigree resource (2001)

Model with various covariates including Gleason score

Independent studies showing no evidence of linkage Berthon et al. Progene pedigree resource (1998)

Linkage results

2-point LOD scores = −1.89 to −13.12 (θ = 0.0)

Eeles et al. (1998)

136 pedigree prostate cancer genetics resource assembled by an Anglo/Canadian/Texas/ Australian/Norwegian/EU Biomed consortium (ACTANE)

2-point LOD scores = −2.49 to −11.42 (θ =0.00)

Berry et al. (2000a)

Mayo Clinic pedigree resource

2-point LOD scores = −25.4 to −68.9 (θ = 0)

Suarez et al. (2000b)

45 new multiplex sibships and 4 expanded families from WUSM pedigree resource

PCAP at 1q41-43 Hypothesis generating linkage analysis Berthon et al. Progene pedigree resource (1998)

Stratification of pedigrees by age of onset

Confirmatory and/or subsequent supportive studies Suarez et al. WUSM pedigree resource Stratification of the pedigrees on (2000a) the basis of the family history


Gibbs et al. (2000)

PROGRESS pedigree resource Recessive model analysis Recessive model analysis and stratification of pedigrees by average age at diagnosis

Remarks

LOD score = 3.30

PCAP is reported to be responsible for 40 to 50% of French and German prostate families. Stronger evidence was reached with early-onset families (< 65 yrs)

Z score = 2.10

Pedigrees with greater family history showed modest evidence of linkage in the region (ⱖ 3 first-degree relatives with a diagnosis of prostate cancer)

2-point LOD score = 1.99 2-point LOD score = 1.46

This analysis provides some supportive evidence under a recessive analysis model. Most of the evidence was found in the earlier onset group (< 66 yrs) Previous study using the PROGRESS pedigree resource, Gibbs et al. (1999a) found suggestive, but not significant, evidence for linkage

Simard et al.: Prostate cancer susceptibility genes

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Table 1 Continued


Table 1 Continued References


Cancel-Tassin Progene pedigree resource et al. (2001a) (expanded pedigree set)

Xu et al. (2001b)


Linkage results

Remarks

Entire data set Stratification of pedigrees by average age at diagnosis

NPL score = 2.80 NPL score = 2.03

Analysis of 64 prostate cancer families from south and west Europe. Significant evidence of linkage from families with an earlier age of diagnosis (ⱕ 65 yrs) Although the linkage results were not statistically significant, results were consistent with a prostate susceptibility locus

Johns-Hopkins pedigree resource


Model with various covariates including male-to-male transmission

Independent studies showing no evidence of linkage Whittemore et Stanford/USC pedigree al. (1999) resource Berry et al. (2000a)



Stratification of pedigrees by male-to-male disease transmission, number of affected individuals and average age at diagnosis

Multipoint NPL score = 1.45

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57 Finnish prostate cancer families (Tampere pedigree resource)

Suggestive evidence for linkage was found in a subset 21 families with male-to-male disease transmission, average age at diagnosis < 66 yrs and at least 5 affected individuals

Multipoint KC Z score ⱕ 0

Stratification of pedigrees by evidence of male-to-male disease transmission Stratification of pedigrees by male-to-male disease transmisison and age at diagnosis

2-point LOD score = 4.60 and multipoint LOD score = 3.85

Linkage was estimated to account for 16% of prostate cancer in the data set of 360 families

NPL Z score = 1.89 at marker DXS294

Evidence of linkage was marginally higher in the subset of families without male-to-male transmission and early-onset prostate cancer (< 65 yrs). However, the highest LOD score from their study is observed in the families with male-to-male transmission which is counterintuitive for an X-linkage

NPL Z score = 1.51 at marker DXS1108

Stratification of pedigrees by 2-point maximum LOD score = male-to-male disease transmission 3.12 and average age at diagnosis

Most of the HPCX positivity came from a subgroup of families having no male-to-male transmission and a late age of diagnosis (> 65 yrs)


Schleutker et al. (2000)

Subsequent analysis of the genome scan of Suarez et al. (2000a) (WUSM pedigree resource) with various covariates, weak evidence of linkage remained

Multipoint Z scores = −10.18 to −14.69

Entire data set

Hsieh et al. Stanford/USC pedigree (2001) resource HPCX at Xq27-28 Hypothesis generating linkage analysis Xu et al. Johns-Hopkins, Mayo Clinic (1998) (United States), Tampere (Finland) and Umea (Sweden) pedigree resources Confirmatory and/or subsequent studies Lange et al. 153 prostate cancer pedigrees (1999) (University of Michigan Prostate Cancer Genetics Project)

LOD score = 1.90

References Hsieh et al. (2001)



Linkage results

Remarks

Standford/USC pedigree resource

Entire data set

1-pont KC Z score = 2.57

The 1-point KC Z-scores at two markers were elevated in families without evidence of male-to-male transmission. However, most of the multipoint evidence of linkage is in the families with male-to-male transmisison

Stratification of pedigrees by Multipoint KC Z score = 2.06 in male-to-male disease transmission families with male-to-male transmission 1-point KC Z score = 2.10 in families without male-to-male transmission Bochum et al. (2002)

104 German prostate cancer families


Independent studies showing no evidence of linkage Suarez et al. WUSM pedigree resource Entire data set (2000a) Peters et al. PROGRESS pedigree resource (2001)


HPC20 at 20q11-13 Hypothesis generating linkage analysis Berry et al. Mayo Clinic pedigree resource (2000b)


Bock et al. (2001)

172 hereditary prostate cancer families (University of Michigan Prostate Cancer Genetics Project)

The subset of families with an early age at onset (ⱕ 65 yrs) contributed disproportionately to the evidence of linkage

Multipoint Z score = −0.163 Althought this analysis did not show statistically significant evidence for linkage, the results are consistent with a small percentage of families being linked.

Model without covariate Model with various covariates: Gleason score was the covariate

LOD score = 0.26 LOD score = 3.06

They did not observe an increase in the evidence for linkage among families with transmission that was consistent with an X-linkage mode of inheritance (i.e. families that did not have male-to-male transmission)

Entire data set

2-point LOD score = 2.69 and Multipoint NPL score = 3.02 Multipoint NPL score = 3.69

Multipoint NPL and multipoint hetLODs were higher in families with < 5 cases, age at diagnosis ⱖ 66 yrs and without male-to-male transmission. Linkage in the no male-to-male transmission group was unanticipated.

NPL score = 1.94

Stronger evidence of linkage was found in subsets of families with later age at diagnosis (ⱖ 65 yrs), ⱕ 4 affected family members, or without male-to-male transmission

Stratification of pedigrees by male-to-male disease transmission, number of affected individuals and average age at diagnosis Confirmatory and/or subsequent studies Zheng et al. Subset of Johns-Hopkins (2001) pedigree resource

NPL Z score = 1.20 NPL Z score = 2.32

Stratification of pedigrees by average age at diagnosis Stratification of pedigrees by the number of affecteds

NPL score = 1.74 Z score = 1.99

The strongest evidence for linkage was seen in a subset of 16 African-American families.


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Table 1 Continued





Linkage results

Remarks

Independent studies showing no evidence of linkage Smith et al. Johns-Hopkins pedigree (1996) resource Suarez et al. (2000a)

WUSM pedigree resource

Cancel-Tassin et al. (2001b) Hsieh et al. (2001)

Multipoint KC Z score ⱕ 0


CAPB at 1p36-35 Hypothesis generating linkage analysis Gibbs et al. PROGRESS pedigree resource (1999b) Confirmatory and/or subsequent studies Suarez et al. WUSM pedigree resource (2000a)

LOD score = 3.22

A subset of 12 pedigrees with both prostate cancer and primary brain cancer

Stratification of pedigrees according to whether they were positive for breast cancer

Z score = 3.78

Suggestive linkage has been observed in a subset of prostate cancer pedigrees that reported a family history of breast cancer


Gleason score was used as a quantitative trait of prostate tumor aggressiveness

P = 0.003

The analysis demonstrated slight linkage to Gleason score (P < 0.01) with peaks between D1S1622 and D1S3721

Badzioch et al. (2000)

207 pedigree prostate cancer genetics resource assembled by an Anglo/Canadian/Texas/ Australian/Norwegian/EU Biomed consortium (ACTANE)

Stratification of pedigrees into quartiles by average age at diagnosis

NPL score = 1.60 (youngest quartile: mean age at onset < 59 yrs) NPL score = 1.02 (second quartile: mean age at onset 60–69 yrs)

Slight evidence of linkage in subsets of families with earlier age at diagnosis. No evidence for linkage in any two-tumor type combination (for instance brain and prostate)

Xu et al. (2001b)

Johns-Hopkins pedigree resource

LOD score = 0.61 (P = 0.09)

Slight evidence of linkage in families with both prostate cancer and primary brain cancer


There was no evidence for linkage to CABP in the brain cancer-prostate cancer subset

Independent studies showing no evidence of linkage Smith et al. Johns-Hopkins pedigree (1996) resource Berry et al. (2000a)


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Witte et al. (2000)

References



Linkage results

Remarks

2-point LOD score 앑 1.6

In the initial genome scan of the Johns-Hopkins pedigree resource, the second-highest 2-point LOD score was on chromosome 4q at D4S430


2-point LOD score 앑 1.3 Z score = 2.85

The linkage signal occurs in the late-age-at-onset group (ⱖ 65 yrs) at a marker 12 cM from the linkage hint observed in the Johns-Hopkins data

Model with various covariates: number of affecteds was the covariate

LOD score = 2.80

Subsequent analysis of the genome scan of Suarez et al. (2000a) (WUSM pedigree resource) with various covariates, evidence at 4q remained

2-point Z scores between 1.8 and 2.0

Best evidence is 30–40 cM distal to the best evidence reported by the WUSM group.

4q24-25 Hypothesis generating linkage analysis Smith et al. Johns-Hopkins pedigree (1996) resource Confirmatory and/or subsequent studies Suarez et al. WUSM pedigree resource (2000a) Goddard et al. (2001)


Hsieh et al. (2001)


Independent studies showing no evidence of linkage Gibbs et al. PROGRESS pedigree resource (2000) 8p23-22 Linkage analysis (arguably a pre-existing hypothesis from tumor LOH studies) Smith et al. Johns-Hopkins pedigree (1996) resource Gibbs et al. (2000)

PROGRESS pedigree resource The entire data set was analyzed under a recessive model Recessive model analysis and stratification of pedigrees by average age at diagnosis

Goddard et al. WUSM pedigree resource (2001) Confirmatory and/or subsequent studies Xu et al. Johns-Hopkins pedigree (2001c) resource

2-point LOD score = 2.17 2-point LOD score = 2.05

Evidence of linkage was strongest in the later age at diagnosis subset (ⱖ 66 yrs)


LOD score = 2.56

Subsequent analysis of the genome scan of Suarez et al. (2000a) (WUSM pedigree resource) with various covariates, modest hints of linkage were detected

Stratification of pedigrees by average age at diagnosis

NPL score = 2.64

Pedigrees linked tend to have late onset (ⱖ 65 yrs), large number of affecteds and male-to-male disease transmission


16p13 Hypothesis generating linkage analysis Suarez et al. WUSM pedigree resource (2000a) Gibbs et al. (2000)

Modest hints of linkage were detected

PROGRESS pedigree resource Recessive model analysis and stratification of pedigrees by average age at diagnosis

Z score = 2.81 at 16p Z score = 3.15 at 16q 2-point LOD score = 1.58

Evidence of linkage was strongest in the younger age at diagnosis subset (< 66 yrs)


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Table 2 Group 2 linkages




Confirmatory and/or subsequent studies Goddard et al. WUSM pedigree resource (2001)


Linkage results

Remarks


LOD score = 2.68

Subsequent analysis of the genome scan of Suarez et al. (2000a) (WUSM pedigree resource) with various covariates, evidence at 16p was stronger than at 16q

Independent studies showing no evidence of linkage Smith et al. Johns-Hopkins pedigree (1996) resource Hsieh et al. (2001)

multipoint KC Z score ⱕ 0


HPC2/ELAC2 at 17p11 Hypothesis generating linkage analysis Tavtigian et Utah high-risk prostate cancer al. (2001) pedigrees

The mean number of cases per pedigrees was 10.2 and the mean age at diagnosis was 68.3 yrs

2-point Z score = 2.44

The 2-point Z-score was observed at D17S1303, a marker within the HPC2/ELAC2 region


P = 0.0004

Evidence for prostate cancer aggressiveness genes


P = 0.0001

Significant evidence for an aggressiveness locus

Confirmatory and/or subsequent studies Hsieh et al. Stanford/USC pedigree (2001) resource Independent studies showing no evidence of linkage Xu et al. Johns-Hopkins pedigree (2001a) resource Suarez et al. (2001)


19q13 Hypothesis generating linkage analysis Witte et al. WUSM pedigree resource (2000) Confirmatory and/or subsequent studies Slager et al. Mayo Clinic pedigree resource (2002)

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2-point LOD score = 4.50

A dominant model integrated with Utah age-specific incidence was used

Simard et al.: Prostate cancer susceptibility genes Sources of the four genome scans that have, to date, been well described are: a Johns-Hopkins/Sweden collaboration – ‘Johns-Hopkins set’ (Smith et al. 1996); the Seattle based Prostate Cancer Genetic Research Study – ‘PROGRESS set’ (Gibbs et al. 1999b, 2000); a family collection ascertained largely through staff urologists at the Washington University School of Medicine and consisting mostly of affected sib pairs – ‘WUSM set’ (Suarez et al. 2000a, Witte et al. 2000, Goddard et al. 2001) and a family collection that developed out of a multiethnic case-control study ascertained in Hawaii, California, British Columbia, and Ontario – ‘Stanford/USC set’ (Hsieh et al. 2001). Sources of three additional genome scans that have both identified candidate loci and contributed to replication studies are: a collection of large Utah pedigrees ascertained through a genealogy/cancer diagnosis resource for an excess of closely and distantly related prostate cancer cases among the descendants of a single ancestor – ‘Utah set’ (Neuhausen et al. 1999, Tavtigian et al. 2001); a family collection ascertained through the Mayo Clinic radical prostatectomy database – ‘Mayo set’ (Berry et al. 2000a); and a set of French and German prostate cancer pedigrees – ‘Progene set’ (Berthon et al. 1998). Largely as a result of analysis of these seven collections of prostate cancer pedigrees, hints of linkage have been described on every autosome as well as the X chromosome. Many of the stronger hints have either been cross-referenced between genome scans, reevaluated on one or more of the independent family sets used in one of the other genome scans, or further evaluated on an extended version of the family set from which the hint of linkage was originally derived. Recognizing that strength of evidence in support of these various hints of linkage exists on a continuum which is complicated by different ascertainment criteria for the underlying family collections as well as differences in analytical methods, it seems useful to summarize two groups of linkages. The first group (five linkages) (Table 1) is supported by at least one analysis with LOD > 3.0 and nominal support from at least two or more independent analyses. In chronological order by when the hypothesis-generating linkage was first described, these are: HPC1 at 1q23-25 (Johns-Hopkins set) (Smith et al. 1996, Xu et al. 2001b), PCAP at 1q41-43 (Progene set) (Berthon et al. 1998), HPCX at Xq27-28 (Johns-Hopkins set) (Xu et al. 1998), CAPB at 1p36-35 (PROGRESS set) (Gibbs et al. 1999b), and HPC20 at 20q11-13 (Mayo set) (Berry et al. 2000b) (Fig. 1). The second group (five linkages) (Table 2) is supported by at least one analysis with LOD > 2.5 and nominal support from at least one independent study, but without reaching the group one criteria. This time ordered by chromosomal location with reference given here to the report presenting strongest evidence of linkage to the locus, these are: a hint of linkage at chromosome (Chr) 4q24-25 (WUSM set)

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(Suarez et al. 2000a), a hint of linkage at Chr 8p23-22 (Johns-Hopkins set) (Xu et al. 2001c), a hint of linkage at Chr 16p13 (WUSM set) (Suarez et al. 2000a), a hint of linkage at Chr 17p11 (HPC2/ELAC2) (Utah set) (Tavtigian et al. 2001), and a hint of linkage to tumor aggressiveness at Chr 19q (WUSM set) (Witte et al. 2000) (Fig. 1). As one considers the evidence supportive of each of the linkages presented in Tables 1 and 2, it is important to recognize that the multiple testing inherent in executing a complete genome scan for disease susceptibility will generate falsepositive hints of linkage. Even without error in genotyping or analysis, it is very common to generate false positives with LOD scores between 2.0 and 3.0. Indeed common problems such as miss-specifying allele frequencies contribute to an appreciable level of false positives with LOD scores between 3.0 and 4.0. Until an underlying susceptibility gene has been found, the best evidence in support of a candidate linkage is concordance with independent genome scans or independent targeted analyses of the region with evidence of linkage. Given the number of independent genome scans for prostate cancer susceptibility gene(s) that have been reported to date, along with the multiple testing burden created by the analysis of those data with many different models, it would not be surprising to find examples of false-positive results that have been independently corroborated by other false-positive results. However, it is very clear from segregation studies that sequence variants that confer risk of prostate cancer do exist which implies that some of the reported hints of linkage, and most likely those with stronger independent support, almost certainly reflect the presence of an underlying prostate cancer susceptibility gene.

Genes contributing to familial prostate cancer It is one thing to have a hint of linkage, or better still a well supported linkage, for a disease susceptibility locus. It is quite another thing to identify the underlying susceptibility gene and risk conferring sequence variants in that gene. From the point of view of the positional cloner, every gene within reasonably well defined bounds of a genetic linkage is a candidate gene for the linked trait. When a research group finds sequence variants in such a gene that appear to explain an appreciable fraction of the apparently linked families and appear to confer increased risk of the trait in question, the gene is then properly recognized as a ‘strong’ candidate gene. However, one must recognize that as mutation screening/ gene sequencing technology has improved, positional cloners have been able to thoroughly screen more and more genes within regions of linkage. This is a form of multiple testing; consequently, as the number of candidate genes screened within any given region or for any given trait increases, so does the likelihood of observing a false positive. Therefore,



Figure 1 Localization of prostate cancer susceptibility loci reported in the literature. The first group of linkages identified by ovals, are supported by at least one analysis with LOD > 3.0 and nominal support from at least two or more independant analyses. HPC1 at 1q23-25 (Smith et al. 1996, Xu et al. 2001b), PCAP at 1q41-43 (Berthon et al. 1998), HPCX at Xq27-28 (Xu et al. 1998), CAPB at 1p36-35 (Gibbs 1999b). The second group of linkages identified by boxes, are supported by at least one analysis with LOD > 2.5 and nominal support from at least one independant study. 4q24-25 (Suarez et al. 2000a), 8p23-22 (Xu et al. 2001c), 16p13 (Suarez et al. 2001), HPC2/ELAC2 at 17p11 (Tavtigian et al. 2001) and 19q13 (Witte et al. 2000), HPC20 at 20q11-13 (Berry et al. 2000b).

when the discovery of a strong candidate susceptibility gene is published, the publication should be regarded as an hypothesis-generating study and should then be judged both on the basis of how well the initial hypotheses (or new closely related hypotheses) stand up to independent reanalysis and on the basis of how well the data indicating that the gene is in fact a susceptibility gene explain the genetic linkage from which the gene was localized. To date, three strong candidate familial prostate cancer susceptibility genes have been described, one each from three of the linkages described in the proceeding section. These are in chronological order ELAC2 (Chr 17p11/HPC2/ELAC2 region) (Tavtigian et al. 2001), 2′-5′-oligoadenylate-


dependent ribonuclease L (RNASEL) (Chr 1q23-25/HPC1 region) (Carpten et al. 2002), and macrophage scavenger receptor 1(MSR1) (Chr 8p region) (Xu et al. 2002).

ELAC2 (Chr 17p11/HPC2/ELAC2 region) The discovery of the first prostate cancer susceptibility gene characterized by positional cloning was achieved through a long-standing collaboration between Myriad Genetics and several academic groups, taking advantage of the Utah Family Resource which has proven to be an invaluable asset for cloning of cancer susceptibility genes in the past (Cannon 1982, Cannon-Albright et al. 1992, Miki et al. 1994, Wooster

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Figure 2 Recombinant, physical and transcript map centered at the human ELAC2 locus on chromosome 17p. Key recombinants: key recombinants under the arrows, which represent meiotic recombinants, are indicated by the number of the kindred in which the recombinant occurred and, in parentheses, the number of cases carrying the haplotype on which the recombinant occurred. BAC contig: BAC contig tilling path across the interval. The T7 end of each BAC is denoted with an arrowhead. Candidate genes: candidate genes are identified in the interval and below is an expanded view of the structure of the ELAC2 gene (Tavtigian et al. 2001). From Simard et al. (2002a); copyright owner, The Endocrine Society.

et al. 1994). A genome-wide search for prostate cancer predisposition loci using a small set of Utah high risk prostate cancer pedigrees and a set of 300 polymorphic markers carried out by Cannon-Albright’s group provided evidence for linkage to a locus on chromosome 17p (Fig. 2) (Tavtigian et al. 2001). These pedigrees were not selected for early age of cancer onset, but consisted of a subset of families ascertained using the Utah Population Database. Positional cloning and mutation screening within the refined interval identified a gene ELAC2 (MIM 605367), harboring a frameshift mutation, 1641insG, that segregated with prostate cancer in the high-risk pedigree kindred 4102. Three out of four male carriers of the frameshift of age > 45 years had been diagnosed with prostate cancer, and the fourth had a PSA of 5.7 at age 71. The frameshift, which occurred within the most highly conserved segment of the protein and eliminated one-third of the protein including several other conserved segments, was predicted to be highly disruptive to the gene product’s function. A second high-risk Utah pedigree was found to segregate an allele of ELAC2 that carried three missense changes: Ser217Leu (q = 0.30), Ala541Thr (q = 0.04) and Arg781His (very rare or pedigree specific). Of 14 prostate cancer cases in the pedigree, six carried the triple missense allele, six did not carry, and two were unknown.

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Of eight male carriers of the triple missense allele who were over age 45 and within the generations of the pedigree for which phenotype information is known, six were prostate cancer cases, one died of heart disease at age 62, but had two sons and a grandson who carried the allele and were cases, and the remaining one had a PSA of 0.6 at age 60. Another interesting point about the pedigree is that the youngest ageat-diagnosis carrier of the triple missense allele (diagnosed at age 50) was homozygous for the Leu217 and Thr541 variants. In addition, an ovarian cancer case in the pedigree, diagnosed at age 43, also carried the triple missense allele. The 17p11 tLOD (Abkevich et al. 2001) for this pedigree, which peaks at a microsatellite marker within ELAC2 and is almost entirely accounted for by the triple missense allele, was 1.3 (Tavtigian et al. 2001).

Towards an understanding of the function of ELAC2 At the time of its cloning, the function of ELAC2 was unclear. Sequence analysis predicted the gene to encode a metal-dependent hydrolase domain conserved among eukaryotes, archaebacteria, and eubacteria, and bearing striking sequence similarity to domains present in two better understood protein families, namely the PSO2 (SNM1) DNA



Figure 3 A schematic multiple protein alignment of ELAC superfamily members including the ELAC1, PSO2 and CPSF73 families and the ELAC2 orthologs. The conserved motifs are indicated by black boxes. Localization of known motifs are outlined by an arrow. From Simard et al. (2002a); copyright owner, The Endocrine Society.

inter-strand crosslink repair proteins and the 73 kDa subunit of mRNA 3′ end cleavage and polyadenylation specificity factor (CPSF73). This gene was designated ELAC2 because it is the larger of two human genes that were found to be homologues of Escherichia coli elaC (Fig. 3) (Tavtigian et al. 2001, Simard et al. 2002a). From analysis of the complete genome sequences available to date, it appears that all prokaryote and archaebacterial genomes encode one or two genes that are orthologous to E. coli elaC, whereas all eukaryotes encode one or two genes that are orthologous to ELAC2, which is actually comprised of homologous amino and carboxy halves and appears to have arisen as a direct repeat-duplication of an ancestral elaC-like gene. The first amino half of ELAC2s has suffered considerable sequence divergence, but the carboxy half is very similar to prokaryotic elaCs. Many eukaryotes, including the so-far sequenced vertebrates and plants, but not the protostomate invertebrates, encode one or two copies of another member of the gene family, ELAC1. This gene is of similar size and structure to the prokaryotic elaCs. Recently, in vitro analyses have clearly demonstrated that the prokaryotic elaCs encode binuclear zinc-dependent phosphodiesterases (Vogel et al.


2002). In addition, both archaebacterial elaCs and plant ELAC1s have been demonstrated to have a tRNA 3′ endonuclease activity, RNase Z, that is required for tRNA maturation (Schiffer et al. 2002). Given that the closely related CPSF73 genes play a role is mRNA 3′ end cleavage and polyadenylation, this latter result in not at all surprising. An interesting remaining question, though, is whether ELAC2s also encode RNase Z and what sort of functional specialization has occurred during the divergence between ELAC1 and ELAC2. However, a first biological insight into the function of ELAC2 has recently been published. It has been shown that overexpression of ELAC2 in tumor cells results in an increase in G2 cells, suggesting that the protein when overexpressed may alter mitotic entry. Korver et al. (2003) provided evidence that overexpressed ELAC2 binds to γ-tubulin and may disrupt normal γ-tubulin function to induce a G2 delay. Northern blots have revealed that the ELAC2 transcript is present in most human tissues (Tavtigian et al. 2001). In order to examine its expression at higher resolution in prostate, we undertook an immunohistochemical study using a polyclonal antibody raised in rabbits against a peptide

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Simard et al.: Prostate cancer susceptibility genes corresponding to amino acids 812-826 of human ELAC2 (Korver et al. 2003). The expression of ELAC2 was evaluated in normal as well as in pathological prostate. Immunostaining was performed using paraffin blocks of normal human prostate, symptomatic benign hyperplasia (BPH), low and high grades of prostatic intraepithelial neoplasia and different Gleason grades of prostatic adenocarcinoma. The prostatic intraepithelial neoplasia (PIN) is believed to be precancerous and high-grade PIN is considered the precursor of most cases of prostate cancer (McNeal et al. 1991, Bostwick 1995, Bostwick & Dundore 1997). For the precise detection of the ELAC2 protein, three serial consecutive sections of each specimen were immunostained. Anti-ELAC2 antibody was used in the first section, anti-high molecular weight cytokeratin antibody was used in the second section as a well known marker for basal cells (Bostwick & Dundore 1997) and finally anti-PSA was used in the third section as a marker for luminal cells and cancerous cells. Thus, the examination of the three immunostained serial consecutive sections facilitated the precise localization of the ELAC2 (Figs 4 and 5). In normal prostate and in BPH, the epithelium is a stratified columnar structure composed of two layers of cells: a continuous basal layer of low cuboidal cells upon which stands a layer of columnar secretory or luminal cells (El-Alfy et al. 2000). Basal cell layer disruption or absence characterizes high-grade PIN and early invasive cancer. The expression of ELAC2 in normal prostate and in BPH was exclusively localized in the basal cells (Fig. 4a,b). In specimens containing adenocarcinoma, only basal cells were labeled in the noncancerous epithelium (Fig. 5a–c). The remaining basal cells of PIN acini were also found to be labeled (Fig. 4c–e) as well as the basal portion of the luminal cells, while the ELAC2 was not detected in the apical region of most luminal cells (Fig. 4a–e). In all the examined adenocarcinoma with different Gleason scores, all cancerous cells were well labeled (Fig. 5).

Association studies of common missense variants in ELAC2 with risk of prostate cancer In the original analysis, both of the common missense changes in ELAC2 were tested for association with familial prostate cancer (Tavtigian et al. 2001); the results suggested that both Leu217 and Thr541 (Fig. 6) conferred increased risk of disease, and allowed us to postulate five hypotheses. (1) There is very strong linkage disequilibrium between the two variants, such that virtually all instances of Thr541 (q = 0.04) occur on an allele that also carries Leu217 (q = 0.30). (2) Both sequence variants confer modestly increased risk of disease. (3) The odds ratio (OR) measured for that risk of disease depends on the nature of the case-control comparison conducted. For instance, when we compared Leu217 carrier frequencies between familial cases and male controls who were cancer free and had little family history of cancer, we

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found an OR for Leu217 homozygotes of 2.4 (P = 0.026), but when we compared those same cases to unaffecteds from the prostate cancer pedigrees, the OR dropped to 1.5 (P = 0.014). Similarly, when we compared Thr541 carrier frequencies between familial cases and male controls who were cancer free and had little family history of cancer, we found an OR for carriage of Thr541 of 3.1 (P = 0.022), but when we compared those same cases to unaffecteds from the prostate cancer pedigrees, there was very little evidence for increased risk of disease. (4) In our data, most of the increased risk appeared to be in the earlier age of onset cases. As essentially all segregation analyses that have examined the familial component of prostate cancer have concluded that early onset cases are disproportionately likely to have a genetic basis, it would seem likely that the missense changes in ELAC2 confer relatively higher risk in early onset rather than later onset prostate cancer cases. (5) Finally, we predicted that the order of risk conferred by the three common missense alleles was Ser217/Ala541 < Leu217/Ala541 < Leu217/Thr541 (Tavtigian et al. 2001) (Fig. 6). To confirm our observation in a cohort unselected for family history, Rebbeck et al. (2000) studied 359 incident cancer prostate case subjects and 266 male control individuals that were frequency matched for age and race and were identified from a large health-system population. Among control individuals, the Leu217 frequency was 31.6%, whereas the Thr541 frequency was 2.9%. They observed that the relative risk of having prostate cancer is increased in men carrying the Leu217/Thr541 allele (OR = 2.37; 95% CI = 1.06–55.29). This risk did not differ significantly by family history or race. Since that time, seven additional analyses of ELAC2 have been published (Rokman et al. 2001, Suarez et al. 2001, Vesprini et al. 2001, Wang et al. 2001, Xu et al. 2001a, Meitz et al. 2002, Shea et al. 2002). Results have varied from significantly higher carrier frequencies of the Leu217/Thr541 allele in familial cases compared with low risk controls (OR = 2.83, P = 0.008), but without evidence of increased risk when familial cases were compared with unaffected men from those same pedigrees (Suarez et al. 2001), to essentially no evidence of any increased risk at all (Vesprini et al. 2001, Shea et al. 2002). Heterogeneity in the association study results led us to prepare a meta-analysis of the data published through July 2002 (Table 3) (Camp & Tavtigian 2002). From that analysis and excluding the data from our hypothesis generating study, there was strong evidence that carriage of the Leu217/Thr541 allele is significantly associated with risk of prostate cancer. However, that risk varied depending on the nature of the case-control comparison made. In very discordant sets (familial cases versus low risk controls, based on familial cases from the Johns-Hopkins and WUSM pedigree resources (Suarez et al. 2001, Xu et al. 2001a)), the OR was relatively higher and the evidence stronger (OR = 1.96, www.endocrinology.org


Figure 4 Paraffin sections of human prostate obtained from a patient with symptomatic benign prostatic hyperplasia (BPH), undergoing transurethral prostatectomy (a and b). Sections were immunostained with anti-ELAC2 antibody after a microwave retrieval technique. To visualize the biotin/streptavidin-peroxidase complex, diaminobenzidine was used as the chromogen under microscope monitoring, followed by hematoxylin counterstaining. In the epithelial cells lining the acini, all basal cells are labeled (arrows), while the ELAC2 is not detected in luminal cells (arrowheads). Fibromuscular stromal cells as seen at low (a) and high (b) magnification are not labeled. Consecutive serial sections (c, d and e) of a needle biopsy specimen displaying high-grade prostatic intraepithelial neoplasia (PIN) are immunostained with anti-ELAC2 antibody (c), or high molecular weight cytokeratin antibody as a marker of basal cells (d), or prostate-specific antigen (PSA) antibody as a marker of luminal cells (e). Acini containing PIN are characterized by the disruption or the absence of their basal cell layer as demonstrated in (d), while the expression of ELAC2 (c) could be detected in the cytoplasm of the remaining basal cells (thick arrow). In the luminal cells of PIN (c), the ELAC2 is detected only in the basal portion of the cells (thin arrows), while no labeling could be detected in their apical region (arrowheads). Only the luminal cells of PIN (arrowheads) are labeled when the PSA antibody is used (e), while the basal cells are not labeled (thick arrow).


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Figure 5 Two sets of consecutive serial sections (a–c and d–f) of two prostatic adenocarcinoma immunostained with anti-ELAC2 antibody (a and d), or high molecular weight cytokeratin antibody as a marker for basal cells (b and e) or PSA as a marker for luminal cells and which also labels cancerous cells (c and f). In a set of serial sections which include identified adenocarcinoma of Gleason score of four (a, b and c) as well as some noncancerous tissue, the expression of the ELAC2 protein is detected in all cancerous cells (arrowheads), while in the noncancerous epithelium, only basal cells are labeled (arrows). Similar expression of ELAC2 is observed in all cancerous cells of an adenocarcinoma graded as Gleason score of six (d, e and f).

P = 0.008), whereas in a comparison of all cases versus all controls, which is numerically dominated by sporadic cases and population controls, the OR was reduced and not quite significant (OR = 1.25, P = 0.081). Results with Leu217 followed a similar trend, but with lower odds ratios and less significant P-values. For instance, in the comparison of familial cases to low risk controls, the result for Leu217 dominant was OR = 1.37, P = 0.017, again based on familial cases from the Johns-Hopkins and WUSM pedigree resources (Suarez et al. 2001, Xu et al. 2001a, Camp & Tavtigian 2002). As the case control comparisons made by the JohnsHopkins and WUSM groups most closely match the format of our original case-control analysis (Tavtigian et al. 2001) and actually corroborate four of the five hypotheses generated from our data, although there was no evidence for rela-

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tively higher risk in early onset cases, this would seem very strong evidence in support of risk conferred by the Leu217 and Thr541 variants, albeit at slightly lower odds ratios than we originally described. Subsequent to the preparation of the meta-analysis, two more ELAC2 association studies were published (Meitz et al. 2002, Shea et al. 2002). Analysis of a series of British prostate cancer cases, many of them diagnosed before the age of 55, and population controls (Meitz et al. 2002) found a trend towards elevated risk in Leu217/Thr541 carriers, although the effect was not significant. Stratification by age at diagnosis demonstrated that most of the risk was present in the earlier onset cases (diagnosis 압 age 55) (OR = 1.50, 95% CI = 0.79-2.85). In addition, very slightly increased risk was seen in Leu217 carriers, although this was not nearly



Figure 6 Location of sequence variants in ELAC2, RNASEL and MSR1 genes. Dark gray boxes indicate homologies to known protein domains. High penetrance mutations of ELAC2 are identified by a box whereas common low penetrance mutations are indicated by an oval. The significance of the other missense mutations detected in ELAC2 is still unknown. Mutations of RNASEL and MSR1, which are identified by a box, have been suggested to be associated with increased risk of prostate cancer. The functional significance of the other missense mutations shown under the RNASEL and MSR1 proteins diagrams are unknown.

significant. Still, as the overall trend matches that observed in the meta-analysis, the result can be viewed as supportive. In contrast, a case control comparison of Afro-Caribbeans from Tobago resulted in OR of 1.0 (Shea et al. 2002). In fact, Thr541 was not even observed in this population, which has relatively little admixture from the European gene pool, suggesting that the Leu217/Thr541 allele is either European or Eurasian in origin. From the meta-analysis, if we assume a carrier frequency of 6.6% for risk genotypes (using pooled data), an OR of 1.3 translates to a population-attributable risk (PAR) of 2% (Lillienfeld & Lillienfeld 1980). This is perhaps a more


realistic expectation for common variants in a complex disease. Thus, to estimate the percentage of PAR for various populations, we have analyzed the frequency distribution of the ELAC2 polymorphisms in a worldwide sample of populations (Table 4). Leu217 allele is evenly spread all over the world, except for South-East Asia where it is virtually absent – found only on one chromosome out of 78 analyzed. In contrast, its frequency might be higher than the average in certain local populations as observed in a number of groups from or of Middle-Eastern descent. The worldwide frequency of Thr541 allele is much lower, in 0–5% range, but its concentration may be higher in certain regions (e.g.

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Simard et al.: Prostate cancer susceptibility genes Table 3 Results of Mantel-Haenszel meta-analysis, including and excluding data of Tavtigian et al. (2001) for the three case/ control comparisons Comparison, inclusiveness and measurea

Analysis Leu 217 dominant

Thr 541 dominant

Multi-locusb

1.96 (1.19–3.22) 0.0080 918

2.21 (1.32–3.69) 0.0026 529

2.23 (1.44–3.46) 0.00033 1495

2.44 (1.55–3.83) 0.00011 856

0.96 (0.67–1.37) 0.81 1706

1.81 (1.23–2.68) 0.0029 1680

1.86 (1.25–2.77) 0.0023 985

1.18 (0.86–1.62) 0.31 2283

2.01 (1.40–2.88) 0.00014 2257

2.05 (1.42–2.96) 0.00012 1312

1.02 (0.81–1.29) 0.86 3596

1.25 (0.97–1.60) 0.081 3571

NA NA NA

1.13 (0.90–1.41) 0.29 4173

1.35 (1.07–1.72) 0.013 4148

NA NA NA

Leu 217 recessive

Men with familial prostate cancer vs low-risk control individuals Without data of Tavtigian et al. (2001) OR (95% CI) 1.37 (1.06–1.78) 1.18 (0.75–1.85) P 0.017 0.48 Total sample size 928 928 With data of Tavtigian et al. (2001) OR (95% CI) 1.30 (1.05–1.61) 1.48 (1.01–2.16) P 0.016 0.044 Total sample size 1505 1505 All men with prostate cancer vs low-risk control individuals Without data of Tavtigian et al. (2001) OR (95% CI) 1.17 (0.96–1.42) P 0.11 Total sample size 1706 With data of Tavtigian et al. (2001) OR (95% CI) 1.17 (0.98–1.39) P 0.075 Total sample size 2283 All men with prostate cancer vs all control individuals Without data of Tavtigian et al. (2001) OR (95% CI) 1.09 (0.95–1.24) P 0.21 Total sample size 3596 With data of Tavtigian et al. (2001) OR (95% CI) 1.10 (0.97–1.24) P 0.15 Total sample size 4173 a

Men with familial prostate cancer vs low risk control individuals comparison includes data from Xu et al. (2001a) (familial prostate cancer only) and Suarez et al. (2001). All men with prostate cancer vs low risk control individuals includes data from Xu et al. (2001a) (familial and sporadic prostate cancer), Suarez et al. (2001), and Rebbeck et al. (2000). All men with prostate cancer vs all control individuals comparison includes data from Xu et al. (2001a) (familial and sporadic prostate cancer), Suarez et al. (2001), Rebbeck et al. (2000), Vesprini et al. (2001) (male control individuals only), and Wang et al. (2001). b Association test for carriage of both Leu217 and Thr541 versus carriage of neither. NA indicates that data were not available from the relevant published papers to perform the multi-locus analysis. Adapted from Camp & Tavtigian (2002).

the Americas) or groups (e.g. Druze or certain Jewish populations). Interestingly and as previously observed, Thr541 always occurs in combination with Leu217 allele, suggesting origin of this mutation on the chromosome carrying this particular allele, and tight linkage disequilibrium between the two of these. As shown in Table 4, frequency of Leu217 and Thr541 varies considerably from one population to the other. Combining these results with ORs estimated in the meta-analysis of Camp and Tavtigian (Table 3) for carriage of a dominant Thr541 allele, it is tempting to speculate that the estimated percentage of population-attributable risk due to this allele in different populations could be as elevated as 15% in Druze or certain Jewish populations as illustrated in Fig. 7. It is interesting to observe in Fig. 7 that a common low penetrance variant may be responsible for a

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percentage of PAR similar or higher than that conferred by a rare but highly penetrant susceptibility gene. Nevertheless, it is important to note that this hypothesis should be confirmed by direct analysis for each population. The diseaseassociated missense variant, Glu622Val (E622V), found in Finnish populations with a 1% population prevalence (Rokman et al. 2001) has not been observed in any of the previous samples of populations. Overall, mutation screening results indicate that inactivating mutations in ELAC2, and even pedigree specific missense changes, are exceedingly rare (Rokman et al. 2001, Suarez et al. 2001, Tavtigian et al. 2001, Wang et al. 2001, Xu et al. 2001a). Consequently, it will be very difficult to determine whether, or to what extent, such variants confer increased risk of prostate cancer. In fact, there is little


Endocrine-Related Cancer (2003) 10 225–259 Table 4 Frequency of Leu217 and Thr541 in different populations Regions

Sub-Saharan Africa Americas Europe South-East Asia Middle-East Palestinian Beduin Druze Jewish Ashkenazian Moroccan Bulgarian & Turkish Iranian Iraquian Yemenite

Number of samplesa

Ser217Leu Leu-frequency (%) ±SD

Ala541Thr Thr-frequency (%) ±SD

46 39 73 39

32.6 ± 4.9 25.6 ± 4.9 26.7 ± 3.7 1.3 ± 1.3

1.6 ± 1.6 8.3 ± 3.6 3.4 ± 1.9 0

22 30 35

22.7 ± 6.3 31.7 ± 6.0 45.7 ± 6.0

4.6 ± 3.1 3.3 ± 2.3 14.3 ± 4.2

40 30 30 21 29 30

48.8 ± 5.6 25.0 ± 5.6 40.0 ± 6.3 59.5 ± 7.6 31.0 ± 6.1 26.7 ± 5.7

12.5 ± 3.7 3.3 ± 2.3 8.3 ± 3.6 14.3 ± 5.4 5.2 ± 2.9 3.3 ± 2.3

a

Sub-Saharan-African sample included African-Americans and African Pygmies from Coriell, as well as African individuals from Montreal. Europe was represented by Canadians of European descent from Montreal and Italians, South-East Asia by individuals from that region living in Montreal, whereas Americas by Amerindians from Ontario and Saskatchewan as well as by Coriell samples from South and Central America (note that not all of the above samples were typed for Ala/Thr541 polymorphism). Middle-East was represented by samples from the collection of the National Laboratory for the Genetics of Israeli populations at Tel-Aviv University. When applicable, the informed consent was obtained from individuals donating genomic samples and the study was approved by the Ethics Committee at the Sainte-Justine Hospital. SD = square root of the variance = freq A × freq B/n; A is allele 1, B is allele 2 and n is the number of chromosomes

evidence that ELAC2 is a tumor suppressor. Knowing that knockout of the ELAC2 ortholog in Saccharomyces cerevisiae is lethal, one might hypothesize that at least one functioning allele is required for cellular viability. On the other hand, the Leu217 and Thr541 missense changes are quite common and will eventually be used to tightly constrain the role that this gene plays in prostate cancer genetics. Finally, it must be noted that while the open reading frame of ELAC2 has been thoroughly screened for sequence variants, the promoter and upstream transcriptional regulatory sequences have not. Thus the possibility remains that some of the inconsistency in current results is due to varying levels of linkage disequilibrium with as yet unknown sequence variants.

RNASEL (HPC1 region)

Figure 7 Population attributable risks (PAR) as a function of carrier frequency of the deleterious genotype in the reference population (f ) and the various levels of odds ratio (OR) for that deleterious genotype. PAR = 100% × f (OR-1)/ [f (OR-1) + 1)] (Lillienfeld & Lillienfeld 1980). Bold lines indicate odds ratio (OR) conferred by genotype. Shaded area represents estimations of the percentage of populationattributable risk conferred by Thr 541 allele in ELAC2 using combined data from tables 3 and 4. It is important to note that additional experiments with large cohorts from each population should be done to confirm or refute the validiy of this hypothesis.


The best supported linkage to prostate cancer susceptibility is the HPC1 locus at Chr 1q23/25. One of the candidate genes within the broadly-defined HPC1 region is 2′-5′oligoadenylate-dependent ribonuclease L (RNASEL; MIM 601518 and 180435). The gene encodes a constitutively expressed latent endoribonuclease that mediates the antiviral and proapoptotic activities of the interferon-inducible 2-5A system. Mutation screening of RNASEL from the germline DNA of one index case from each of 26 pedigrees selected from the Johns-Hopkins pedigree resource, including eight pedigrees that showed linkage to the HPC1 locus and that had at

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Simard et al.: Prostate cancer susceptibility genes least four affected individuals sharing an HPC1 haplotype, revealed two particularly interesting mutations: the nonsense mutation Glu265X and the initiation codon mutation Met1Ile (Carpten et al. 2002) (Fig. 6). The nonsense mutation Glu265X was found in an index case from a pedigree of European ancestry. There were five prostate cancer cases in the pedigree, and their average age at diagnosis was 67.6 years. DNA was available from four of the five cases, all brothers, and they all carried this mutation. It is not known whether the fifth case, the father, was a carrier; however, this may not be relevant because the mother was diagnosed with breast cancer at age 59. The Met1Ile mutation was found in the African-American pedigree 097 and is either very rare or pedigree-specific. The six prostate cancer cases in pedigree 097 had an average age at diagnosis of 59. The four out of six cases who carried the mutation had an average age at diagnosis of 57.8 years while the two non carriers were diagnosed at ages 59 and 64. Interesting data in support of a role for these mutations in their carrier’s prostate tumors was that tumor material was available from several carriers, PCR from microdissected tumor material indicated that loss of heterozygosity (LOH) was present, and it was the wild-type allele that was lost. On the other hand, genotyping indicated that the Glu265X mutation has an appreciable frequency in the US Caucasian population, about 0.5%, and there was no obvious carrier frequency difference between cases and controls. RNASEL was subsequently mutation screened in a series of Finnish familial prostate cancer cases and certain sequence variants from the gene typed in a Finnish case control series (Rokman et al. 2002). The Glu265X nonsense mutation was found in five of 116 patients with familial prostate cancer and seemed to be most common in families with four or more cases. Genotyping in the case-control series revealed that the nonsense mutation was most common in familial cases (q = 0.022), at intermediate frequency in sporadic cases (q = 0.010), and least common in controls (q = 0.009). The difference between cases and controls was significant (OR = 4.56, P = 0.04). In addition, one of four common missense variants, Arg462Gln, also trended towards being more common in cases than controls (OR = 1.96, P = 0.07). Mutation screening of RNASEL in a series of Ashkenazi prostate cancer patients revealed a founder mutation, 471delAAAG, at appreciable allele frequency in that ethnic group (Rennert et al. 2002). In a small case control series, the frequency of this variant was highest in cases (q = 0.035), intermediate in population controls (q = 0.020), and lowest in elderly cancer-free men (q = 0.012). Although the carrier frequency difference between cases and controls was not significant (OR = 3.0, P = 0.17), cases who carried the variant were younger at diagnosis than cases who did not (65 versus 74.4 years, P < 0.001). In addition to the Finnish group, two other groups have published association studies of the Arg462Gln missense

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variant. Importantly, Casey et al. (2002) compared the in vitro enzymatic activity of protein encoded by the two alleles on a synthetic substrate, finding that the Gln462 variant had only about 30% of the activity of the more common Arg462 allele. In their association study, which was carried out on a series of discordant sibling pairs including 423 cases and 454 controls, they found a trend of increasing risk from Arg462 homozygotes to Gln462 homozygotes (ORs of 1.46 and 2.12 respectively, trend test P = 0.011) (Casey et al. 2002). In contrast, in their analysis of a case control series derived from the Mayo Clinic pedigree resource, Wang et al. (2002) found exactly the opposite trend: ORs were 0.83 and 0.54 (P = 0.02) for heterozygotes and Gln462 homozygotes respectively. In addition, the protective effect of the Gln462 variant was most apparent in early onset cases; ORs were 0.63 and 0.29 (P = 0.0008) for heterozygotes and Gln462 homozygotes diagnosed at 압 64 years respectively (Wang et al. 2002). In summary, published analyses of the three inactivating mutations so far described in RNASEL, Met1Ile, 471delAAAG, and Glu265X, trend towards evidence that these variants confer risk of prostate cancer, with best evidence in earlier onset cases as predicted from the nature of the linkage evidence at HPC1. Data with respect to the missense change Arg462Gln are clearly conflicting. As 471delAAAG appears to be an Ashkenazi founder mutation with an appreciable allele frequency in that population, Glu265X appears to have an appreciable frequency in European populations, and Arg462Gln is a common missense change, it should not take a very long time for independent follow-on studies to tightly determine the risk conferred by these sequence variants and thereby clarify the role of this gene in hereditary prostate cancer.

MSR1 (Chr 8p region) One of the ‘Group 2’ linkages described above in ‘Mapping putative loci for prostate cancer susceptibility genes’ is at Chr 8p. As part of the justification for scrutinizing 8p was longstanding evidence for a prostate cancer tumor suppressor in the region, there is some expectation that any susceptibility gene underlying the linkage should be a tumor suppressor and therefore subject to inactivating mutations. In addition, as this is a region of linkage, one would expect to see such germline mutations at higher frequency in familial as opposed to sporadic cases. Similarly, as the majority of the linkage evidence for the region seems to come from pedigrees with older average age at diagnosis, one would expect to see a germline mutation bias towards older (or at least not markedly towards younger) age at diagnosis cases. Very recently, mutation screening of candidate genes from the 8p region in index cases from the Johns-Hopkins family resource revealed a number of rare mutations in the gene Macrophage Scavenger Receptor 1 (MSR1; MIM


Endocrine-Related Cancer (2003) 10 225–259 176807) (Xu et al. 2002). From the first 159 prostate cancer pedigrees screened, one nonsense mutation and six rare missense mutations were found. After genotyping for these variants was completed on the initial 159 pedigrees plus a second set of 31 prostate cancer pedigrees, a total of 13 of the pedigrees was found to harbor one or another (and in some cases two) of these rare variants. There were individual pedigrees where the sequence variant segregated quite closely with prostate cancer, and others where the pattern of segregation was equivocal. Overall, a family based linkage/segregation test provided evidence that there was disproportionate segregation of these variants with disease (P = 0.0007). From the point of view of follow-up studies, a very useful point was that six of the 13 pedigrees in which a mutation was found, all of European descent, harbored the nonsense mutation Arg293X. That nonsense variant was also found to be more common in ‘non-hereditary’ prostate cancer cases than disease-free male controls (8/317 vs 1/256, Fisher exact test (FET) P-value = 0.047). MSR1 is a transmembrane protein that functions as a homotrimeric receptor for a number of polyanionic ligands including a variety of bacteria (Fig. 6). The Arg293X mutation would remove most of the extracellular ligand binding domain as well as the conserved extracellular scavenger receptor cystein-rich domain. Thus the Arg293X nonsense mutation would clearly interfere with MSR1 function. Overall, the initial report presented modest but plausible evidence that MSR1 is a prostate cancer susceptibility gene. If the allele frequency of the Arg293X turns out be in the range of 1.0% to 1.5% in prostate cancer cases of European ethnicity, as indicated from the initial mutation screening and association evidence, then that specific variant should provide an accessible and powerful tool to evaluate the genetic role that this gene plays in prostate cancer susceptibility. More recently, Xu et al. (2003) studied five common sequence variants of MSR1 in 301 prostate cancer patients at Johns Hopkins Hospital with non hereditary prostate cancer and 250 control subjects who had normal digital rectal examination and PSA levels ( < 4 ng/ml). The five sequence variant genotypes included an SNP in the promoter region, a 15-bp insertion/deletion in intron 1, an SNP in intron 5, a missense change in exon 6 (P275A) and a 3-bp insertion/deletion in intron 7. Haplotype analysis show a significant difference in the haplotype frequencies from a global score test (P = 0.011). Moreover, it appears that the significant association between the common MSR1 sequence variants and the prostate cancer risk is independent of the impact of the known rare MSR1 mutation. Indeed, the haplotype giving the best P-value did not harbor any of the rare mutations

Risk of prostate cancer in BRCA1 and BRCA2 carriers Epidemiological studies of prostate and breast cancer have revealed that clustering of these cancers occurs in certain


families (Anderson & Badzioch 1992, Tulinius et al. 1992). Anderson and Badzioch observed a doubling of breast cancer risk in families with prostate cancer history. An estimated relative risk of prostate cancer of 3.33 was calculated for obligate male carriers of a deleterious BRCA1 mutation when compared with the general population in a cooperative study using 33 BRCA1-linked breast/ovarian cancer families (Ford et al. 1994). More recently, the Breast Cancer Linkage Consortium conducted another study including 11 487 individuals from 699 families segregating a BRCA1 mutation that were ascertained in 30 centers across Europe and North America. There was again some evidence of an elevated risk of prostate cancer in BRCA1 mutation carriers younger than 65 years old (relative risk (RR) = 1.82, 95% CI = 1.01–3.29, P = 0.05), but not in those 65 years old or older (RR = 0.84, 95% CI = 0.53–1.33, P = 0.45). On the other hand, in another recent study from the Breast Cancer Linkage Consortium including 173 breast/ ovarian families with a deleterious BRCA2 (MIM 600185) mutation, a significantly increased risk (RR = 4.65) for prostate cancer was observed. Furthermore, this risk was even higher before age 65 (RR = 7.33) and the estimated cumulative incidence before 70 was 7.5%–33%, depending on which reference population was used (The Breast Cancer Linkage Consortium 1999). Moreover, the founder Icelandic BRCA2 mutation (999del5) was also associated with increased risk of prostate cancer (Sigurdsson et al. 1997, Thorlacius et al. 1996). The relative risk of prostate cancer was calculated to be 4.6 in first-degree relatives and 2.5 in second degree relatives (Sigurdsson et al. 1997). Futhermore, another population-based estimate shows a cumulative risk for 999del5 mutation carriers of only 7.6% at age 70 (Thorlacius et al. 1998). Several analyses of germline DNA from prostate cancer cases with or without a family history have revealed that there is no increased frequency of the founder Ashkenazi Jewish BRCA1 and BRCA2 mutations over that expected in this population (Lehrer et al. 1998, Hubert et al. 1999, Nastiuk et al. 1999, Wilkens et al. 1999). This apparent discrepancy may be consistent with the positional effect of the Ashkenazi Jewish founder BRCA2 mutation 6174delT which lies within the ‘ovarian cancer cluster region’ (OCCR). Indeed, Thompson and Easton (2001) found that the risk of prostate cancer was lower in carriers of BRCA2 mutations located in the OCCR (nucleotides 3035–6629) than in carriers of other mutations (RR = 0.48). Note that mutations in this region, which is coincident with the BRC repeat domain responsible for RAD51 binding are also associated with a reduced risk of breast cancer, but a higher risk of ovarian cancer. A recent study in a Swedish family in which the father and four of his sons were diagnosed with prostate cancer at the exceptionally early ages of 51, 52, 56, 58 and 63 respectively, supports an increased risk of prostate cancer in BRCA2 carriers (Gro¨nberg et al. 2001).

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Simard et al.: Prostate cancer susceptibility genes However, DNA samples from affected individuals in 38 prostate cancer familial clusters were analyzed for germline mutations in BRCA1 and BRCA2 genes to assess the potential contribution of each of these genes to familial prostate cancer (Gayther et al. 2000). No germline mutations were found in BRCA1, but two novel deletions were found in BRCA2 in two of 16 patients who received diagnosis at ages 52 and 56 years, whereas no mutations were found among the 22 older patients who received diagnosis at or after 60 years of onset. These authors proposed that germline mutations in BRCA2 may therefore account for about 5% of prostate cancers in familial clusters. On the other hand, in another study, BRCA1 and BRCA2 mutation screening was performed on the prostate cancer proband and on an additional family member affected with breast or prostate cancer from each of the 22 cancer families (Sinclair et al. 2000). None of the 43 samples screened contained a protein truncating mutation in either BRCA1 or BRCA2. It is important to note that, in contrast to the UK study described above (Gayther et al. 2000), these American families were selected from a large collection of high-risk prostate cancer families (at least three cases of prostate cancer) for having at least two cases of breast or ovarian cancer, in order to maximize the odds of detecting mutations in BRCA1 or BRCA2. Very recently, to establish the contribution of BRCA2 mutations to early-onset prostate cancer, Eeles’ group have screened a total of 263 men diagnosed at ages 압 55 years, who were unselected for family history (Edwards et al. 2003). Protein-truncating mutations were found in six men (2.3%; 95% CI = 0.8%-5.0%) and all of these mutations were clustered outside the OCCR. The estimated relative risk of developing prostate cancer by age 56 years for male BRCA2 mutation carriers was 23-fold. They therefore estimate the absolute risk of prostate cancer in BRCA2 carriers to be ~ 1.3% by age 55 years and 10% by age 65 years knowing that the cumulative risk by age 55 and 65 years in the general population in the UK are 앑 0.06% and 1.5% respectively. The Eeles’ team estimated that BRCA2 mutations account for 6% of the excess familial risk of the disease and is responsible for a significant fraction of early-onset prostate cancer cases outside of families with multiple cases of breast-ovarian cancer. Thus, BRCA2 is a high-risk gene for which definitive evidence of susceptibility to prostate cancer has been demonstrated in several independent studies.

Common low-penetrance allelic variants of genes involved in androgen biosynthesis and action In the general population, we observe an inter-individual variability in the susceptibility to cancer; however little is known about the underlying genes contributing to this variability. Although a number of rare highly penetrant loci con-

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tribute to the Mendelian inheritance of prostate cancer as described above, some of the familial risks may be due to shared environment and more specifically to common lowpenetrance genetic variants, which alter predisposition to prostate cancer. Prostate cancer has proven to be the most hormone-sensitive cancer to hormonal manipulation (Labrie 2003). It is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action led to the observation of a significant association between common genetic variants and a susceptibility to prostate cancer (Ross et al. 1999, Singh 2000, Makridakis & Reichardt 2001, Nwosu et al. 2001). Such analyses provided some understanding of how common low-penetrance polymorphisms present in a number of these candidate genes were involved in prostate cancer onset, progression and response to treatment for the disease.

Androgen receptor Because androgen action in prostate cells is mediated through an interaction with the androgen receptor (AR), it was first suggested that abnormalities in the AR gene, which is located on Xq11-12 (~50 cM centromeric to HPCX), could play a key role in prostate cell proliferation and differentiation as well as in carcinogenesis (Fig. 8). In this regard, the precise molecular events leading from androgen-sensitive prostate cancer to androgen-refractory prostate cancer are of special interest (see Grossmann et al. 2001, Henshall et al. 2001, Linja et al. 2001, Montgomery et al. 2001 for reviews). Indeed, some of the pathways identified appear to directly involve the modulation of AR’s ability to respond to specific ligands. Briefly, mutations in the AR hormone binding domain, or amplification of the AR gene could result in an increased sensitivity to androgens made locally in the prostate from the inactive steroid precursors, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S). These androgens of adrenal origin do not bind to the AR, but exert androgenic action after their conversion into active androgens in target tissues. Thus, recurrent hormone-refractory tumors may not always be androgen-independent, as often thought, but rather clonal expansion of hypersensitive cells that are able to grow due to intracrine formation of androgens originating from adrenal precursors and which are converted to bioactive dihydrotestosterone (DHT) in the prostate tissue may cause failure to monotherapy. Secondly, the occurrence of mutations in several portions of the AR could allow this receptor to respond to other steroids or to some antiandrogens. Alternatively, coactivators may increase the sensitivity of the AR to androgens and even to other nonandrogenic molecules (Grossmann et al. 2001). Furthermore, there is accumulating evidence that additional mechanisms, that do not result from mutations in the AR, may involve stimulation of AR transactivation by various factors and cytokines independently of androgens, thus



Figure 8 Chromosomal localization and schematic representation of HSD3B1, HSD3B2, SRD5A2 and AR genes, mRNA species and corresponding proteins. Exons are represented by black boxes indicating the coding regions, whereas open boxes represent the non-coding regions. Introns are represented by black bold lines. Positions of sequence variants are shown by an arrow in reference to nucleic or amino acid sequences on the genes or proteins. Polymorphisms which have been suggested to be associated with increased risk of prostate cancer are encircled.

facilitating the growth of prostate cancer cells despite maximal androgen blockade or acquisition of metastatic phenotype (Grossmann et al. 2001). Accounting for more than half of the AR, the NH2terminal transactivation domain is encoded by exon 1. Within this domain, there are two polymorphic microsatellite trinucleotide repeats located ~1.1 kb apart, namely a CAG repeat and a downstream GGN polymorphism encoding variable length polyglutamine and polyglycine regions respectively. The CAG repeat varies in length between 11 and 31 repeats in the germline DNA of normal men (see Montgomery et al. 2001 for a review) and shows an inverse relationship between the length of repeats and the transcriptional activity of the AR (Chamberlain et al. 1994, Kazemi-Esfarjani et al. 1995, Beilin et al. 2000). A recent study using the rat probasin promoter, an androgen- and prostate-specific reporter,


further supported the inverse relationship between AR transcriptional activity and the number of CAG repeats (15 versus 31 CAG) and provided evidence that this finding was cell specific, thus suggesting the involvement of accessory factors differentially expressed between different cell lines (Beilin et al. 2000). It is also of interest to mention that extended polyglutamine tract interacts with caspase-8 and -10 in nuclear aggregates (U et al. 2001) and increasing its length negatively affects p160-mediated coactivation of the AR (Irvine et al. 2000). Coetzee and Ross (1994) have suggested that enhanced activity of the AR, attributable to polymorphisms in the AR gene, might alter the risk of prostate cancer. Accordingly, the association of CAG repeat length and prostate cancer risk has been examined in several casecontrol studies but the results are inconclusive (Table 5). As several of these studies show an association between shorter

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Simard et al.: Prostate cancer susceptibility genes Table 5 Comparison of case/control studies of AR-CAG and AR-GGC/N polymorphism and prostate cancer risk References

Study population

No. cases/ controls

CAG comparison

OR/RR

95% CI

Remarks

Studies showing association between shorter CAG repeat length and increased prostate cancer risk Irvine et al. Non-Hispanic 19/15 ⱖ 22 1.0 Referent Modest association (1995) white men (Los 38/24 < 22 1.25 0.88–1.73 Angeles county) Hakimi et al. (1997)

Caucasians (United States)

Ingles et al. (1997)

Non-Hispanic white men (Los Angeles county)

Xue et al. (2000)


Hsing et al. (2000a)

53/359 6/11

>17 ⱕ 17

19/68 14/56 24/45

ⱖ 22 20–21 < 20

1.0 3.7

Referent 1.3–10.5

1.0 0.89 1.91 adjusted OR = 2.1

Referent 0.41–1.94 0.94–3.88 1.01–4.0

This study was an extension of the earlier Irvine et al. (1995) investigation. The AR short alleles (< 20) were more strongly associated with advanced disease than with localized disease

33/114 24/42

> 20 < 20

1.0 1.97

Referent 1.05–3.72

A statistically significant increase in risk was conferred by either a short CAG repeat or PSA genotype GG, either alone or in combination

Chinese

74/154 116/146

ⱖ 23 < 23

1.0 1.65


The median repeat length among the China population was longer – 23 repeats – than that observed for Western men.

Giovannucci et al. (1997)

Predominantly Caucasians

60/72 98/115 116/119 113/101 69/65 62/61 69/55

ⱖ 26 24–25 22–23 21 20 19 ⱕ 18

1.0 1.02 1.17 1.32 1.28 1.22 1.52

Referent 0.66–1.58 0.76–1.80 0.87–2.09 0.79–2.08 0.75–2.00 0.92–2.49

An association was observed for both advanced stage (RR = 2.2) and high grade tumors (RR = 1.9)

Stanford et al. (1997)


136/140 145/126

ⱖ 22 < 22

1.0 1.23


Miller et al. (2001)


71/34 66/35

ⱖ 22 < 22

1.0 1.13


The OR for prostate cancer associated with short CAG repeats was higher in sibships with a median age of < 66 yrs at diagnosis (OR = 1.72)

Studies showing no significant association between shorter CAG repeat length and increased prostate cancer risk Ekman (1999) Swedish and No difference was observed in Japanese number of CAG repeats between sporadic and hereditary prostate cancer. CAG repeats were shorter among Swedish prostate cancer patients than among Swedish controls; Japanese prostate cancer patients had longer repeats than Japanese controls Bratt et al. (1999)

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Swedish

92/93

1 CAG decrement

0.97

0.91–1.04

For men with non-hereditary prostate cancer, shorter CAG repeats correlated with younger age at diagnosis (P = 0.03) high grade (P = 0.07) and high stage (P = 0.07)


Endocrine-Related Cancer (2003) 10 225–259 Table 5 Continued References

Study population

No. cases/ controls

CAG comparison

OR/RR

95% CI

CorreaCerro et al. (1999)

French and German

39/28 30/22 34/35 29/20

ⱖ 24 22–23 20–21 ⱕ 19

1.0 1.02 1.43 0.96

Referent 0.49–2.13 0.73–2.82 0.45–2.03

Edwards et al. (1999)

Caucasians (United Kingdom)

74/178 88/212

> 21 ⱕ 21

1.0 1.0


Lange et al. (2000)


133/305

ⱖ 26 ⱕ 18

1.0 0.73


Beilin et al. (2001)

Australian

456/456

Latil et al. (2001)

White French origin

Chang et al. (2002b) Chen et al. (2002)

References

No evidence of a relationship of CAG repeat length to severity of prostate cancer was found. However, a shorter repeat CAG sequence was associated with earlier age at diagnosis

41/30 55/36 61/45 68/45

> 24 23–24 21–22 ⱕ 20

1.0 1.12 0.99 1.11

Referent 0.59–2.10 0.54–1.82 0.60–2.02

Predominantly Caucasians (United States)

164/81 162/99

ⱖ 22 ⱕ 21

1.0 0.81



156/147 144/153

ⱖ 22 < 22

1.0 0.89


No. cases/ controls

GGC/N comparison

OR/RR

95% CI

Study population

Remarks

Remarks

Studies showing association between shorter GGC/N repeat length and increased prostate cancer risk Hakimi et al Caucasians 46/106 > 14 1.0 Referent (1997) (United States) 8/4 ⱕ 14 4.6 1.3–16.1 Men with GGC ⱕ 16 were at increased risk regardless of age at diagnosis (OR = 1.40 in men < 60 yrs and OR = 2.23 in men 60–64 yrs)

Stanford et al. (1997)


56/75 201/175

> 16 ⱕ 16

1.0 1.60


Chang et al. (2002b)


100/72 227/102

ⱖ 17 ⱕ 16

1.0 1.58


Platz et al. (1998)

United States male participants in the Physician’s Health Study

244/369 338/425

Not 23 23

1.0 1.2


Modest association but not statistically significant

Irvine et al. (1995)


10/21 27/16

16 Not 16

1.0 1.18

Referent Not given



Chinese

147/239 39/56

ⱖ 23 < 23

1.0 1.12




249

Simard et al.: Prostate cancer susceptibility genes Table 5 Continued References

Study population

No. cases/ controls

GGC/N comparison

OR/RR

95% CI

Remarks

Studies showing no significant association between shorter GGC/N repeat length and increased prostate cancer risk Edwards et al. Caucasians 64/116 > 16 1.0 Referent (1999) (United 98/168 ⱕ 16 1.06 0.57–1.96 Kingdom) Miller et al. (2001)


51/25 82/44

> 16 ⱕ 16

1.0 0.98


A reduced risk was found among men diagnosed at age < 66 yrs (OR = 0.36) and an increased risk among men diagnosed at age ⱖ 66 yrs (OR = 1.56)

Chen et al. (2002)


115/100 185/200 144/127 156/173

> 17 ⱕ 17 Not 17 17

1.0 0.8 1.0 0.79

Referent 0.57–1.12 Referent 0.57–1.09

A reduced risk associated with ⱕ 17 GGC/N repeats in men ⱖ 70 yrs (OR = 0.51) was observed

References

Study population

No. cases/ controls

CAG and GGC/N comparison

OR/RR

95% CI

Remarks

Studies showing association between CAG and GGC/N repeat length and increased prostate cancer risk Irvine et al. Non-Hispanic 34/28 Other 1.0 Referent (1995) white men (Los 23/9 < 22, not 16 2.10 Not given Angeles county) Stanford et al. (1997)


22/32 32/41 97/93 98/77

Platz et al. (1998)

United States male participants in the Physician’s Health Study

66/119 90/133 75/116 152/185 103/134 96/107


Chinese

Chang et al. (2002b)


ⱖ 22, > 16 ⱖ 22, ⱕ 16 < 22, > 16 < 22, ⱕ 16

1.0 1.15 1.54 2.05

Referent 0.56–2.35 0.83–2.86 1.09–3.84

23 23 23 23 23 23

1.0 1.17 1.39 1.22 1.49 1.62

Referent 0.77–1.77 0.93–2.06 0.82–1.83 1.02–2.15 1.07–2.44

53/120 19/29 94/115 20/26

ⱖ 23, ⱖ 23 ⱖ 23, < 23 < 23, ⱖ 23 < 23, < 23

1.0 1.48 1.85 1.75

Referent 0.76–2.88 1.21–2.82 0.9–3.41

42/30 109/46 50/39 99/54

ⱖ 22, ⱖ 22, ⱕ 21, ⱕ 21,

1.0 1.62 0.92 1.29

Referent 0.92–2.95 0.49–1.72 0.72–2.29

> 23, not > 23, 21–23, not 21–23, < 21, not < 21,

ⱖ 17 ⱕ 16 ⱖ 17 ⱕ 16

Studies showing no significant association between CAG and GGC/N repeat length and increased prostate cancer risk Miller et al. Caucasians 21/8 ⱖ 22, > 16 1.0 Referent (2001) (United States) 45/26 ⱖ 22, ⱕ 16 0.63 0.18–2.2 29/17 < 22, > 16 0.69 0.17–2.74 35/17 < 22, ⱕ 16 1.06 0.25–4.46 Chen et al. (2002)


49/29 107/118 66/71 78/82

ⱖ 22, > 17 ⱖ 22, ⱕ 17 < 22, > 17 < 22, ⱕ 17

1.0 0.54 0.55 0.56

Referent 0.32–0.91 0.31–0.98 0.32–0.98

Adapted from Coughlin & Hall (2002) and Chen et al. (2002).

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Endocrine-Related Cancer (2003) 10 225–259 AR CAG repeat lengths (a short CAG has been defined as ranging from < 17 to < 23 repeats, depending on the study) and increased prostate cancer risk, it is not entirely clear whether the association is with diagnosis of prostate cancer, response to endocrine therapy or severity of disease. On the other hand, several other studies suggested that CAG repeat length is not associated with prostate cancer risk, age of onset, histological grade and stage of disease at diagnosis or several clinical parameters, including response to hormonal therapy, time to progression after hormonal therapy, diseasefree survival and overall survival (see Montgomery et al. 2001, Chen et al. 2002, Coughlin & Hall 2002 for recent reviews). Finally, a recent study compared repeat lengths of 140 men with prostate cancer with their brothers (n = 70) without disease from 51 high-risk sibships, stratified by median age at diagnosis of affected men within each sibship. Men with both a short CAG repeat length ( < 22) and a short GGN repeat ( 압 16) array were not at higher risk (OR = 1.06; 95% CI = 0.25–4.46) compared with men with two long repeats (CAG repeat 암 22 and a GGN repeat > 16), thus suggesting that the CAG and GGN repeats in the AR gene do not play a major role in familial prostate cancer (Miller et al. 2001). More recently, a case-control study nested within the β Carotene and Retinol Efficacy Trial including 300 cases and 300 controls showed there was no appreciable difference in the mean number of GGC repeats between cases and controls and the risk in men at or below the mean number of GGC repeats (17) was 0.80 (95% CI = 0.57–1.12) (Chen et al. 2002). Moreover, these authors found a decrease in prostate cancer risk among men with CAG < 22 and GGC 압 17, or CAG < 22 and GGC > 17 or CAG 암 22 and GGC 압 17 when compared with men with CAG 암 22 and GGC > 17. These results are thus in contrast with two other studies showing that the presence of a short repeat length for either or both CAG and GGC alleles was associated with an increased risk of prostate cancer (Stanford et al. 1997, Hsing et al. 2000a). Finally, using the Johns Hopkins set, a significant association was observed in the frequencies of the 압 16 GGC repeat alleles in 159 hereditary prostate cancer (HPC) (71%), 245 sporadic cases (68%) compared with 211 controls (59%), thus supporting the thesis that GGC repeats were associated with prostate cancer risk (P = 0.02) (Chang et al. 2002b). Furthermore, male-limited X-linked transmission/ disequilibrium (XLRC-TDT) was also used by these authors to demonstrate the preferential transmission of short 압 16 GGC repeat alleles from heterozygous mothers to their affected sons (z′ = 2.65, P = 0.008). The stronger evidence for linkage in the families with male-to-male transmission may be explained by the hypothesis that AR is a strong modifier gene that works in conjunction with autosomal susceptibility gene(s). In support of this interpretation, Cui et al. (2001) observed that the two-loci model, combining autosomal dominant with either an autosomal recessive or X-linked model, fit their data better than did a single-locus model in


segregation analyses. Further association studies using larger cohorts of preferably > 1000 blood samples from prostate cancer cases versus ethnically matched controls, and well characterized clinical data, will thus be important to clarify the role of these low-penetrance trinucleotide polymorphic repeats in prostate cancer development and progression, taking into account their potential gene-gene and geneenvironment interactions, which likely cumulate to contribute to an overall prostate cancer risk and to disease characteristics.

5α-Reductase type 2 One of the best candidate genes is the 5α-reductase type 2 gene (SRD5A2), which catalyzes the conversion of testosterone into the more active androgen DHT and maps to 2p22-23 (Morissette et al. 1996) (Fig. 8). Intraprostatic DHT is the most meaningful parameter of androgen action in prostatic tissue (Fig. 9). Indeed, the importance of intracrine formation of active androgens is in concordance with the observation that after elimination of testicular androgens by medical or surgical castration, the intraprostatic concentration of DHT remains approximately 40% of that measured in the prostate of intact 65-year-old men, thus leaving important amounts of free androgen to continue stimulating the growth of the prostate cancer (Labrie et al. 1998). However, male pseudohermaphrodites with 5α-reductase deficiency caused by mutations in the SRD5A2 gene exhibit external genital ambiguity and hypoplastic prostate, thus supporting the crucial role of this enzyme in normal prostate development. Modulation of 5α-reductase activity may account for part of the substantial racial/ethnic disparity in prostate cancer risk (Ross et al. 1992, Reichardt et al. 1995, Makridakis et al. 1997). Furthermore, one variant, Ala49Thr, has been reported to increase the catalytic activity of this enzyme (Makridakis et al. 2000) and is associated with an increased risk of advanced prostate cancer (Makridakis et al. 1999, Jaffe et al. 2000, Margiotti et al. 2000). This low-penetrance allele appears to increase the risk of prostate cancer in African-Americans, Latinos and Italians by 7.2- (P < 0.001), 3.6- (P < 0.04) and 7.7-fold (P < 0.11) respectively (Makridakis et al. 1999, Jaffe et al. 2000, Margiotti et al. 2000). In contrast, the prevalence of the A49T variant in 449 Finnish prostate cancer patients was 6.0%, not differing significantly from 6.3% observed in 223 patients with BPH or 5.8% in 588 population-based controls. Furthermore, there was no association between A49T and the family history of the patients nor with tumor stage or grade (Mononen et al. 2001). Finally, the T allele was not observed in a populationbased case control study in China after the genotyping of 191 cases and 304 controls (Hsing et al. 2001). It is also of interest to know that substantial pharmacogenetic variation among the SRD5A2 sequence variants was observed when three competitive inhibitors (Finasteride, GG745 and

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Figure 9 Major enzymatic pathways involved in the formation and inactivation of androgens in human, and the relative importance (%) of adrenal steroid precursors in the intraprostatic concentration of DHT in adult men. A-DIONE, androstanedione; ADT, androsterone; ADT-G, androsterone glucuronide; ADT-S, androsterone sulfate; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; PREG, pregnenolone; PROG, progesterone; epi-ADT, epi-androsterone; TESTO, testosterone; AR, androgen receptor; CYP17, cytochrome P450c17, 17α-hydroxylase/17,20 lyase; P450scc, cholesterol side-chain cleavage enzyme; RoDH-1, retinol dehydrogenase type 1; UGT, UDP-glucuronosyltransferase; 3α-DIOL, 5α-androstane-3α, 17β-diol; 3α-DIOL-G, 5α-androstane-3α, 17β-diol-glucuronide; 3α HSD, 3α-hydroxysteroid dehydrogenase; 3(α 씮 β) HSE, 3(α 씮 β) hydroxysteroid epimerase; 3β-DIOL, 5α-androstane-3β, 17β-diol; 3β HSD, 3β hydroxysteroid dehydrogenase/∆5-∆4-isomerase; 4-DIONE, androstenedione; 5-DIOL, androst-5-ene-3β,17β-diol; 5-DIOL-S, androst-5-ene-3β,17β-diol sulfate; 17β HSD, 17β hydroxysteroid dehydrogenase. From Simard et al. (2002a); copyright owner, The Endocrine Society.

PNU157706) were tested, thus providing relevant information to take into account when prescribing such inhibitors for the chemoprevention or treatment of prostate diseases (Makridakis et al. 1999, 2000).

CYP17 Another key enzyme involved in the testicular synthesis of androgens is encoded by the CYP17 gene, namely the cytochrome P450c17, which catalyzes 17α-hydroxylase and 17,20-lyase activities (Fig. 9). The CYP17 gene is mapped to 10q24.3 and consists of 8 exons. A single-base change (a T (A1 allele) to C (A2 allele) transition) creates an additional

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putative Sp1-type (CCACC box) transcriptional factor binding site that was postulated to increase its gene expression. Nedelcheva Kristensen et al. (1999) showed that neither the A1 nor A2 allele could form a complex with the Sp1 protein in electrophoretic mobility shift assays. Moreover, a recent study using a promoter/reporter gene construct containing sequences from −227 to + 61 with either a T or C at position + 27 demonstrated that this polymorphism is not associated with an altered transcriptional activity (Lin & Miller 2001). Nevertheless, three independent association studies reported a small but positive association between the A2 allele and an increased risk for prostate cancer (Lunn et al. 1999, Gsur et al. 2000, Yamada et al. 2001). On the other


Endocrine-Related Cancer (2003) 10 225–259 hand, two other studies showed that the A1 allele is the risk allele for prostate cancer (Wadelius et al. 1999, Habuchi et al. 2000). Considering its essential role in androgen biosynthesis, a recent study was designed to further evaluate the impact of this polymorphism and to investigate what is the potential role of this gene in hereditary prostate cancer (Chang et al. 2001). These authors performed a genetic linkage study and family-based association analysis in 159 families (Johns-Hopkins set), each of which contained at least three first-degree relatives with prostate cancer. It is of interest to note that a linkage analysis is insensitive to allelic heterogeneity, thus if a mutation has a high penetrance and there are multiple such mutations within a gene, a linkage study is likely to detect such a gene, whereas family-based or population-based association approaches are likely to fail (Chang et al. 2001). Thus, information concerning specific sequence variants within a gene is not necessary for a linkage study, but is essential for association studies. Their analyses suggest evidence for linkage at marker D10S222 with a LOD score of 1.03 (P < 0.01). However, they did not observe a statistically increased risk of sporadic prostate cancer or hereditary prostate cancer in subjects with the A2 variant following genotyping of the polymorphism in 159 HPC probands, 249 sporadic cases and 211 unaffected control subjects. They concluded that CYP17 gene or other genes in this region may increase the susceptibility to prostate cancer, whereas the polymorphism in the 5′ promoter region has a minor if any effect in increasing prostate cancer susceptibility in their study sample.

3β-Hydroxysteroid dehydrogenases The 3β-hydroxysteroid dehydrogenase/∆5-∆4 isomerase (3β-HSD) isoenzymes are responsible for the oxidation and isomerisation of ∆5-3β-hydroxysteroid precursors into ∆4ketosteroids, thus catalyzing an essential step in the formation of all classes of active steroid hormones. In humans, expression of the type I isoenzyme accounts for the 3β-HSD activity found in placenta and peripheral tissues, whereas the type II 3β-HSD isoenzyme is predominantly expressed in the adrenal gland, ovary and testis and its deficiency is responsible for a rare form of congenital adrenal hyperplasia (Simard et al. 2002b). To evaluate the possible role of these enzymes encoded by HSD3B genes (Fig. 9) in prostate cancer susceptibility, a recent study screened a panel of DNA samples collected from 96 men with or without prostate cancer for sequence variants in the putative promoter region, exons, exon-intron junctions, and 3′-untranslated region of HSD3B1 and HSD3B2 genes by direct sequencing (Chang et al. 2002a). Four of the 11 single nucleotide polymorphisms (SNPs) were informative. These four SNPs were further genotyped in a total of 159 hereditary prostate cancer probands (Johns-Hopkins set), 245 sporadic prostate cancer cases, and 222 unaffected controls. Although a weak associa-


tion between prostate cancer risk and a missense polymorphism (HSD3B1-N367T) was found, stronger evidence for association was found when the joint effect of the two genes was considered. Indeed, men with the variant genotypes at either HSD3B1-N367T or HSD3B2-c7519g had a relative risk of 1.76 (95% CI = 1.21–2.57, P = 0.003) of developing prostate cancer compared with men who were homozygous wild-type at both genes, whereas the risk for the hereditary type of prostate cancer was stronger, with a relative risk of 2.17 (95% CI = 1.29–3.65, P = 0.003). Most importantly, the subset of hereditary prostate cancer probands, whose families provided evidence for linkage at 1p13, predominantly contributed to the observed association (Chang et al. 2002a). Additional studies are warranted to confirm these findings.

Conclusion The clearest conclusion emerging from the linkage studies described above is perhaps that no single susceptibility locus mapped to date is by itself responsible for a large portion of familial prostate cancers, at least not with the combination of penetrance and clinical features that allowed linkage to and positional cloning of the so-far known colon and breast cancer predisposition genes. Thus, locus heterogeneity is a major parameter in the identification or confirmation of linkage for many data sets. Indeed, the possible existence of multiple prostate cancer genes may well explain why there has been limited confirmatory evidence of linkage for currently known highly-penetrant susceptibility loci/genes. As methods for statistical modeling improve, geneticists will have better tools to deal with the apparent extreme heterogeneity within data sets (Goddard et al. 2001, Nwosu et al. 2001, Schaid et al. 2001). To clarify the role of low-penetrance polymorphisms in prostate cancer development and progression, association studies using larger cohorts of preferably > 1000 blood samples from prostate cancer cases versus ethnically matched controls, and well characterized clinical data, will thus be important (Singh et al. 2000). It will also be necessary to investigate, using various complementary genetic epidemiological approaches, the potential role of the other key steroidogenic enzymes involved in the formation and/or inactivation of androgens, such as the numerous 17β-HSDs, 3α-HSDs, UDP-glucuronosyltransferases etc. (Fig. 9). We should also take into account the potential gene–gene and gene–environment interactions of low or moderate penetrance genes, which likely cumulate to contribute to an overall prostate cancer risk and to disease characteristics. In this regard, when several SNPs occur in the same gene/locus or a chromosomal region, it will be crucial to establish in each individual tested using haplotyping, if possible, an exhaustive genomic profiling for all selected sequence variants. This will allow a better estimate of their global contribution in various mechanisms involved in prostate cancer, such as in pathways

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Simard et al.: Prostate cancer susceptibility genes involved in the fine control of intracellular androgen bioavailability and in the signal transduction of their cellspecific action. In parallel, characterization of gene expression profiles that molecularly distinguish prostatic neoplasms may identify new target candidate genes involved in prostate cancer risk in addition to elucidating useful new clinical biomarkers leading to an improved classification of prostate cancer. This will be of special interest if such a signature may help to distinguish hereditary versus sporadic prostate carcinomas, as has recently been achieved for breast cancer (van ‘t Veer et al. 2002). Moreover, the integration of gene expression data with the knowledge of the human genome sequence as well as those of experimental models will be useful to accelerate positional cloning approaches that are often hampered by incomplete phenotypic penetrance, small pedigree size and limited access to DNA samples from affected individuals. The elucidation of transcriptomes of normal and tumoral prostate tissues can effectively focus efforts on a manageable subset of genes, thus facilitating the candidate gene approaches, especially when genetic maps cover a broad chromosomal region as frequently observed for prostate cancer susceptibility loci. Integrating both expression and functional information may further speed gene discovery via the candidate gene approach, as recently suggested for retinal disease genes (Blackshaw et al. 2001). We are at the very early phases of functional genomics and rapid advances are also anticipated in more quantitative proteomics and bioinformatics, which should dramatically increase the likelihood of finding clinically relevant candidate genes, gene clusters and signaling pathways that will translate into better diagnostic or more targeted therapeutic strategies for men with prostate cancer.

Acknowledgments J. Simard is chairholder of the Canada Research Chair in Oncogenetics funded by the Canada Research Chair Program.

References Abkevich V, Camp NJ, Gutin A, Farnham JM, Cannon-Albright L & Thomas A 2001 A robust multipoint linkage statistic (tlod) for mapping complex trait loci. Genetic Epidemiology 2001 21 S492–S497. Anderson DE & Badzioch MD 1992 Breast cancer risks in relatives of male breast cancer patients. Journal of the National Cancer Institute 1992 84 1114–1117. Badzioch M, Eeles R, Leblanc G, Foulkes WD, Giles G, Edwards S, Goldgar D, Hopper JL, Bishop DT, Moller P, Heimdal K, Easton D & Simard J 2000 Suggestive evidence for a site specific prostate cancer gene on chromosome 1p36. The CRC/ BPG UK Familial Prostate Cancer Study Coordinators and

254

Collaborators. The EU Biomed Collaborators. Journal of Medical Genetics 37 947–949. Beilin J, Ball EM, Favaloro JM & Zajac JD 2000 Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. Journal of Molecular Endocrinology 2000 25 85–96. Beilin J, Harewood L, Frydenberg M, Mameghan H, Martyres RF, Farish SJ, Yue C, Deam DR, Byron KA & Zajac JD 2001 A case-control study of the androgen receptor gene CAG repeat polymorphism in Australian prostate carcinoma subjects. Cancer 2001 92 941–949. Berry R, Schaid DJ, Smith JR, French AJ, Schroeder JJ, McDonnell SK, Peterson BJ, Wang ZY, Carpten JD, Roberts SG, Tester DJ, Blute ML, Trent JM & Thibodeau SN 2000a Linkage analyses at the chromosome 1 loci 1q24–25 (HPC1), 1q42.2–43 (PCAP), and 1p36 (CAPB) in families with hereditary prostate cancer. American Journal of Human Genetics 66 539–546. Berry R, Schroeder JJ, French AJ, McDonnell SK, Peterson BJ, Cunningham JM, Thibodeau SN & Schaid DJ 2000b Evidence for a prostate cancer-susceptibility locus on chromosome 20. American Journal of Human Genetics 67 82–91. Berthon P, Valeri A, Cohen-Akenine A, Drelon E, Paiss T, Wohr G, Latil A, Millasseau P, Mellah I, Cohen N et al. 1998 Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2–43. American Journal of Human Genetics 62 1416–1424. Blackshaw S, Fraioli RE, Furukawa T & Cepko CL 2001 Comprehensive analysis of photoreceptor gene expression and the identification of candidate retinal disease genes. Cell 107 579–589. Bochum S, Paiss T, Vogel W, Herkommer K, Hautmann R & Haeussler J 2002 Confirmation of the prostate cancer susceptibility locus HPCX in a set of 104 German prostate cancer families. Prostate 52 12–19. Bock CH, Cunningham JM, McDonnell SK, Schaid DJ, Peterson BJ, Pavlic RJ, Schroeder JJ, Klein J, French AJ, Marks A, Thibodeau SN, Lange EM & Cooney KA 2001 Analysis of the prostate cancer-susceptibility locus HPC20 in 172 families affected by prostate cancer. American Journal of Human Genetics 68 795–801. Bostwick DG 1995 High grade prostatic intraepithelial neoplasia. The most likely precursor of prostate cancer. Cancer Epidemiology, Biomarkers and Prevention 75 1823–1836. Bostwick DG & Dundore PA 1997 Biopsy Pathology of the Prostate. London: Chapman & Hall. Bratt O, Borg A, Kristoffersson U, Lundgren R, Zhang QX & Olsson H 1999 CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk. British Journal of Cancer 81 672–676. Camp NJ & Tavtigian SV 2002 Meta analysis of associations of the Ser217Leu and Ala541Thr variants in ELAC2 (HPC2) and prostate cancer. American Journal of Human Genetics 71 1475– 1478. Cancel-Tassin G, Latil A, Valeri A, Mangin P, Fournier G, Berthon P & Cussenot O 2001a PCAP is the major known prostate cancer predisposing locus in families from south and west Europe. European Journal of Human Genetics 9 135–142. Cancel-Tassin G, Latil A, Valeri A, Guillaume E, Mangin P, Fournier G, Berthon P & Cussenot O 2001b No evidence of


Endocrine-Related Cancer (2003) 10 225–259 linkage to HPC20 on chromosome 20q13 in hereditary prostate cancer. International Journal of Cancer 93 455–456. Cannon L, Bishop DT, Skolnick M, Hunt S, Lyon JL & Smart CR 1982 Genetic epidemiology of prostate cancer in the Utah mormon genealogy. Cancer Surveys 1 47–69. Cannon-Albright LA, Goldgar DE, Meyer LJ, Lewis CM, Anderson DE, Fountain JW, Hegi ME, Wiseman RW, Petty EM, Bale AE et al. 1992 Assignment of a locus for familial melanoma MLM, to chromosome 9p13-p22. Science 258 1148– 1152. Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J, Faruque M, Moses T, Ewing C, Gillanders E et al. 2002 Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nature Genetics 30 181–184. Carter BS, Beaty TH, Steinberg GD, Childs B & Walsh PC 1992 Mendelian inheritance of familial prostate cancer. PNAS 89 3367–3371. Casey G, Neville PJ, Plummer SJ, Xiang Y, Krumroy LM, Klein EA, Catalona WJ, Nupponen N, Carpten JD, Trent JM, Silverman RH & Witte JS 2002 RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases. Nature Genetics 4 581–583. Chamberlain NL, Driver ED & Miesfeld RL 1994 The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Research 22 3181–3186. Chang B, Zheng SL, Isaacs SD, Wiley KE, Carpten JD, Hawkins GA, Bleecker ER, Walsh PC, Trent JM, Meyers DA, Isaacs WB & Xu J 2001 Linkage and association of CYP17 gene in hereditary and sporadic prostate cancer. International Journal of Cancer 95 354–359. Chang BL, Zheng SL, Hawkins GA, Isaacs SD, Wiley KE, Turner A, Carpten JD, Bleecker ER, Walsh PC, Trent JM, Meyers DA, Isaacs WB & Xu J 2002a Joint effect of HSD3B1 and HSD3B2 genes is associated with hereditary and sporadic prostate cancer susceptibility. Cancer Research 62 1784–1789. Chang BL, Zheng SL, Hawkins GA, Isaacs SD, Wiley KE, Turner A, Carpten JD, Bleecker ER, Walsh PC, Trent JM, Meyers DA, Isaacs WB & Xu J 2002b Polymorphic GGC repeats in the androgen receptor gene are associated with hereditary and sporadic prostate cancer risk. Human Genetics 110 122–129. Chen C, Lamharzi N, Weiss NS, Etzioni R, Dightman DA, Barnett M, DiTommaso D & Goodman G 2002 Androgen receptor polymorphisms and the incidence of prostate cancer. Cancer Epidemiology, Biomarkers and Prevention 11 1033–1040. Coetzee GA & Ross RK 1994 Re: Prostate cancer and the androgen receptor. Journal of the National Cancer Institute 86 872–873. Cooney KA, McCarthy JD, Lange E, Huang L, Miesfeldt S, Montie JE, Oesterling JE, Sandler HM & Lange K 1997 Prostate cancer susceptibility locus on chromosome 1q: a confirmatory study. Journal of the National Cancer Institute 89 955–959. Correa-Cerro L, Wohr G, Haussler J, Berthon P, Drelon E, Mangin P, Fournier G, Cussenot O, Kraus P, Just W, Paiss T, Cantu JM & Vogel W 1999 (CAG)nCAA and GGN repeats in the human androgen receptor gene are not associated with prostate cancer in a French-German population. European Journal of Human Genetics 7 357–362. Coughlin SS & Hall IJ 2002 A review of genetic polymorphisms and prostate cancer risk. Annals of Epidemiology 12 182–196. Cui J, Staples MP, Hopper JL, English DR, McCredie MR & Giles GG 2001 Segregation analyses of 1476 population-based


Australian families affected by prostate cancer. American Journal of Human Genetics 68 1207–1218. Edwards SM, Badzioch MD, Minter R, Hamoudi R, Collins N, Ardern-Jones A, Dowe A, Osborne S, Kelly J, Shearer R et al. 1999 Androgen receptor polymorphisms: association with prostate cancer risk, relapse and overall survival. International Journal of Cancer 84 458–465. Edwards SM, Kote-Jarai Z, Meitz J, Hamoudi R, Hope Q, Osin P, Jackson R, Southgate C, Singh R, Falconer A et al. 2003 Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. American Journal of Human Genetics 72 1–12. Eeles R 1999 The UK Familial Prostate Study Co-ordinating Group and The CRC/BPG UK Familial Prostate Study Collaborators. Prostate Cancer and Prostatic Diseases 2 9–15. Eeles R, Cannon-Albright LA, Ponder SAJ, Easton DF & Horwich A 1996 Familial prostate cancer and its management. In Genetic Predisposition to Cancer, Eds RA Eeles and A Horwich pp 320–332. New York, USA: Chapman and Hall Medical. Eeles RA, Durocher F, Edwards S, Teare D, Badzioch M, Hamoudi R, Gill S, Biggs P, Dearnaley D, Ardern-Jones A et al. 1998 Linkage analysis of chromosome 1q markers in 136 prostate cancer families. The Cancer Research Campaign/British Prostate Group UK Familial Prostate Cancer Study Collaborators. American Journal of Human Genetics 62 653– 658. Ekman P 1999 Genetic and environmental factors in prostate cancer genesis: identifying high-risk cohorts. European Urology 35 362–369. El-Alfy M, Pelletier G, Hermo LS & Labrie F 2000 Unique features of the basal cells of human prostate epithelium. Microscope Research Techniques 51 436–446. Ford D, Easton DF, Bishop DT, Narod SA & Goldgar DE 1994 Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343 692–695. Gayther SA, de Foy KA, Harrington P, Pharoah P, Dunsmuir WD, Edwards SM, Gillett C, Ardern-Jones A, Dearnaley DP, Easton DF et al. 2000 The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer Research 60 4513–4518. Gibbs M, Chakrabarti L, Stanford JL, Goode EL, Kolb S, Schuster EF, Buckley VA, Shook M, Hood L, Jarvik GP & Ostrander EA 1999a Analysis of chromosome 1q42.2–43 in 152 families with high risk of prostate cancer. American Journal of Human Genetics 64 1087–1095. Gibbs M, Stanford JL, McIndoe RA, Jarvik GP, Kolb S, Goode EL, Chakrabarti L, Schuster EF, Buckley VA, Miller EL et al. 1999b Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. American Journal of Human Genetics 64 776–787. Gibbs M, Stanford JL, Jarvik GP, Janer M, Badzioch M, Peters MA, Goode EL, Kolb S, Chakrabarti L, Shook M et al. 2000 A genomic scan of families with prostate cancer identifies multiple regions of interest. American Journal of Human Genetics 67 100–109. Giovannucci E, Stampfer MJ, Krithivas K, Brown M, Dahl D, Brufsky A, Talcott J, Hennekens CH & Kantoff PW 1997 The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. PNAS 94 3320–3323.

255

Simard et al.: Prostate cancer susceptibility genes Goddard KA, Witte JS, Suarez BK, Catalona WJ & Olson JM 2001 Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4. American Journal of Human Genetics 68 1197–1206. Goode EL, Stanford JL, Chakrabarti L, Gibbs M, Kolb S, McIndoe RA, Buckley VA, Schuster EF, Neal CL, Miller EL et al. 2000 Linkage analysis of 150 high-risk prostate cancer families at 1q24-25. Genetic Epidemiology 18 251–275. Goode EL, Stanford JL, Peters MA, Janer M, Gibbs M, Kolb S, Badzioch MD, Hood L, Ostrander E A & Jarvik GP 2001 Clinical characteristics of prostate cancer in an analysis of linkage to four putative susceptibility loci. Clinical Cancer Research 7 2739–2749. Gro¨nberg H, Isaacs SD, Smith JR, Carpten JD, Bova GS, Freije D, Xu J, Meyers DA, Collins FS, Trent JM, Walsh PC & Isaacs WB 1997 Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus. Journal of the American Medical Association 278 1251– 1255. Gro¨nberg H, Ahman AK, Emanuelsson M, Bergh A, Damber JE & Borg A 2001 BRCA2 mutation in a family with hereditary prostate cancer. Genes Chromosomes Cancer 30 299–301. Grossmann ME, Huang H & Tindall DJ 2001 Androgen receptor signaling in androgen-refractory prostate cancer. Journal of the National Cancer Institute 93 1687–1697. Gsur A, Bernhofer G, Hinteregger S, Haidinger G, Schatzl G, Madersbacher S, Marberger M, Vutuc C & Micksche M 2000 A polymorphism in the CYP17 gene is associated with prostate cancer risk. International Journal of Cancer 87 434–437. Habuchi T, Liqing Z, Suzuki T, Sasaki R, Tsuchiya N, Tachiki H, Shimoda N, Satoh S, Sato K, Kakehi Y, Kamoto T, Ogawa O & Kato T 2000 Increased risk of prostate cancer and benign prostatic hyperplasia associated with a CYP17 gene polymorphism with a gene dosage effect. Cancer Research 60 5710–5713. Hakimi JM, Schoenberg MP, Rondinelli RH, Piantadosi S & Barrack ER 1997 Androgen receptor variants with short glutamine or glycine repeats may identify unique subpopulations of men with prostate cancer. Clinical Cancer Research 3 1599– 1608. Henshall SM, Quinn DI, Lee CS, Head DR, Golovsky D, Brenner PC, Delprado W, Stricker PD, Grygiel JJ & Sutherland RL 2001 Altered expression of androgen receptor in the malignant epithelium and adjacent stroma is associated with early relapse in prostate cancer. Cancer Research 61 423–427. Hsieh CL, Oakley-Girvan I, Gallagher RP, Wu AH, Kolonel LN, Teh CZ, Halpern J, West DW, Paffenbarger RS Jr & Whittemore AS 1997 Re: prostate cancer susceptibility locus on chromosome 1q: a confirmatory study. Journal of the National Cancer Institute 89 1893–1894. Hsieh CL, Oakley-Girvan I, Balise RR, Halpern J, Gallagher RP, Wu AH, Kolonel LN, O’Brien LE, Lin IG, Van Den Berg DJ et al. 2001 A genome screen of families with multiple cases of prostate cancer: evidence of genetic heterogeneity. American Journal of Human Genetics 69 148–158. Hsing AW, Gao YT, Wu G, Wang X, Deng J, Chen YL, Sesterhenn IA, Mostofi FK, Benichou J & Chang C 2000a Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: a population-based case-control study in China. Cancer Research 60 5111–5116. Hsing AW, Tsao L & Devesa SS 2000b International trends and patterns of prostate cancer incidence and mortality. International Journal of Cancer 85 60–67.

256

Hsing AW, Chen C, Chokkalingam AP, Gao YT, Dightman DA, Nguyen HT, Deng J, Cheng J, Sesterhenn IA, Mostofi FK, Stanczyk FZ & Reichardt JK 2001 Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population-based case-control study. Cancer Epidemiology, Biomarkers and Prevention 10 1077–1082. Hubert A, Peretz T, Manor O, Kaduri L, Wienberg N, Lerer I, Sagi M & Abeliovich D 1999 The Jewish Ashkenazi founder mutations in the BRCA1/BRCA2 genes are not found at an increased frequency in Ashkenazi patients with prostate cancer. American Journal of Human Genetics 65 921–924. Ingles SA, Ross RK, Yu MC, Irvine RA, La Pera G, Haile RW & Coetzee GA 1997 Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. Journal of the National Cancer Institute 89 166–170. Irvine RA, Yu MC, Ross RK & Coetzee GA 1995 The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Research 55 1937–1940. Irvine RA, Ma H, Yu MC, Ross RK, Stallcup MR & Coetzee GA 2000 Inhibition of p160-mediated coactivation with increasing androgen receptor polyglutamine length. Human Molecular Genetics 9 267–274. Jaffe JM, Malkowicz SB, Walker AH, MacBride S, Peschel R, Tomaszewski J, Van Arsdalen K, Wein AJ & Rebbeck TR 2000 Association of SRD5A2 genotype and pathological characteristics of prostate tumors. Cancer Research 60 1626– 1630. Kazemi-Esfarjani P, Trifiro MA & Pinsky L 1995 Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies. Human Molecular Genetics 4 523–527. Korver W, Guevara C, Chen Y, Neuteboom S, Bookstein R, Tavtigian SV & Lees E 2003 The product of the candidate prostate cancer susceptibility gene ELAC2 interacts with the g– tubulin complex. International Journal of Cancer 104 283–288. Labrie F 2003 Cancer of the prostate. In The UICC Manual of Clinical Oncology, 8th edition. Eds R Pollock, B O’Sullivan and A Nakao. Etobicoke Canada: John Wiley and Sons (In Press). Labrie F, Belanger A, Luu-The V, Labrie C, Simard J, Cusan L, Gomez JL & Candas B 1998 DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging. Steroids 63 322–328. Lander E & Kruglyak L 1995 Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genetics 11 241–247. Lange EM, Chen H, Brierley K, Perrone EE, Bock CH, Gillanders E, Ray ME & Cooney KA 1999 Linkage analysis of 153 prostate cancer families over a 30-cM region containing the putative susceptibility locus HPCX. Clinical Cancer Research 5 4013–4020. Lange EM, Chen H, Brierley K, Livermore H, Wojno KJ, Langefeld CD, Lange K & Cooney KA 2000 The polymorphic exon 1 androgen receptor CAG repeat in men with a potential inherited predisposition to prostate cancer. Cancer Epidemiology, Biomarkers and Prevention 9 439–442. Latil AG, Azzouzi R, Cancel GS, Guillaume EC, Cochan-Priollet B, Berthon PL & Cussenot O 2001 Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways. Cancer 92 1130–1137.


Endocrine-Related Cancer (2003) 10 225–259 Lehrer S, Fodor F, Stock RG, Stone NN, Eng C, Song HK & McGovern M 1998 Absence of 185delAG mutation of the BRCA1 gene and 6174delT mutation of the BRCA2 gene in Ashkenazi Jewish men with prostate cancer. British Journal of Cancer 78 771–773. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A & Hemminki K 2000 Environmental and heritable factors in the causation of cancer – analyses of cohorts of twins from Sweden, Denmark, and Finland. New England Journal of Medicine 343 78–85. Lillienfeld AM & Lillienfeld DE 1980 Foundations of Epidemiology. New York: Oxford University Press. Lin C & Miller WL 2001 The T/C allelic polymorphism at nucleotide + 27 of the human CYP17 gene is not associated with altered transcriptional activity. In The Endocrine Society’s 83rd Annual Meeting, p P2-1. Denver, Colorado. Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL & Visakorpi T 2001 Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Research 61 3550–3555. Lunn RM, Bell DA, Mohler JL & Taylor JA 1999 Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17) and steroid reductase (SRD5A2). Carcinogenesis 20 1727–1731. McIndoe RA, Stanford JL, Gibbs M, Jarvik GP, Brandzel S, Neal CL, Li S, Gammack JT, Gay AA, Goode EL, Hood L & Ostrander EA 1997 Linkage analysis of 49 high-risk families does not support a common familial prostate cancersusceptibility gene at 1q24-25. American Journal of Human Genetics 61 347–353. McNeal JE, Villers A, Redwine EA, Freiha FS & Stamey TA 1991 Microcarcinoma in the prostate: its association with duct-acinar dysplasia. Human Pathology 22 644–652. Makridakis NM & Reichardt JK 2001 Molecular epidemiology of hormone-metabolic loci in prostate cancer. Epidemiology Reviews 23 24–29. Makridakis N, Ross RK, Pike MC, Chang L, Stanczyk FZ, Kolonel LN, Shi CY, Yu MC, Henderson BE & Reichardt JK 1997 A prevalent missense substitution that modulates activity of prostatic steroid 5alpha-reductase. Cancer Research 57 1020– 1022. Makridakis NM, Ross RK, Pike MC, Crocitto LE, Kolonel LN, Pearce CL, Henderson BE & Reichardt JK 1999 Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA. Lancet 354 975–978. Makridakis NM, di Salle E & Reichardt JK 2000 Biochemical and pharmacogenetic dissection of human steroid 5-alpha-reductase type II. Pharmacogenetics 10 407–413. Margiotti K, Sangiuolo F, De Luca A, Froio F, Pearce CL, Ricci-Barbini V, Micali F, Bonafe M, Franceschi C, Dallapiccola B, Novelli G & Reichardt JK 2000 Evidence for an association between the SRD5A2 (type II steroid 5 alpha-reductase) locus and prostate cancer in Italian patients. Disease Markers 16 147–150. Meitz JC, Edwards SM, Easton DF, Murkin A, Ardern-Jones A, Jackson RA, Williams S, Dearnaley DP, Stratton MR, Houlston RS & Eeles RA 2002 HPC2/ELAC2 polymorphisms and prostate cancer risk: analysis by age of onset of disease. British Journal of Cancer 87 905–908. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W et al.


1994 A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266 66–71. Miller EA, Stanford JL, Hsu L, Noonan E & Ostrander EA 2001 Polymorphic repeats in the androgen receptor gene in high-risk sibships. Prostate 48 200-205. Mononen N, Ikonen T, Syrjakoski K, Matikainen M, Schleutker J, Tammela TL, Koivisto PA & Kallioniemi OP 2001 A missense substitution A49T in the steroid 5-alpha-reductase gene (SRD5A2) is not associated with prostate cancer in Finland. British Journal of Cancer 84 1344–1347. Monroe KR, Yu MC, Kolonel LN, Coetzee GA, Wilkens LR, Ross RK & Henderson BE 1995 Evidence of an X-linked or recessive genetic component to prostate cancer risk. Nature Medicine 1 827–829. Montgomery JS, Price DK & Figg WD 2001 The androgen receptor gene and its influence on the development and progression of prostate cancer. Journal of Pathology 195 138– 146. Morganti G, Gianferrari L, Cresseri A, Arrigoni G & Lovati G 1956 Recherches clinico-statistiques et geńe´tiques sur les neóplasie de la prostate. Acta Genetica Statistica 6 304–305. Morissette J, Durocher F, Leblanc JF, Normand T, Labrie F & Simard J 1996 Genetic linkage mapping of the human steroid 5 alpha-reductase type 2 gene (SRD5A2) close to D2S352 on chromosome region 2p23Λp22. Cytogenetics and Cell Genetics 73 304–307. Narod SA, Dupont A, Cusan L, Diamond P, Gomez JL, Suburu R & Labrie F 1995 The impact of family history on early detection of prostate cancer. Nature Medicine 1 99–101. Nastiuk KL, Mansukhani M, Terry MB, Kularatne P, Rubin MA, Melamed J, Gammon MD, Ittmann M & Krolewski JJ 1999 Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men. Prostate 40 172–177. Nedelcheva Kristensen V, Haraldsen EK, Anderson KB, Lonning PE, Erikstein B, Karesen R, Gabrielsen OS & Borresen-Dale AL 1999 CYP17 and breast cancer risk: the polymorphism in the 5′ flanking area of the gene does not influence binding to Sp-1. Cancer Research 59 2825–2828. Neuhausen SL, Farnham JM, Kort E, Tavtigian SV, Skolnick MH & Cannon-Albright LA 1999 Prostate cancer susceptibility locus HPC1 in Utah high-risk pedigrees. Human Molecular Genetics 8 2437–2442. Nwosu V, Carpten J, Trent JM & Sheridan R 2001 Heterogeneity of genetic alterations in prostate cancer: evidence of the complex nature of the disease. Human Molecular Genetics 10 2313–2318. Ostrander EA & Stanford JL 2000 Genetics of prostate cancer: too many loci, too few genes. American Journal of Human Genetics 67 1367–1375. Peters MA, Jarvik GP, Janer M, Chakrabarti L, Kolb S, Goode EL, Gibbs M, DuBois CC, Schuster EF, Hood L, Ostrander EA & Stanford JL 2001 Genetic linkage analysis of prostate cancer families to Xq27-28. Human Heredity 51 107–113. Platz EA, Giovannucci E, Dahl DM, Krithivas K, Hennekens CH, Brown M, Stampfer MJ & Kantoff PW 1998 The androgen receptor gene GGN microsatellite and prostate cancer risk. Cancer Epidemiology, Biomarkers and Prevention 7 379–384. Rebbeck TR, Walker AH, Zeigler-Johnson C, Weisburg S, Martin AM, Nathanson KL, Wein AJ & Malkowicz SB 2000 Association of HPC2/ELAC2 genotypes and prostate cancer. American Journal of Human Genetics 67 1014–1019. Reichardt JK, Makridakis N, Henderson BE, Yu MC, Pike MC & Ross RK 1995 Genetic variability of the human SRD5A2 gene:

257

Simard et al.: Prostate cancer susceptibility genes implications for prostate cancer risk. Cancer Research 55 3973– 3975. Rennert H, Bercovich D, Hubert A, Abeliovich D, Rozovsky U, Bar-Shira A, Soloviov S, Schreiber L, Matzkin H, Rennert G et al. 2002 A novel founder mutation in the RNASEL gene, 471delAAAG, is associated with prostate cancer in Ashkenazi Jews. American Journal of Human Genetics 71 981–984. Rokman A, Ikonen T, Mononen N, Autio V, Matikainen MP, Koivisto PA, Tammela TL, Kallioniemi OP & Schleutker J 2001 ELAC2/HPC2 involvement in hereditary and sporadic prostate cancer. Cancer Research 61 6038–6041. Rokman A, Ikonen T, Seppala EH, Nupponen N, Autio V, Mononen N, Bailey-Wilson J, Trent J, Carpten J, Matikainen MP et al. 2002 Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer. American Journal of Human Genetics 70 1299– 1304. Ross RK, Bernstein L, Lobo RA, Shimizu H, Stanczyk FZ, Pike MC & Henderson BE 1992 5-Alpha-reductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet 339 887–889. Ross RK, Coetzee GA, Pearce CL, Reichardt JK, Bretsky P, Kolonel LN, Henderson BE, Lander E, Altshuler D & Daley G 1999 Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. European Urology 35 355–361. Schaid DJ, McDonnell SK, Blute ML & Thibodeau SN 1998 Evidence for autosomal dominant inheritance of prostate cancer. American Journal of Human Genetics 62 1425–1438. Schaid DJ, McDonnell SK & Thibodeau SN 2001 Regression models for linkage heterogeneity applied to familial prostate cancer. American Journal of Human Genetics 68 1189–1196. Schiffer S, Rosch S & Marchfelder A 2002 Assigning a function to a conserved group of proteins: the tRNA 3′-processing enzymes. EMBO Journal 21 2769–2777. Schleutker J, Matikainen M, Smith J, Koivisto P, Baffoe-Bonnie A, Kainu T, Gillanders E, Sankila R, Pukkala E, Carpten J et al. 2000 A genetic epidemiological study of hereditary prostate cancer (HPC) in Finland: frequent HPCX linkage in families with late-onset disease. Clinical Cancer Research 6 4810–4815. Shea PR, Ferrell RE, Patrick AL, Kuller LH & Bunker CH 2002 ELAC2 and prostate cancer risk in Afro-Caribbeans of Tobago. Human Genetics 111 398–400. Sigurdsson S, Thorlacius S, Tomasson J, Tryggvadottir L, Benediktsdottir K, Eyfjord JE & Jonsson E 1997 BRCA2 mutation in Icelandic prostate cancer patients. Journal of Molecular Medicine 75 758–761. Simard J, Dumont M, Soucy P & Labrie F 2002a Perspective: prostate cancer susceptibility genes. Endocrinology 143 2029– 2040. Simard J, Moisan AM & Morel Y 2002b Congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase/ delta5-delta4 isomerase deficiency. Seminars in Reproductive Medicine 20 255–276. Sinclair CS, Berry R, Schaid D, Thibodeau SN & Couch FJ 2000 BRCA1 and BRCA2 have a limited role in familial prostate cancer. Cancer Research 60 1371–1375. Singh RER, Durocher F, Simard J, Edwards S, Badzioch M, Kote-Jarai Z, Teare D, Ford D, Dearnaley D, Ardern-Jones A, Murkin A, Dowe A, Shearer R, Kelly J, The CRC/BPG UK Familial Prostate Cancer Study Collaborators, Labrie F, Easton D, Narod SA, Tonin PN & Foulkes WD 2000 High risk genes

258

predisposing to prostate cancer – do they exist? Prostate Cancer and Prostatic Diseases 3 241–247. Slager SL, Schaid DJ, Cunningham JM, McDonnell SK, French A, Peterson BJ, Marks AF, Hebbring S, Koch B, Anderson S & Thibodeau SN 2002 Linkage analysis on prostate cancer agressiveness. American Journal of Human Genetics 71 (Suppl) S247. Smith JR, Freije D, Carpten JD, Gro¨nberg H, Xu J, Isaacs SD, Brownstein MJ, Bova GS, Guo H, Bujnovszky P et al. 1996 Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 274 1371–1374. Stanford JL, Just JJ, Gibbs M, Wicklund KG, Neal CL, Blumenstein BA & Ostrander EA 1997 Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Research 57 1194–1198. Steinberg GD, Carter BS, Beaty TH, Childs B & Walsh PC 1990 Family history and the risk of prostate cancer. Prostate 17 337– 347. Suarez BK, Lin J, Burmester JK, Broman KW, Weber JL, Banerjee TK, Goddard KA, Witte JS, Elston RC & Catalona WJ 2000a A genome screen of multiplex sibships with prostate cancer. American Journal of Human Genetics 66 933–944. Suarez BK, Lin J, Witte JS, Conti DV, Resnick MI, Klein EA, Burmester JK, Vaske DA, Banerjee TK & Catalona WJ 2000b Replication linkage study for prostate cancer susceptibility genes. Prostate 45 106–114. Suarez BK, Gerhard DS, Lin J, Haberer B, Nguyen L, Kesterson NK & Catalona WJ 2001 Polymorphisms in the prostate cancer susceptibility gene HPC2/ELAC2 in multiplex families and healthy controls. Cancer Research 61 4982–4984. Tavtigian SV, Simard J, Teng DH, Abtin V, Baumgard M, Beck A, Camp NJ, Carillo AR, Chen Y, Dayananth P et al. 2001 A candidate prostate cancer susceptibility gene at chromosome 17p. Nature Genetics 27 172–180. The Breast Cancer Linkage Consortium 1999 Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. Journal of the National Cancer Institute 91 1310– 1316. Thompson D & Easton D 2001 Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. American Journal of Human Genetics 68 410–419. Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, Tavtigian SV, Tulinius H, Ogmundsdottir HM & Eyfjord JE 1996 A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nature Genetics 13 117–119. Thorlacius S, Struewing JP, Hartge P, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, Wacholder S, Tulinius H & Eyfjord JE 1998 Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 352 1337–1339. Tulinius H, Egilsson V, Olafsdottir GH & Sigvaldason H 1992 Risk of prostate, ovarian, and endometrial cancer among relatives of women with breast cancer. British Medical Journal 305 855–857. U M, Miyashita T, Ohtsuka Y, Okamura-Oho Y, Shikama Y & Yamada M 2001 Extended polyglutamine selectively interacts with caspase-8 and -10 in nuclear aggregates. Cell Death and Differentiation 8 377–386. van ‘t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT et al. 2002 Gene expression profiling predicts clinical outcome of breast cancer. Nature 415 530–536.


Endocrine-Related Cancer (2003) 10 225–259 Vesprini D, Nam RK, Trachtenberg J, Jewett MA, Tavtigian SV, Emami M, Ho M, Toi A & Narod SA 2001 HPC2 variants and screen-detected prostate cancer. American Journal of Human Genetics 68 912–917. Vogel A, Schilling O, Niecke M, Bettmer J & Meyer-Klaucke W 2002 ElaC encodes a novel binuclear zinc phosphodiesterase. Journal of Biological Chemistry 277 29078–29085. Wadelius M, Andersson AO, Johansson JE, Wadelius C & Rane E 1999 Prostate cancer associated with CYP17 genotype. Pharmacogenetics 9 635–639. Wang L, McDonnell SK, Elkins DA, Slager SL, Christensen E, Marks AF, Cunningham JM, Peterson BJ, Jacobsen SJ, Cerhan JR, Blute ML, Schaid DJ & Thibodeau SN 2001 Role of HPC2/ ELAC2 in hereditary prostate cancer. Cancer Research 61 6494– 6499. Wang L, McDonnell SK, Elkins DA, Slager SL, Christensen E, Marks AF, Cunningham JM, Peterson BJ, Jacobsen SJ, Cerhan JR, Blute ML, Schaid DJ & Thibodeau SN 2002 Analysis of the RNASEL gene in familial and sporadic prostate cancer. American Journal of Human Genetics 71 116–123. Whittemore AS, Lin IG, Oakley-Girvan I, Gallagher RP, Halpern J, Kolonel LN, Wu AH & Hsieh CL 1999 No evidence of linkage for chromosome 1q42.2–43 in prostate cancer. American Journal of Human Genetics 65 254–256. Wilkens EP, Freije D, Xu J, Nusskern DR, Suzuki H, Isaacs SD, Wiley K, Bujnovsky P, Meyers DA, Walsh PC & Isaacs WB 1999 No evidence for a role of BRCA1 or BRCA2 mutations in Ashkenazi Jewish families with hereditary prostate cancer. Prostate 39 280–284. Witte JS, Goddard KA, Conti DV, Elston RC, Lin J, Suarez BK, Broman KW, Burmester JK, Weber JL & Catalona WJ 2000 Genomewide scan for prostate cancer-aggressiveness loci. American Journal of Human Genetics 67 92–99. Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D et al. 1994 Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265 2088–2090. Xu J 2000 Combined analysis of hereditary prostate cancer linkage to 1q24-25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics. American Journal of Human Genetics 66 945–957.


Xu J, Meyers D, Freije D, Isaacs S, Wiley K, Nusskern D, Ewing C, Wilkens E, Bujnovszky P, Bova GS et al. 1998 Evidence for a prostate cancer susceptibility locus on the X chromosome. Nature Genetics 20 175–179. Xu J, Zheng SL, Carpten JD, Nupponen NN, Robbins CM, Mestre J, Moses TY, Faith DA, Kelly BD, Isaacs SD et al. 2001a Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer. American Journal of Human Genetics 68 901–911. Xu J, Zheng SL, Chang B, Smith JR, Carpten JD, Stine OC, Isaacs SD, Wiley KE, Henning L, Ewing C et al. 2001b Linkage of prostate cancer susceptibility loci to chromosome 1. Human Genetics 108 335–345. Xu J, Zheng SL, Hawkins GA, Faith DA, Kelly B, Isaacs SD, Wiley KE, Chang B, Ewing CM, Bujnovszky P et al. 2001c Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22-23. American Journal of Human Genetics 69 341–350. Xu J, Zheng SL, Komiya A, Mychaleckyj JC, Isaacs SD, Hu JJ, Sterling D, Lange EM, Hawkins GA, Turner A et al. 2002 Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Nature Genetics 32 321–325. Xu J, Zheng SL, Komiya A, Mychaleckyj JC, Isaacs SD, Chang B, Turner AR, Ewing CM, Wiley KE, Hawkins GA et al. 2003 Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. American Journal of Human Genetics 72 208–212. Xue W, Irvine RA, Yu MC, Ross RK, Coetzee GA & Ingles SA 2000 Susceptibility to prostate cancer: interaction between genotypes at the androgen receptor and prostate-specific antigen loci. Cancer Research 60 839–841. Yamada Y, Watanabe M, Murata M, Yamanaka M, Kubota Y, Ito H, Katoh T, Kawamura J, Yatani R & Shiraishi T 2001 Impact of genetic polymorphisms of 17-hydroxylase cytochrome P-450 (CYP17) and steroid 5alpha-reductase type II (SRD5A2) genes on prostate cancer risk among the Japanese population. International Journal of Cancer 92 683–686. Zheng SL, Xu J, Isaacs SD, Wiley K, Chang B, Bleecker ER, Walsh PC, Trent JM, Meyers DA & Isaacs WB 2001 Evidence for a prostate cancer linkage to chromosome 20 in 159 hereditary prostate cancer families. Human Genetics 108 430– 435.

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