0163-769X/99/$03.00/0 Endocrine Reviews 20(1): 22– 45 Copyright © 1999 by The Endocrine Society Printed in U.S.A.
Molecular Genetics and Epidemiology of Prostate Carcinoma EMIEL RUIJTER, CHRISTINA VAN DE KAA, GARY MILLER, DIRK RUITER, FRANS DEBRUYNE, AND JACK SCHALKEN Departments of Urology (E.R., F.D., J.S.) and Pathology (E.R., C.v.d.K., D.R.), University Hospital Nijmegen, 6500 HB, Nijmegen, The Netherlands; Department of Pathology (G.M.), University of Colorado, Health Sciences Center, Denver, Colorado 80260, U.S.A.; and Department of Pathology and Companion Animals (J.S.), Veterinarian Faculty, University of Utrecht, 3508 TD, Utrecht, The Netherlands
I. Introduction A. Prostate carcinoma epidemiology: mortality rates, incidence, and prevalence B. Familial clustering of prostate carcinoma C. Scope of the review II. Somatic Genetic Alterations in Prostate Carcinoma A. Alterations in DNA methylation B. The androgen signaling cascade C. Vitamin D and prostate carcinoma D. Oncogenes E. TSGs F. Metastasis suppressor genes (MSGs) G. Telomerase activity III. Etiology of Familial Clustering of Prostate Carcinoma IV. Human Papillomavirus and Prostate Carcinoma V. Morphological Diversity of Prostate Carcinoma VI. Concluding Remarks
enough to die of PCa (1, 2). The number of men diagnosed each year with PCa has shown a 30% increase over the last 25 yr, and for the next decade, a similar trend of rising incidence is expected (3). Moreover, PCa incidence is estimated to double by the year 2030 (4). This is due to the strong association of PCa with age in combination with the rising average age of American men, improvements in detection techniques, and programs for early detection of PCa (5) The number of males diagnosed each year with PCa is not similar among different racial populations. Bernstein and Ross (6) observed that PCa is most commonly diagnosed in African-Americans (116/100,000 persons per yr). Intermediate incidence rates are found in Caucasians (71/100,000) and lowest rates among Asians (Japanese, 39/100,000; Chinese, 28/100,000). Thus, this particular registration found a more than 4-fold difference in PCa incidence worldwide. This difference is a conservative estimate when compared to cancer registration studies that found a 30-fold difference or more in PCa incidence between African-Americans and Asians (7). Interestingly, autopsy cases and cystoprostatectomy specimens removed for bladder cancer reveal a high prevalence of PCa lesions that have not been diagnosed clinically (8 –10). It has been estimated that 15–30% of males over the age of 50 and as many as 80% of the males over the age of 80 harbor such clinically undetected foci of PCa (9, 10). Consequently, 8 million US males older than 50 yr are estimated to have PCa, which makes PCa the most prevalent cancer in man (3, 5). Comparing the incidence and prevalence rates, the vast majority of men who harbor PCa lesions will not be diagnosed with this disease. Geographically, the prevalence of PCa in autopsy cases without a prior clinical diagnosis of this disease is roughly the same worldwide (10 –12). Thus, although men from different races harbor foci of carcinoma in their prostates at a similar frequency, the number of men whose tumors will become clinically apparent is much higher among men from African-American populations compared to Caucasians or Asians. Interestingly, Whitmore (2) found that African-American men appear to have a larger volume of PCa at autopsy compared to Caucasians. These relatively large carcinomas are likely to progress to clinically apparent disease at a faster rate. Consistent with this hypothesis is the observation that African-American men typically present with PCa at younger ages with larger volume,
I. Introduction A. Prostate carcinoma epidemiology: mortality rates, incidence, and prevalence
A
FTER lung cancer, prostatic adenocarcinoma (PCa) is the second leading cause of male cancer deaths in the United States. A total of 41,800 men died of PCa in 1997, and in men over the age of 55 yr, PCa is responsible for nearly 4% of all deaths (1). The age-specific PCa mortality rate has increased approximately 14% over the past six decades (1). However, the PCa-related mortality is relatively low when compared to the total number of patients diagnosed each year with PCa, i.e., clinically diagnosed PCa. In 1997 in the United States, 334,500 new cases of PCa were estimated to be diagnosed clinically, 3 times more than those from the respiratory tract (1). Thus, the vast majority of the PCa patients will die with this disease rather than from it. This might be explained by the advanced age of men at the time of diagnosis in combination with relatively slow tumor growth, implying that a large number of men may not live long
Address reprint requests to: Emiel Ruijter, M.D., Ph.D., Department of Pathology, University Hospital Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
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higher stage, and often higher grade tumors than Caucasian men, with consequently higher mortality rates (6, 13). These studies also suggest that the events that account for racial/ ethnic differences in PCa incidence had occurred very early in the process of carcinogenesis, possibly already at the stage of (pre)malignant transformation. Interestingly, some studies have focused on racial/ethnic differences in the characteristics of prostatic intraepithelial neoplasia (PIN), the lesion considered to be the precursor of PCa (11, 14). Sakr et al. (11) revealed that the overall prevalence of high-grade PIN lesions found during autopsy in African-American men (n 5 314) exceeded that in their Caucasian counterparts (n 5 211). High-grade PIN lesions in African-American men also tended to be more diffuse with multifocal or extensive involvement of the prostate compared to Caucasians (11, 14). In addition, extensive high-grade PIN appeared approximately a decade earlier in African-American males compared to Caucasians (11). The finding of differences in the prevalence of high-grade PIN lesions in African-Americans vs. Caucasians seems to contradict similar worldwide rates of PCa found at autopsy. One likely explanation is that high-grade PIN is not a precursor lesion to carcinomas that remain ’clinically silent’ but to those PCa lesions that will progress to be detected clinically. The above-mentioned observations of PCa epidemiology make this disease unique among other types of malignancies (Fig. 1). B. Familial clustering of prostate carcinoma
Epidemiological studies have clearly demonstrated that PCa has an inherited component. After some early reports suggested an increased risk of PCa mortality among relatives of PCa probands (15, 16), Cannon et al. (17) presented a study in which the Utah cancer registry data were linked to the Mormon genealogy registry. It appeared that familial clustering among 2,821 patients with PCa was much stronger than that of an age- and race-matched control group. Familial clustering of PCa patients was also much stronger than that
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of two types of cancer for which the existence of a hereditary subtype was widely accepted: breast and colon cancer. Subsequently, Meikle et al. (18) reported that brothers of young PCa patients (age at diagnosis 62 yr or less) have a 4-fold increased risk of PCa compared with brothers-in-law and the general population. Similarly, brothers and fathers of PCa probands had a statistically significant, 76% higher risk of PCa than the male first-degree relatives of control subjects (19). When families were selected for the presence of PCa, risks for cancer at other sites appeared not to be increased. These authors proposed that familial clustering of PCa is a site-specific disease that is not part of other hereditary cancer syndromes (19). In addition, twin studies demonstrated that the concordance rate for PCa was significantly higher for monozygous twins than for dizygous twins (20, 21). Current understanding suggests that accumulation of multiple genetic alterations is important for cancer to occur. Persons who inherit one of these genetic alterations are thought to be predisposed to cancer development and are at higher risk for cancer at an early age than individuals who acquire these alterations later in life. Therefore, one feature of an inherited form of cancer is an increased clustering of cancers in the families of cases with early onset. Indeed, Carter et al. (22) reported cumulative risks of PCa of 14%, 25%, and 40% for first-degree relatives of PCa cases with an age at diagnosis .65, 53– 65, and ,53, respectively (22). The consistent finding of a younger age at diagnosis in hereditary PCa case patients has raised the issue as to whether or not to screen in men with a strong family history of PCa, starting at age 40 yr (23). The best fitting model that explained the familial aggregation and age at diagnosis is a rare autosomal dominant susceptibility gene, and this model fitted best when probands were diagnosed at 60 yr of age or less (24). The model predicted that the frequency of the susceptibility gene in the population is 0.006 and that the risk of PCa by age 85 yr is 89% among carriers of the gene and 3% among noncarriers (24). Of all PCa occurrences, approximately 9% were estimated to result from such a gene (22). Based on the results of a segregation analysis, three criteria for hereditary PCa were defined: 1) a cluster of three or more first-degree relatives with PCa, or 2) PCa in each of three generations in the paternal or maternal lineage, or 3) two or more first- or second-degree relatives with PCa under the age of 55 (22). C. Scope of the review
FIG. 1. Frequency of PCas among the general population. If the prevalence of US citizens among men more than 50 yr of age is 30%, then approximately 8,000,000 Americans harbor foci of carcinoma in their prostate. Yet, in 1997 only 334,500 men were estimated to be clinically diagnosed with this malignancy, and the vast majority of these males died from causes other than prostate carcinoma.
The epidemiological characteristics of PCa have been recognized for several decades (3). It is of great importance to understand the factors responsible for prostate carcinogenesis: why some carcinomas remain ’clinically silent’ during life whereas other tumors progress to present clinically and may lead to PCa-related death. A better understanding of these mechanisms in molecular genetic terms will likely point to more rational approaches to disease prevention, intervention, and treatment. A number of reviews have focused on molecular genetic changes associated with prostate carcinogenesis, such as viral oncogenesis (25) and the role of oncogenes (26) or tumor suppressor genes (TSGs) (27), whereas others have provided reviews with a wider scope
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(28, 29). This review seeks to provide a comprehensive overview of the current state of our knowledge regarding the etiology and molecular pathogenesis of PCa in relation to the epidemiological characteristics of the disease. II. Somatic Genetic Alterations in Prostate Carcinoma A. Alterations in DNA methylation
In human cancer cells, some genomic alterations are characterized by abnormal methylation. The patterns of abnormal methylation include hypermethylation, redistribution of methylation, and demethylation of normally methylated regions. Loss of 59-methylcytosines, or hypomethylation, has been reported to occur in human PCa, but its significance is not entirely clear (30). Of more biological importance are genomic regions of hypermethylation. The most important site of abnormal methylation occurs in regions of high-density C–G dinucleotide sequences, referred to as CpG islands. These CpG islands are generally found in or near the 59region of genes, which may contain the promotor and one or more exons of its associated gene. Methylation of CpG-rich islands may be associated with transcriptional inactivation of the associated gene, such as the CDKN2 (p16) gene (31). This gene, located at 9p21, encodes a cyclin-dependent kinase-inhibitory protein that controls passage through the G1 phase of the cell cycle (32). Inactivation of the CDKN2 gene by homozygous deletion, point mutation, or aberrant methylation in the 59-promotor region may induce progression through the cell cycle. It has been shown that homozygous deletion of this gene occurs in approximately 20% of the PCa samples (33). Methylation analysis of a CpG-rich promotor region in exon 1 of the CDKN2 gene revealed dense methylation in three PCa cell lines (TSU-PR1, PPC-1, PC-3), and this was found to correlate with a lack of mRNA expression by RT-PCR (32). Importantly, in vitro treatment of these PCa cell lines with the demethylating agent 5-aza-29-deoxycytidine induced reexpression of CDKN2 transcripts (34). In human PCa samples, Jarrard et al. (31) showed that 3 (13%) of 24 primary and 1 (8%) of 12 metastatic tumor samples demonstrated promotor methylation. In the same study, deletions near the CDKN2 gene were detected in 12 (20%) of 60 primary tumors and in 13 (46%) of 28 metastases. In early stage PCa, Gu et al. (35) could not find any intragenic alteration of the methylation pattern (35). However, two samples did have deletions proximal to or within the p16 gene. These results indicate that mutations in p16 or that inactivation of p16 by DNA methylation may not be a dominant pathway for the transformation into PCa, but may be involved in progression of disease. Recently, Lee et al. examined the methylation status of the glutathione S-transferase (GST) gene promotor in prostate tissue (36). The GST gene, located on chromosome 11q13, is an essential part of an important cellular pathway to prevent damage from a wide range of carcinogens. Analysis of a CpG island within the promotor region revealed hypermethylation of the GST gene in all 20 PCa samples. A striking decrease of GSTP1 expression was found to accompany pros-
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tate carcinogenesis. Further analysis of 91 PCa samples by immunohistochemical staining with an anti-GSTP1 antibody revealed that no GSTP1 expression could be detected in 88 of these cancer specimens (36). Methylation alterations at the GST gene were not detected in DNA samples from 12 nonmalignant tissues, including 5 samples from benign prostatic hyperplasia (36). However, hypermethylation has been found in nonmalignant tissues, e.g., at the ‘hypermethylated in cancer’ (Hic1) gene. Hypermethylation of Hic1 was also found in 25 of 26 PCa specimens (37). Methylation of the GST gene promotor and the Hic1 gene appears to be a common phenomenon in PCa. This finding warrants further study to understand its biological implications. Clinical studies are currently undertaken to design a GSTP1 CpG-island methylation assay that may serve as a new molecular diagnostic tool for PCa detection. The finding of hypermethylation of the Hic1 gene in nonmalignant tissues may provide further insight into the marked tendency of the prostate toward malignant transformation. B. The androgen signaling cascade
Testosterone (T) is the principal male sex hormone secreted by the testis that circulates in the blood bound to albumin and steroid-binding globulins (38). Only free T is able to enter the cell, after which more than 90% is irreversibly converted into the main prostatic androgen, dihydrotestosterone (DHT) through the action of the enzyme 5areductase (Fig. 2) (38). The binding affinity to the prostatic androgen receptor (AR) of DHT is 5 times higher than that of T (39). The AR is normally associated with heat shock proteins and in this state cannot bind to androgen-responsive elements (40). Androgen binding induces dissociation from heat shock proteins, hyperphosphorylation, conformational changes, and dimerization of the receptor. This allows binding of the AR to specific DNA sequences called androgenresponsive elements located within the promoters of androgen-responsive genes. In conjunction with cofactor proteins and other transcriptional factors, the AR is then able to upor down-regulate the transcription of genes (Fig. 2) (41). In PCa treatment the AR is the target of endocrine therapy by reducing the levels of T and DHT. This can be achieved either by orchidectomy (surgical castration) and/or the administration of (anti)hormones, also referred to as chemical castration, antiandrogen therapy, androgen blockage, or androgen ablation therapy. Androgen ablation therapy may be
FIG. 2. Concepts of androgen activation through receptor binding. HSP, Heat-shock protein; ARE, androgen-responsive elements.
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divided into partial androgen ablation (surgical castration or agents that inhibit or block testicular androgens) and complete androgen ablation (combining agents that inhibit or block both testicular and adrenal androgens). Blockade of the androgen signal kills PCa cells through induction of programmed cell death (38). As many as 80% of the patients initially respond to partial or complete androgen ablation, but the duration of response is in most patients only 12 to 18 months (42) because essentially all tumors have gained the ability to maintain growth even when androgens are present at very low concentrations (43). Complete androgen ablation prolongs the time of response by 3– 6 months but increases the treatment-related side effects and expense (44). Many different terms, such as hormone-escaped, therapyresistant, androgen-refractory, or androgen-independent disease, have been used to describe the process of therapy failure; the latter term will be used in this review. Androgenindependent growth of PCa may portend a poor prognosis as it reflects the acquisition of new growth advantages by the cancer cells. Therefore, it is of major clinical importance to elucidate the qualitative and quantitative alterations of AR gene alterations in PCa specimens. It has been suggested previously that the AR is the cause of androgen independence of PCa. Therefore, it was not anticipated that immunohistochemical and RT-PCR methods proved expression of the AR in almost all primary and advanced tumor lesions, irrespective of the sensitivity of the tumors to androgen ablation therapy (45, 46). Thus, mechanisms other than loss of AR expression are likely to be involved in progression of PCa to an androgen-independent state. These might involve both androgen-independent mechanisms, such as activation of growth factor pathways, and androgen-dependent mechanisms, such as rate of metabolism, hypersensitivity to residual nontesticular androgens, increased androgen biosynthesis from adrenal precursor steroids, or alterations of the AR gene. To date, 39 AR gene mutations in PCa samples have been collected on an Internet site (http://www.mcgill.ca/androgendb) (47). Twenty additional mutations have been described in two other reports (48, 49). A total of 12 PCa specimens contained a mutation in the amino-terminal domain (exon 1), which encodes more than half of the AR protein. Other mutations have been found in the DNA-binding domain (exons 2–3, 3 PCa specimens) and in the hinge region (exon 4, 2 PCa specimens) of the AR gene. Mutations in the steroid-binding domain (exons 4 – 8, 42 PCa specimens) of the AR gene are of particular clinical importance because they could render the mutant receptor constitutively active due to loss of the normal repression of AR transactivation in the absence of androgen. Another effect of AR gene mutations is that the AR can be activated not just by DHT but also by other steroid metabolites that otherwise have a low affinity for the AR (43, 50, 51). For example, Culig et al. (51) reported an AR gene mutation in the steroid-binding domain of a metastatic PCa sample (51). The transcriptional activity of the mutant AR was similar to that of the normal AR in the presence of DHT but was increased in the presence of progesterone and adrenal androgens. Growth stimulation of tumors with such receptor mutations would be expected to occur after surgical castra-
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tion alone (due to adrenal androgens) or estrogen or progesterone therapy (cyproterone acetate, chlormadinone acetate) (Fig. 3). Of similar clinical importance is the finding that one of the currently available antiandrogens, flutamide, has an increased affinity for the mutant AR (52). Flutamide is able to induce dissociation of heat shock protein on binding to the 868 (Thr 3 Ala) mutant, which subsequently enables the AR to bind to androgen-responsive elements, resulting in the expression of agonist activity (Fig. 3) (40). The benefits of discontinuation of flutamide in patients whose metastatic PCa becomes androgen independent has been referred to as the ’flutamide withdrawal syndrome’ (53). There is also preliminary evidence that withdrawal responses to the antiandrogen, chlormadinone acetate, are associated with the presence of a mutated AR (54). In primary untreated PCa, AR gene mutation rates have been found in between 0% and 41% of the specimens (51, 54 – 60). The apparent absence of AR gene mutations in the majority of primary tumors may indicate that the development of clinical PCa occurs predominantly in the presence of a normal AR gene. If functional AR mutations occur before androgen ablation therapy, broadened ligand specificity of the AR may contribute to a growth advantage since PCa has lower levels of 5a-reductase (5-aR) and thus of DHT than normal (50, 60). Similarly, during androgen ablation therapy, patients with mutant ARs in their tumors have been shown to exhibit a rapid failure of therapy, whereas men without AR mutations showed a prolonged response to the therapy (60). Mutation rates in androgen-independent PCa samples varies in between 0% (58, 61, 62) and 50% (43, 54, 57). The differences in the prevalence of AR gene mutations could be attributed to the examination of small fragments of the AR gene rather than the complete AR coding region. Different AR gene mutation rates may also be due to the variability in the exons examined and to techniques used for mutation analysis, including single-stranded conformation polymorphism and denaturating and temperature gradient gel electrophoresis. In addition, mutations may not be detected if a considerable amount of somatic DNA is present in the sample analyzed. Such contamination is especially a problem with PCa because these carcinomas characteristically expand through diffuse penetration of the adjacent stroma by small abortive glands and single cells. More reliable estimates of AR mutation rates are anticipated when nonmalignant tissue is carefully removed from the sample to be analyzed, e.g., by (laser) microdissection.
FIG. 3. The mutant androgen receptor (AR) can be activated by a variety of steroid hormones, antiandrogens, and growth factors.
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AR gene amplification may also contribute to the development of androgen-independent growth of PCa (63, 64). Koivisto et al. (63) examined tumor specimens from 26 PCa patients at the time of, and before, androgen-independent disease. Fifteen (28%) of the recurrent androgen-independent tumors, but none of the untreated primary tumors, contained AR gene amplification as determined by fluorescence in situ hybridization. This group also demonstrated that AR gene amplification does not commonly occur during the clinical progression of cancer in patients who had not received androgen ablation therapy. These findings strongly suggest that it had occurred as a result of selection during androgen ablation therapy. Of note, the median survival time after recurrence of androgen ablation therapy was significantly 2 times longer for patients with AR amplification in comparison to those with no amplification (63). This observation was not anticipated because DNA amplification is usually associated with genetically highly unstable (65) and aggressive tumors (66). Koivisto et al. (63) speculated that the AR-amplified tumor cells, although being genetically unstable, are still subject to rigorously regulated androgen-dependent growth and therefore show a lower level of malignant potential. The realization that the AR receptor is expressed and obviously active during all stages of prostate carcinogenesis has changed our concept of the androgen-independent cancer. The androgen-signaling cascade also is apparently still a reasonable target for therapy in advanced stages of PCa. However, the currently available therapeutic means are not sufficient to block androgen stimuli through a hyperactive AR during these later stages of the disease. Consequently, it will be important to determine in clinical trials whether complete androgen ablation therapy is effective as a second-line therapy for recurrent androgen-independent tumors with AR amplification. In addition, it is important to establish whether complete androgen ablation as a primary treatment also leads to recurrence through AR gene mutations or through AR amplification. There is increasing evidence that peptide growth factors can also activate the AR through a ligand-independent mechanism, such as the cAMP, protein kinase A, and protein kinase C pathway (67). For example, Culig et al. (68) demonstrated that insulin-like growth factor-1 was able to induce AR-mediated transcription in the DU-145 cancer cell line. Less potent stimulatory effects were observed with keratinocyte growth factor and epidermal growth factor. In the PCa cell line LNCaP, insulin-like growth factor-1 increased the level of prostate-specific antigen (68). Interestingly, the paracrine mode of action of growth factors in the nonmalignant prostate and during early stages of PCa is altered toward autocrine stimulation of epithelial cells during advanced stages of disease. Thus, in androgen-independent PCa, the tumor cells might have gained the ability to produce growth factors by themselves, resulting in proliferation through action of the AR (Fig. 4) (69). Moreover, some of the mutant AR may be activated more efficiently by polypeptide growth factors than the wild-type receptor (Fig. 3). These observations may be another explanation why some tumors continue to grow after androgen ablation therapy. There are at least
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FIG. 4. Site and action of polypeptide growth factors in nonmalignant and malignant prostate. In nonmalignant prostate tissue and during early stages of prostate carcinoma, some growth factors are produced by stromal cells with resultant effects on the population of epithelial cells. However, during advanced stages of prostate carcinoma, the cancer cells gain the ability to produce some of the growth factors by themselves.
two therapeutic implications related to the above mentioned observations. First, AR activation by insulin-like growth factor-1, keratinocyte growth factor, or epidermal growth factor can be completely inhibited by the nonsteroidal antiandrogen, casodex. Thus, some antiandrogens can still be beneficial after loss of response to androgen ablation therapy (68). Second, these findings may open the avenue for chemopreventive intervention of dysregulated signal transduction pathways, protein tyrosine kinases being essential components of these pathways (70). Because loss of tyrosine kinase-regulatory mechanisms has been implicated in neoplastic growth, the epidermal growth factor receptor (EGFr) has been selected as a potential target for chemoprevention (70). Zolfaghari and Djakiew (71) demonstrated that the PCa cell line TSU-PR1 expresses a functional EGFr, which when antagonized reduced epidermal growth factor-mediated chemomigration of this cell line. Similarly, immunoprecipitation of EGFr or immunoneutralizing antibodies against its ligands, epidermal growth factor and transforming growth factor-a, resulted in a significant decrease of cell proliferation (72). Further characterization of cross-talk between the androgensignaling cascade and growth factors will certainly provide information that is necessary for a better understanding of the molecular basis of PCa progression. These findings may influence the design of new modalities of endocrine therapy for advanced PCa. A lifelong enhanced activity of the AR due to an inherited polymorphism in the AR gene might also alter the risk of PCa. Two highly polymorphic CAG (73) and GGN (74 –76) (where N is any of the four nucleotides) microsatellite repeats are present in exon 1 of the AR gene, residing the transactivation domain. With respect to the GGN repeat, the most frequently occurring alleles among 73 white men were 22 (51%) and 23 (42%) repeats, counting only GGC and GGT triplets (76). Limiting their counts to the number of GGN repeats to those contiguous triplets in which the third nucleotide was cytosine, Irvine et al. (77) reported that CAG and GGC repeats were in linkage disequilibrium among PCa cases, but not among controls.
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The odds ratio for PCa comparing any GGC repeat length to the control group mean of 16 was 1.18 (P 5 0.08) (77), and in another study the odds ratio for PCa was 1.60 among men with 16 or fewer repeats compared with those with more than 16 repeats (78). In a recent study by Platz et al. (74), 582 PCa cases and 794 controls were analyzed for GGN repeats. No statistically significant difference in the mean GGN repeat length was observed between cases and controls. However, cases had a narrower spread of repeat lengths than controls (P 5 0.03), with fewer extreme lengths in either direction. For every one repeat deviation in either direction from 23, the risk of PCa decreased by 8% (P 5 0.04) (74). Reasons for the disparity in the direction and/or magnitude of the effect between the three studies are unclear but possibly include instability in the estimates of effect due to small numbers, especially at the extreme of the GGN repeat length distribution; genetic variability in the underlying populations from which the case-controls were drawn; different proportions of cases who were older at diagnosis; and etiological differences due to an increased proportion of early lesions resulting from screening for prostate-specific antigen in recent years (74). The second polymorphic AR gene microsatellite is the CAG repeat (73). An expansion of the microsatellite to 40 – 62 CAG repeats is associated with X-linked spinal and bulbar muscular atrophy (Kennedy’s disease) (79). The average length of the CAG microsatellite in the normal population is 21 6 2 (range 11–35) (73). Giovannuci et al. (80) found an association between CAG repeat length less than 19 and higher risk of PCa relative to more than 25 CAG repeats (relative risk, 1.52; 95% confidence interval, 0.92–2.49; P 5 0.04) (80). This group also demonstrated that men with shorter repeats were at particularly high risk for metastatic PCa. Similarly, Stanford et al. observed a 3% decrease of PCa risk for each additional CAG repeat (78). The above mentioned data have been confirmed by other studies (77, 81, 82). Several investigators have tried to correlate the expansion of the CAG repeats with a particular alteration in AR action, but the results remain ambiguous. A reduced amount of specific androgen binding in tissue of patients with Kennedy’s disease has been reported as a result of the expanded CAG repeats (83, 84), although this finding could not be confirmed by Chamberlain et al. (85). Others have indicated that expansion of the Gln repeat in the AR N-terminal region results in a structurally altered protein with reduced transcriptional capacity (85– 88). However, three studies demonstrated that an AR lacking the CAG repeats transactivates normally (89 –91). Also, functional analysis of a CAG repeat expansion in two brothers with Kennedy’s disease revealed that hormone binding, transactivation, and transrepression potentials were identical to that of a wild-type receptor (92). An alternative molecular mechanism was raised by Choong et al. (91) who observed that CAG repeat expansion in the region of the first exon of the AR gene reduced AR mRNA and protein levels. It is obvious from these studies that definitive conclusions regarding the mode of action of CAG repeats on AR function still remain to be determined. Interestingly, the frequency distribution of the AR gene CAG repeat length varies among different racial/ethnic
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groups. Shorter alleles, associated with increased risk of PCa, are found more frequently in African-American men who have a higher incidence of PCa. Conversely, populations at lower risk of PCa (Asians and whites) exhibit a relative high number of CAG repeats (73, 77) (Fig. 5). The resultant effect of any inherited polymorphism of a given gene encoding hormone receptors is present throughout life. Therefore, even polymorphisms associated with modest fluctuations in risk of PCa could explain a large proportion of the racial/ ethnic differences in PCa incidence. In contrast, rare mutations associated with substantially increased risk are likely to account for a smaller fraction of these differences. To date, only one group has evaluated AR gene mutations among various ethnic populations (49). No AR gene mutations were found in clinically detected PCa samples from 26 American and 38 Japanese men. Remarkable was the finding of 18 mutations identified in 79 clinically undetected PCa samples from Japanese male autopsy cases, while none were found in 43 similar tumors from American autopsy cases (49). The authors proposed that these mutations might block further cellular expansion and genetic progression in these latent PCa lesions. None of the AR gene mutations, however, was characterized functionally. This interesting observation merits further study. Other genes involved in the androgen-signaling cascade may also play a role in racial/ethnic differences of PCa risk, such as genes encoding 3b-hydroxysteroid dehydrogenase (3b-HD) type 2 and 5aR type 2. Devgan et al. (93) reported the existence of a complex (TG)n (TA)n (CA)n dinucleotide repeat in 3b-hydroxysteroid dehydrogenase type 2 gene (HSD3B2) (93). A total of 25 different alleles were identified of which the 289-bp allele was shown to be the most common allele in all populations studied. Interestingly, a 275-bp allele was significantly more common among African-Americans, a 340-bp allele among European-Americans, and 281-bp and 302- to 334-bp alleles were found to be significantly more frequent among Asian men (93). Because the 3b-hydroxysteroid dehydrogenase type 2 is one of the two enzymes involved in catabolism of DHT, polymorphisms in the HSD3B2 gene may alter DHT degradation and consequently risk of PCa (93). Unfortunately, functional effects of the different allelotypes have not yet been reported. There are two distinct 5-aR genes in man, each coding a
FIG. 5. Frequency distribution of the AR gene CAG repeat length in the African-American and African-Asian male population. [Data based on A. Edwards et al.: Genomics 12:241–253, 1992 (73).]
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biochemically distinct enzyme: the SRD5A1 gene encodes type 1 enzyme (expressed mostly in newborn scalp, in skin, and in liver), and the SRD5A2 gene encodes type 2 enzyme (primarily expressed in genital skin and the prostate). The latter gene was cloned independently by two groups and maps to a single band on the short arm of chromosome 2 (2p23) spanning more than 40 kb of genomic DNA (94, 95). Ross et al. (96) demonstrated that young Japanese men have lower 5-aR activity than young Caucasian-American and African-American men. Similarly, Wu et al. (97) reported that the DHT-to-T ratio was highest in African-Americans, intermediate in whites, and lowest in Asian-Americans, corresponding to the respective risk of developing PCa in these groups. These studies have provided part of the rationale for using finasteride, a 5-aR inhibitor, as a chemopreventive agent for PCa (98). A 5-aR inhibitor acts selectively inside its target cells, and for this reason it does not lower the serum concentration of T and causes almost no adverse reactions, such as reduction of libido and potency (99). Davis and Russell (100) reported a polymorphic threeallele system in the 39-untranslated region (UTR) of the SRD5A2 gene. This polymorphism consists of a variable numbers of TA dinucleotide repeats. The most frequent allele found in 87% of men without PCa is (TA)0, i.e., a chromosome lacking TA dinucleotide repeats in the amplified region (101). The remaining two alleles, (TA)9 and (TA)18, are found in a minority of the men (101). Other groups have confirmed the SRD5A2 gene polymorphisms, although the frequency of the three alleles differed slightly between the studies (100, 102, 103). The functional effects of polymorphisms in the SRD5A2 gene are not completely understood. Because the TA repeat is located in the 39-UTR of the SRD5A2 gene, it should not affect the structure or function of the resulting protein. However, it has been proposed that certain SRD5A2 polymorphisms may encode for 5-aR enzyme variants with different activities (102) that influence regulation of the 5-aR enzyme production (101), probably by altering mRNA stability (104). As a result, these polymorphisms might alter DHT levels and consequently risk of PCa (102). There are currently no studies available that have addressed length of the TA repeats in parallel with intraprostatic levels of DHT. Such evaluations would more directly assess the biological implications of this polymorphism. Reichardt et al. showed that 18% of healthy African-Americans have at least one (TA)18 allele, while no such alleles have been identified in any healthy Asian-Americans or nonHispanic whites (102). This difference in prevalence of the (TA)18 alleles by ethnicity proved to be statistically significant in this study. The hypothesis that longer TA alleles are associated with an increased risk of PCa could not be confirmed in a predominantly Caucasian population (101). However, the at-risk functional allele may be in linkage disequilibrium with different marker alleles in different ethnic groups, with short alleles increasing the risk of PCa in Caucasians (101). The resultant effect of different alleles in an African-American population still needs to be determined. The molecular rationale for racial/ethnic differences in PCa risk linked to 5-aR metabolism has been investigated further by Makridakis et al. (103). This group demonstrated that a missense substitution in the SRD5A2 gene, which
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replaces valine at codon 89 with leucine (V89L), is distributed differentially among races. This substitution is associated with a reduced 5-aR activity in vivo (103). Interestingly, African-Americans who are at particular high risk for developing PCa also have the highest frequency for valine 89 allele of the V89L amino acid substitution. Asians, the lower risk population, exhibit the lowest frequency of the valine variant and the highest frequency of the leucine variant (103). Latinos, at intermediate risk of PCa, also have intermediate frequencies of the V89L substitution. Thus, a gradient of the V89L substitution exists among racial/ethnic groups that parallels PCa risk. Other groups have investigated whether racial/ethnic variations in hormone levels exist. Ross et al. (105) demonstrated that serum T levels were approximately 15% higher in young African-American males compared with their white counterparts. In a study by Ellis and Nyborg (106), however, serum T levels are only 3.3% higher in 525 black individuals compared with 3,654 non-Hispanic whites. Inconsistency in the magnitude of the effect between those two studies might be related to age. Ross et al. studied only college-aged men, while in the study of Ellis and Nyborg, men aged 31–50 yr were enrolled. The study by Ellis and Nyborg (106) found that the racial/ ethnic difference in serum T levels was age related. In the youngest age group (31–34.9 yr), black men had a mean T level that was 6.7% higher than white men, but it declined to 3.7% by age 35–39 and to 0.5% by ages 40 –50. These observations suggest that at the time PCa evolves, T levels are higher in blacks than in whites. Higher levels of sex hormone-binding globulin (SHBG) have also been associated with a higher risk of PCa (107). Interestingly, American males were found to have higher levels of SHBG than did their Japanese counterparts, consistent with the risk of PCa among these populations (96). C. Vitamin D and prostate carcinoma
In addition to androgenic steroids, the secosteroid, 1,25dihydroxyvitamin D3 [1,25-(OH)2D3], also plays an important role in the growth and function of the normal prostate, as well as in prostate carcinogenesis. Vitamin D, which is supplied physiologically by UV irradiation through a precursor in the skin or obtained from the diet, undergoes sequential cytochrome P450-dependent hydroxylations to form 25-hydroxyvitamin D3 [25(OH)D3] in the liver and 1,25(OH)2D3 and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] in the kidney (108). The metabolites 25(OH)D3 (25–100 nm) and 24,25(OH)2D3 (2–10 nm) are both present in the plasma at much higher concentrations than the hormonally active metabolite 1,25-dihydroxyvitamin [1,25-(OH)2D3; 100 pm], but they have limited biological activity with respect to calcium homeostasis (108). This is because most of the actions of vitamin D are mediated through an intracellular receptor that has much higher affinity for 1,25-(OH)2D3 than for the other metabolites. 1,25-(OH)2D3 is capable of acting through both nongenomic signaling pathways involving a membrane-associated receptor and genomic pathways involving the nuclear vitamin D receptor (VDR) (109). Hormone bound to the VDR induces changes in gene expression much like the
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steroid receptors. In the absence of hormone, the VDR binds to vitamin D-response element in the DNA as a heterodimeric complex with retinoid X receptor. Recent studies have suggested that ligand binding promotes the dissociation of corepressors such as NCoR (nuclear receptor corepressor) and binding of coactivators such as steroid receptor coactivator-1 causing transactivation (110). The initial hypothesis that vitamin D may have a protective effect against developing prostate carcinoma was raised by Schwartz and Hulka (111). They showed that PCa incidence increases with age, and the elderly are known to have lower levels of vitamin D. There is a high incidence of PCa in blacks, also known to have relative low levels of vitamin D (112). Also, there is an increased incidence of PCa in migrant Asians as they adopt a Western diet, i.e., lacking the large amount of vitamin D-rich fish oil (111). Lastly, US mortality rates from PCa demonstrate a negative correlation with UV radiation exposure (113). In addition to these epidemiological observations, several studies have shown that vitamin D metabolites have antiproliferative and prodifferentiating effects on PCa cell lines in vitro and in vivo (109, 114 –118). Moreover, physiological levels of 1,25-(OH)2D3 significantly reduce the invasive potential of DU-145 cells (119) and reveal impressive antimetastatic effects on PCa cells in vivo (120). It should be noted, however, that different PCa cell lines may exhibit varying sensitivity to growth inhibition by 1,25-(OH)2D3 (117). If such variability also exists in human PCa, the effectiveness of 1,25-(OH)2D3 and analogs as therapeutic agents may be limited. Thus, it is critical to understand which factors influence the actions of 1,25(OH)2D3 on PCa cell proliferation. Relative insensitivity to 1,25-(OH)2D3-mediated growth inhibition in the PCa cell lines PC-3 and DU-145 was associated with low functional VDR levels (117). Transfection of these cell lines with a VDR cDNA-expression vector induces growth sensitivity to 1,25(OH)2D3. Similarly, the cell line JCA-1 fails to express a detectable number of VDRs and is not measurably affected by 1,25-(OH)2D3 in growth studies (109). Transfection with a wild-type VDR cDNA construct in JCA-1 cells resulted in expression of high affinity nuclear VDRs and a dose-dependent inhibition of growth by 1,25-(OH)2D3 (109). These studies suggest that low VDR levels are responsible for the failure of these cell lines to respond to vitamin D. LNCaP cells are highly sensitive to growth inhibition by 1,25-(OH)2D3 and contain approximately 2- to 3-fold more VDR than the relatively 1,25-(OH)2D3-insensitive PC-3 and DU-145 cell lines. However, the PCa cell line ALVA-31 displays less than 20% growth inhibition to 1,25-(OH)2D3, yet it contains the highest levels of VDRs of these four cell lines (117). Thus, sensitivity of growth inhibition to 1,25-(OH)2D3 does not correlate with VDR content in ALVA-31 and LNCaP cells. Because VDR is capable of transactivating reporter gene expression in ALVA-31 and LNCaP cell lines, differential growth sensitivity to 1,25-(OH)2D3 is not likely to result from VDR or retinoid X receptor mutations or from differences in 1,25-(OH)2D3 metabolism (117). From the above-mentioned studies it was suggested that expression of functional VDR is necessary, but not sufficient, for maximal growth inhibition by 1,25-(OH)2D3 (121). Differential expression and/or regulation of the retinoblastoma pathway, the cyclin-depen-
29
dent kinase inhibitor (CDKI), p21, or 1,25-(OH)2D3 regulation of cyclin-dependent kinase may also explain some of the differences in sensitivity to the antiproliferative effects of 1,25-(OH)2D3 among PCa cell lines (121, 122). The finding that 1,25-(OH)2D3 demonstrates antiproliferative, prodifferentiation and antimetastatic effects could open new avenues to the development and targeting of prophylactic interventions. However, 1,25-(OH)2D3 may not be the suitable agent for use as a chemopreventive agent because of the risk of hypercalcemia (123). Interestingly, Schwartz et al. (124) recently demonstrated that the PCa cell lines DU-145 and PC-3 could synthesize 1,25-(OH)2D3 from its precursor 25(OH)D3. Therefore, supplementation of men with 25(OH)D3 could promote the local synthesis of 1,25-(OH)2D3 by prostate cells and thereby inhibit invasiveness of PCa cells (124). If the prostate cells synthesize 1,25-(OH)2D3 in vivo, then systemic levels of 1,25(OH)2D3 measured in the serum may not reflect levels of 1,25(OH)2D3 at the site of the target cell. Thus, the risk of PCa may be influenced by intraprostatic and systemic levels of vitamin D3 (124). This could explain, at least in part, inconsistent results reported from several prospective epidemiological studies of PCa that assessed vitamin D metabolite levels in blood samples (125, 126). As with the androgenic steroids, the vitamin D signaling cascade might be altered by genetic changes. Although studies on VDR gene mutations in PCa have to date not been reported, a series of common polymorphisms in this gene have been identified. The alleles of human VDR gene can be distinguished by restriction fragment length polymorphisms (RFLPs) found for BsmI and ApaI (intron 8) and TaqI (exon 9) (127). The presence (b, a, t) or absence (B, A, T) of a restriction site defines the specific allele. The RFLPs are highly linked in the population. The BsmI cleavage site (b) is associated in 97% of individuals with the absence of a TaqI site (T) (128). This strong linkage disequilibrium results in two common haplotypes BAt and baT. A fourth polymorphism, a poly (A) microsatellite, is in the 39-UTR (81, 128). In a study of nonHispanic whites, the S (short) and L (long) alleles of the poly(A) microsatellite were 97% concordant with the BsmI alleles, with B corresponding to S and b corresponding to L (129). Several groups have evaluated whether VDR gene polymorphisms could alter the risk of PCa (81, 129, 130). Two recent case-control studies [117 (128) and 591 controls (131)] reported significantly higher serum 1,25-(OH)2D3 levels among individuals who were homozygous for the BAt haplotype compared with individuals who were heterozygous or homozygous for the baT haplotype. Therefore, the BAt haplotype may have a protective effect on developing PCa. Indeed, Taylor et al. (130) estimated that men who were homozygous for the presence of a TaqI restriction site (genotype tt) have one-third the risk of developing PCa requiring prostatectomy compared with men who are heterozygotes or homozygotes for the T allele (odds ratio 5 0.34; 95% confidence interval, 0.16 – 0.76; P , 0.01). Similarly, Ingles et al. (81) reported an odds ratio of 0.22 (95% confidence interval, 0.06 – 0.75) for the risk of PCa among men with the SS genotype compared with men with the SL or LL genotypes. Ma et al. (131) could demonstrate only a 57% reduction in
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risk of PCa related to the BB genotype in older men with plasma 25(OH)D3 levels below the median. Because the elderly are more likely to have restricted sunlight exposure, low vitamin D intake, and reduced capacity of the skin to produce vitamin D, any genetic influence on vitamin D levels may be stronger among older than younger men (131). Similarly, low levels of 25(OH)D3 may result from active conversion of this metabolite into 1,25-(OH)2D3 by 1a-hydroxylase activity. If higher 1,25-(OH)2D3 in the presence of lower 25(OH)D3 is beneficial with respect to PCa, this could explain the reduced risk observed for the BB genotype among men with lower 25(OH)D3 (131). However, in their entire study population of 372 cases and 591 controls, no significant associations between VDR gene polymorphisms and PCa risk was found (131). Differences in the control selection were probably not the reason for the divergent results, as the prevalence of the polymorphisms was similar among the three above-mentioned studies (81, 130 –131). No association between VDR polymorphisms with tumor aggressiveness was found, reducing the probability of this form of bias by case selection among the different reports (130 –131). Thus, studies that did find a difference between VDR polymorphisms and risk of PCa may have resulted from selection of men that had lower 25(OH)D3 levels. A major difficulty in accepting the hypothesis that VDR gene polymorphisms may alter risk of PCa is that, unlike the AR polymorphism, none of the BsmI, ApaI, and TaqI polymorphisms alter the predicted amino acid sequence of the translated VDR protein. The BsmI and ApaI polymorphisms are located in intron 8 of the VDR gene (132). Only the TaqI polymorphism is located in the coding region but leads to a silent codon change in exon 9, with ATT and ATC both coding for isoleucine (133). Therefore, it has been proposed that expression of these receptor alleles or the functional activities of their products are potential discriminating factors (81, 134). Morrison et al. (128) found that in minigene reporter constructs, in which the 39-UTR of alleles BAt and baT were fused 39 to a luciferase reporter gene, luciferase activity was 30 – 40% lower when the baT construct was transfected in COS cells. Therefore, this group proposed that T mRNA was less stable than t mRNA. Verbeek et al. (134) kept all influences equal for both VDR mRNAs transcribed either from the T or t allele by choosing a heterozygous system (Tt) as opposed to the comparison of two (TT vs. tt) homozygous cell lines. This group consistently found approximately 30% less RTPCR product derived from the t allele than the T allele in normal lymphocytes, the hematopoietic cell line NB4, and the PCa cell lines, PC-3 and DU-145 (128). They could not demonstrate any difference in VDR mRNA stability between the two alleles in either the cell lines or the normal lymphocytes. These results indicate the existence of a variation in transcriptional regulation rather than mRNA stability between the alleles. Therefore, it has been suggested that unknown gene(s) in linkage with the polymorphisms might be responsible for the relationship between risk of PCa and VDR gene polymorphisms, and these factors merit further study. Baker et al. (132) have cloned a second group of polymorphisms in the VDR gene. The VDR gene has two ATG translational initiation sites that are separated by three codons. A
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polymorphism located in the first ATG presumably determines the site of translation initiation (135). Consequently, the variants in this polymorphic site would differ in length by three amino acids. Two studies have shown that the elongated VDR allele is associated with an increased risk of osteoporosis (136, 137). However, it has not yet been proven whether this start codon polymorphism results in a change in VDR function. It will be of interest to determine whether this VDR polymorphism, which has no known relationship to the poly(A)-linked polymorphisms, is also associated with altered risk for PCa. As for the AR gene, polymorphisms of the VDR gene have also been evaluated for their potential role in racial/ethnic differences in risk of PCa. In Caucasians, the at-risk allelic variant is associated with the bAT-poly(A)L haplotype. In a study restricted to African-American individuals, however, the poly(A)L allele genotype was not associated with risk of PCa (138). Moreover, BsmI b alleles were associated with a 2-fold decrease in risk of advanced PCa in African-American men, in contrast to a 4-fold increase risk of PCa in a Caucasian population (81, 138). Although these results might seem inconsistent, the at-risk functional allele may be in linkage disequilibrium with different marker alleles in different ethnic groups, e.g., BsmI b in Caucasians and B in AfricanAmericans (113). D. Oncogenes
To date, more than 100 cellular oncogenes have been identified. Only oncogenes that have been studied more extensively for their possible role in the development of PCa will be discussed. 1. ras Oncogene. ras Oncogenes are activated by point mutations in the protooncogene. Mutations most commonly occur at codons 12, 13, or 61, thereby altering the ability of the ras protein to affect signal transduction, leading to unregulated cellular growth (139). The low frequency of ras mutations in PCa samples obtained from Western study populations (4/ 146; 2.7%) indicates that this oncogene is apparently not commonly involved in PCa initiation or progression (140 – 146). However, when PCa samples from only Japanese cases are considered, mutations in the ras gene occur in as many as 18% of the cases evaluated (25/138) (140 –146). This difference in ras mutation rate may reflect a different etiology causing PCa or affecting its progression between the two populations. 2. myc Oncogene. c-myc Is a cellular protooncogene that encodes a nuclear phosphoprotein. Potential functions of c-myc include the promotion of DNA replication, regulation of the G0/G1 cell-cycle transition, and control of cellular differentiation (147). Few studies have examined the frequency of myc alterations in PCa (148 –153). Using Northern blot analysis, these studies have shown a significantly higher level of c-myc RNA transcripts in PCa specimens of varying grades compared with samples of benign prostatic hyperplasia (BPH) (148, 150 –153). However, the Northern blot technique makes it impossible to establish which cell type gives rise to higher mRNA levels.
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Interestingly, such a correlation is possible with in situ hybridization, and the two studies that have performed such an analysis did not confirm a relationship between c-myc and PCa (149, 151). Thus, the role of c-myc in PCa needs to be extended by additional studies in which it is also possible to evaluate the origin of increased levels of c-myc mRNA and to determine whether the c-myc protein is simultaneously elevated. 3. erbB2 Oncogene. Localized on chromosome 17p21, the HER2/neu oncogene encodes a 185-kDa transmembrane tyrosine kinase growth factor receptor with substantial homology to the EGFr (154). More than 100 previous reports have studied the HER-2/neu gene and its protein product in a variety of malignant tumors, indicating the significance of this gene in carcinogenesis (154). Given the significant recent interest in the use of anti-p185neu antibodies for the treatment of advanced stage refractory ovarian and breast carcinoma, the documentation of a subset of PCa patients with HER-2/neu overexpression that have a significant risk for disease progression might be of potential therapeutic interest (155). Some studies have revealed a higher protein expression or gene amplification in patients with clinically detected PCa compared with nonmalignant specimens (156 –160), whereas others did not find such a correlation (161) or even found overexpression of the oncoprotein in BPH lesions (160). Similarly, a consensus as to the predictive value of HER-2/neu gene amplification and p185neu protein expression in PCa patients has not been reached (156 –164). Possible explanations for the disparity in the direction and magnitude of these results include a variety of technical factors. For example, the use of various antibodies with differing sensitivities and specificities may produce either cytoplasmic or membranous staining, be ineffective when certain fixatives are used, or be impacted by the temperature of the immunohistochemical reaction (156, 165–166). In addition, fixation and processing protocols significantly affect the reactivity of the antigenic determinants detected by HER-2/neu antibodies, such as MAB-1 and pAB-60 (156, 165, 167). Antigen retrieval techniques featuring either enzymatic digestion or microwave irradiation contribute additional variables that may affect staining levels (156). Finally, interobserver variability of staining interpretation has also been reported (168). It has recently been demonstrated that fluo-
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rescence in situ hybridization (FISH) is more sensitive than immunohistochemistry for detection of abnormalities in the HER-2/neu gene, and future studies should be undertaken to determine whether a FISH-based HER-2/neu detection method may prove to be important in the prediction of prognosis in PCa patients (169). E. TSGs
Malignant progression not only involves the enhancement of oncogene-derived transforming functions, but also requires the loss of regulatory functions of TSGs. Mutations of TSGs generally are considered recessive, and both copies of these genes must be inactivated before the cell is at risk for transformation. The first mutation of the gene is a somatic event or is inherited in the germline from one of the parents. The second hit is likely to inactivate the normal copy or allele of the gene that functioned as a ’repressor’ of the mutant allele. 1. Loss of heterozygosity (LOH) studies. Sites of consistent chromosomal deletion resulting from LOH studies may uncover the location of TSG. Several groups have investigated the frequency of LOH at different chromosomal regions, and their results are summarized in Fig. 6 (170 –199). Interestingly, chromosome 8p shows frequent LOH in a variety of other common human tumors including colorectal and lung cancer. Whether the same gene is a target of these LOH events in prostate, colon, and lung cancer is unclear, but it is interesting to speculate that a gene that is inactivated in a large fraction of human cancers may reside in this region of the genome (28). 2. Retinoblastoma gene. This TSG, located on the short arm of chromosome 13, encodes a 110-kDa protein that functions in regulating the cell cycle progression (200). In addition to being present in all cases of retinoblastoma (201), mutations of the Rb gene have been identified in various human neoplasms. Studying Rb expression in three human PCa cell lines, Bookstein et al. (202) found that one of these (DU-145) contained an abnormally small protein translated from a Rb mRNA transcript that lacked 105 nucleotides encoded by exon 21. To assess the functional consequences of this mutation, normal Rb expression was restored in DU-145 cells by
FIG. 6. The average reported rate of LOH on several chromosomal arms in localized and advanced prostate carcinoma (after failure of androgen ablation therapy or metastatic disease).
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retrovirus-mediated transfer of a cloned normal Rb cDNA. Transfected cells expressing normal Rb lost their tumorigenic ability in nude mice (203). The same group also analyzed seven human PCa specimens for Rb alterations. One sample revealed absence of Rb protein in a tumor that was believed to result from a deletion of 103 nucleotides in the promotor region in combination with loss of the second Rb allele (202). The finding of a short-sized mRNA transcript in DU-145 PCa cells has been confirmed by two studies (204, 205). To date, human PCa samples have not revealed Rb promotor alterations or short-sized mRNA transcripts (204, 205). Molecular-based studies of Rb alterations in PCa have been limited. Performing single-stranded conformation polymorphism analysis of RNA, Kubota et al. (206) revealed that 4 (16%) of 25 human primary PCa samples had Rb alterations. Several other groups have evaluated genetic alterations in the region of the Rb gene using polymorphic markers; reported LOH rates in primary PCa varied between 27% and 60% (191–193, 207). Interestingly, LOH at Rb have also been found in BPH samples (191, 208). It is unclear from those latter results whether Rb alterations also have a role in the genesis or progression of BPH. Absence of Rb protein (pRb) by immunohistochemistry has been reported to vary between 17% and 78% (191–193, 205, 209). Several difficulties remain regarding the value of pRb alterations in PCa, such as the lack of complete correlation between LOH at Rb and absent pRb expression (192, 193). For example, one study demonstrated that three PCa samples without LOH at Rb, using an intragenic microsatellite marker, did not express pRb (193). Discordances between LOH at Rb and pRb expression might be due to the large size of the Rb gene (27 exons spread over 200 kb of genomic DNA), which poses problems for the detection of small deletions. It is also difficult to determine in some case whether the low rate of loss of pRb staining in tumors with LOH on 13q is caused by the presence of stable mutant pRb or the involvement of a second TSG closely linked to Rb. In addition, the evaluation of pRb expression may be confounded by fixation artifacts and by variables in the immunohistochemical reaction, such as sensitivity and specificity of the antibody and interpretation of the staining results (192, 193). Whether the reduction of pRb staining has any significance as to the prediction of the malignant potential of a given carcinoma lesion is a topic that requires further study in a well characterized population of PCa patients. 3. p53 Gene. Located at 17p13.1, the p53 gene encodes a 53-kDa phosphoprotein that negatively regulates cell growth (210). When DNA damage has occurred, the p53 gene will either induce growth arrest via activation of a downstream inhibitor pathway or commit the cell to a programmed death pathway depending on the extent of damage. Inactivation of this gene contributes to the genesis and progression of numerous human cancers, including these of the breast, colon, and lung (211). Several methods can be used to screen for p53 alterations, such as single-stranded conformation polymorphism of exons 5– 8 (where the majority of mutations within the p53 gene are known to occur) and immunohistochemistry. The latter method exploits the increase in biological half-life of many mutations of the p53 protein (TP53) (212).
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Such an increase in half-life results in the intranuclear accumulation of detectable quantities of the TP53 by a number of commercially available antibodies. While TP53 accumulations as determined by immunohistochemical detectable intranuclear staining and p53 gene mutations are not synonymous terms, most studies support a close relationship between them (213, 214). The frequency of p53 mutations in primary PCa ranges from 1– 42% (48, 143, 196, 213–222). LOH studies have shown that deletions in the region of the p53 gene occur in approximately 16% of primary, nonmetastatic PCas (range 0 –50%) (215, 169 –171, 178, 183, 186, 196). Accumulation of TP53 by immunohistochemistry has been demonstrated in between 2% and 22% of the primary PCa samples (143, 196, 213, 214, 220, 223–226). The only exception is a study by Veldhuizen et al. (227) in which TP53 accumulation was detected in as many as 79% of the cases. This study did not differ from other reports in the grade and stage composition of the specimens analyzed. Unfortunately, mutation analysis to confirm these results was not performed. This might be important to know since the predominant cytoplasmic pattern of TP53 staining identified in this latter study is not necessarily associated with p53 gene mutations. For example, immunohistochemistry may detect a wild-type TP53 protein that has been stabilized as a result of DNA damage induced by exogenous factors (27). The disparity in the above-mentioned data with respect to the rate of p53 alterations may result from various factors. Interpretation of TP53 staining is prone to interobserver variability. Therefore, quantitative measurements are important to more objectively relate the number of nuclei with protein accumulation to variables such as grade, stage, and follow-up data of the patient. Another factor is that commercially available antibodies may differ in sensitivities and specificities. Similarly, variation in p53 gene mutation rates may result from using different techniques, such as temperature- or denaturating gradient gel electrophoresis or singlestranded conformation polymorphisms. In addition to these technical factors, variations in reported incidence of p53 alterations also result from heterogeneity in the topographical distribution of the alterations (222, 226). This implicates that the outcome of incidence of any p53 alteration would depend not only on which tumors but also which regions of the tumors are being analyzed. A consistent observation from the vast majority of the studies is that the predictive value of p53 depends on its association with high-grade and advanced stage PCa (27, 214, 217, 224, 225, 228). Consequently, it is anticipated that p53 is not useful as a prognostic marker in most patients with PCa (196, 229). However, it is important to consider that alterations in the p53 gene may play a role in the development of radiation resistance (230 –233). Several regulatory genes influencing the cellular commitment to apoptosis have been identified in various tumors, including bcl-2, p53, c-myc, and ras. It has been speculated that defects in such regulatory genes may limit the ability of the cell to induce programmed cell death, resulting in resistance to agents that exert cytotoxicity via induction of apoptosis (230). A number of studies have shown that the lethal effects of ionizing radiation are attenuated in certain cells harboring mutations in the p53
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gene (231–233). Although not all studies are supportive (234), genetic alteration of the p53 gene may thus be used as a pretreatment marker to predict local treatment failure with ionizing radiation (230, 234). Similarly, p53 gene mutations have been shown to adversely predict overall survival for patients treated with androgen ablation therapy in locally advanced cancer of the prostate after radiotherapy (235). This suggests that induction of apoptosis after androgen ablation may also be blocked in patients whose tumors have p53 gene mutations. F. Metastasis suppressor genes (MSGs)
Acquisition of metastatic ability is the ultimate biological hallmark for the aggressiveness of PCa. Genetic control of metastasis may be exerted by the increased expression of specific genes involved in transformation to the metastatic phenotype. On the other hand, deactivation of specific MSGs may promote the evolution of metastasis in a manner analogous to the action of TSGs on tumor initiation. At present, there is evidence suggesting several MSGs may play a role in PCa, of which E-cadherin, KAI1 and CD44, and PTEN will be reviewed. 1. E-cadherin. The frequent finding of LOH at chromosome 16q in PCa (Fig. 6) led to an examination of putative candidate genes in this region. Although 16q reveals three commonly deleted regions (195), the E-cadherin gene located on 16q22.1 is of particular interest. E-cadherin is involved in developmental morphogenesis and maintenance of the epithelial phenotype by mediating epithelial cell-cell recognition and adhesion processes (236). The role of this Ca21dependent cellular adhesion molecule in maintaining various aspects of epithelial cell differentiation has led a number of investigators to examine E-cadherin expression in carcinomas. The functional importance of E-cadherin in preserving epithelial tissue integrity was demonstrated by using antibodies against E-cadherin, leading to dissociation of epithelial cell layers in cell culture and to an increased invasive potential of cells (237). Increased invasive behavior can also be induced by introducing E-cadherin antisense transcripts into cells (238). Conversely, transfection of E-cadherin into E-cadherin-negative cell lines can result in reversion to a noninvasive phenotype (238 –240). These data have provided the rationale to further investigate the role of E-cadherin in the development and progression of PCa. Relevant approaches include immunohistochemistry, mutation analysis, and LOH studies on tumor samples. Unfortunately, E-cadherin immunohistochemistry on archival tissue is often unreliable due to a combination of formalin fixation and autolytic artifacts (241). Therefore, the studies that have evaluated E-cadherin immunoreactivity on paraffin material should be interpreted with care. A recently described alternative approach for fixing prostatectomy specimens combines injection of formalin into the prostate at multiple sites and microwave-stimulated heating of the specimen to 50 C (241). With the use of this modified fixation technique, immunohistochemical stains on paraffin tissue equals those on frozen sections. Moreover, much longer fragments of DNA can be extracted from the tissue
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blocks, which expands the possibilities for molecular analysis (241). Retrospective studies using frozen PCa samples have revealed a strong correlation between decreased E-cadherin staining and increased histological grade (242–244), advanced clinical stage (242–244), and the presence of metastasis at diagnosis (244, 245). Of clinical importance is the finding that aberrant E-cadherin expression proved to be a powerful predictor of adverse prognosis (243, 245). The finding of two PCa metastases with normal E-cadherin expression (242) does not necessarily contradict the role of E-cadherin as a MSG because it is possible that E-cadherin is only transiently down-regulated (246, 247). It is important to clarify the mechanisms by which Ecadherin function is regulated. Interfering with biochemical pathways governing epithelial differentiation and maintenance of epithelial integrity might provide new therapeutic approaches. So far, E-cadherin mutations in PCa samples have been reported in two studies (195, 248). Schalken et al. (248) reported one (4%) mutation in 28 human prostate and bladder carcinoma samples that would lead to a change in the E-cadherin polypeptide sequence. Suzuki et al. (195) found an equal frequency of E-cadherin gene mutations in 48 primary PCa samples that were all found to be silent mutations by sequencing. Considering the infrequent mutational inactivation, defective E-cadherin function is more likely to result from posttransciptional alteration or due to loss of or reduced contact with the cytoskeleton. Interactions between the cytoskeleton and adhesion molecules have been shown to be essential for a variety of cellular functions, including cell-cell and cellmatrix interactions and cell motility. Normally, the highly conserved cytoplasmic domain of E-cadherin associates with three independent proteins, called a-, b-, and g-catenin (249). Significant changes in the cadherin-catenin complex have been shown to disturb the junctional complex, thereby affecting the greater motility of invasive cells. For example, the PCa cell line PC-3 is characterized by the presence of Ecadherin, but the complete lack of a-catenin both at the RNA and protein level due to a homozygous deletion in the a-catenin gene (250). Transfection of these cells with an a-catenin expressing vector has been shown to induce the reversion to a typical epithelial morphology in PC-3 cells (251). The a-catenin gene is mapped to chromosome 5q22 (252). LOH in this region occurs in approximately 20% of the PCa specimens (Fig. 6). Two studies have performed an immunohistochemical evaluation of a-catenin in PCa specimens (243, 253), showing that in a small number of specimens immunohistochemistry predicted invasiveness more accurately than E-cadherin expression. To date, b- and g-catenin immunohistochemistry have not been studied in PCa. Only one study has evaluated the rate of alterations in the b-catenin (CTNNB1) gene in 104 clinically localized PCa samples, finding only five mutations (254). The recent observation that adenomatous polyposis coli gene products interact with b-catenin suggests a potential novel mechanism through which a TSG may alter regulation of cell-cell adhesion (255). A third mechanism resulting in defective E-cadherin function is DNA methylation (256). Graff et al. (256) showed that the 59-CpG islands of the E-cadherin gene are densely meth-
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ylated in E-cadherin-negative breast and PCa cell lines, but is unmethylated in normal breast tissue. Moreover, treatment with a demethylating agent partially restores E-cadherin RNA and protein levels in these E-cadherin-negative breast and PCa cell lines (256). 2. KAI1 and CD44. The KAI1 gene, located on human chromosome 11p11.2, has been shown to suppress the process of tumor metastasis when introduced into the highly metastatic Dunning R-3327 rat PCa subline AT6.1 (257). In addition, expression of this gene is reduced in human cell lines derived from metastatic PCa specimens (257). An additional MSG located near KAI1 is CD44 (258). The CD44 gene (11p13) encodes an integral membrane glycoprotein that was initially discovered to be a lymphocytehoming molecule (259). Subsequent studies demonstrated that numerous normal and tumor tissues express CD44 as well (260) and that CD44 participates in specific cell-cell and cell-extracellular matrix interactions (258). Transfection-induced enhanced expression of the standard form of CD44(s) in the highly metastatic AT3.1 rat prostatic cells greatly suppressed their metastatic ability without suppression of their in vivo growth rate or tumorigenicity (258). In addition, down-regulation of CD44 expression at both the mRNA and protein level correlates with metastatic potential in the Dunning system of rat PCa sublines (258). The number of studies that have evaluated KAI1 or CD44 in PCa samples is limited. In a retrospective study by Dong et al., KAI1 alterations were analyzed in 98 primary and 32 metastatic PCa samples (261). KAI1 protein expression was down-regulated in more than 70% of the 49 primary PCa specimens from untreated patients. In 10 such untreated patients, down-regulation of KAI1 protein occurred in all of the lymph node metastases examined. In 15 patients with metastatic disease who had failed androgen ablation therapy, more than 90% of the primary PCa had down-regulation or even completely negative KAI1 protein expression (261). This down-regulation did not involve a genetic alteration (mutation or LOH) in any of the specimens analyzed. Despite the important results of in vitro studies, there are currently no reports that have evaluated the role of CD44 gene alterations in human PCa samples. Immunohistochemical studies have demonstrated that down-regulation of the standard form of CD44 is associated with high tumor grade (254, 262, 263), aneuploidy (263), and the presence of metastasis (262, 263). 3. PTEN. Located on chromosome 10q23, PTEN appears to behave as a MSG (264). The predicted PTEN protein product has a tyrosine phosphatase domain as well as extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions (265). This homology suggests that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions (265). Genetic changes of PTEN occur in multiple types of cancer, suggesting that inactivation of this gene may play an important, perhaps somewhat general role in the pathogenesis of a variety of human malignancies (266). To date, only a few groups have
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evaluated genetic alterations of PTEN in PCa. Inactivation of the PTEN gene by homozygous deletions occurs in approximately 13% of primary clinically localized PCa (267). Tissues from similar stages of disease revealed LOH over the region spanning the PTEN locus in as many as 48 (37%) of 131 samples analyzed (268, 269). Of 25 samples from localized PCa with LOH, Feilotter et al. (269) found that only one carried a missense mutation in PTEN. In metastatic PCa, Suzuki et al. observed gene alterations (deletions or point mutations) in at least 1 metastatic site in 12 (63%) of the 19 patients analyzed. In addition, LOH at 10q23 was found in as many as 10 (56%) of 18 informative cases, indicating that genetic alterations of the PTEN gene frequently occur in lethal prostate cancer (266). The future development of antibodies for immunohistochemical analysis will facilitate the evaluation whether PTEN may be a marker of high metastatic ability of PCa. G. Telomerase activity
Telomeres, the repetitive noncoding DNA sequences found at the ends of all eukaryotic chromosomes, shorten with each cell division. In vertebrates, telomeres consist of multiple tandem repeats of the sequence TTAGGG (270). Normal cells lose approximately 50 –100 bp of the telomeric DNA with each round of replication (271). Loss of telomeric DNA occurs because DNA polymerase starts at a RNA primer that is subsequently removed (272). The noncoding telomere sequences thereby serve to prevent loss of genetic coding regions (272). It has been proposed that telomere shortening may be the counting element of a mitotic clock that keeps track of cell divisions, with shortening to a critical length acting as a senescence signal underlying cellular aging. In this way, telomeres function to protect genomic DNA from recombination effects (273). Telomerase is a reversetranscriptase containing an RNA template that is complementary to the telomeric repeat (274). Using this RNA template, telomerase adds telomeric sequences to the ends of newly replicated DNA, consequently compensating for the loss of sequences that have occurred during cell replication (272). The enzyme telomerase thus allows unlimited cell division and has therefore been associated with cellular immortalization. The latter phenomenon is one of the major events in the progression from normal cells to cancer. In human specimens, telomerase activity has not been demonstrated in normal prostatic tissue (270, 272, 275, 276). However, when all of the results obtained in clinical specimens of PCa are combined, the incidence of telomerase activity appears to be relatively common: 172 (89%) of 194 tumors harbor activated telomerases, suggesting that this pathway may play an important role in prostate carcinogenesis (270, 272, 275–279). One of these studies also found high levels of telomerase activity more frequently in poorly differentiated PCa samples (276). Recent studies have demonstrated that noncancerous tissue samples that are located adjacent to PCa may also exhibit telomerase activity. For example, 5 (12%) of 42 histologically normal prostatic tissue samples (272, 277), 17 (28%) of 61 BPH samples (272, 276, 277), and as many as 14 (74%) of 19 PIN samples (277)
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revealed telomerase activity. None of the 26 tissue samples obtained from noncancerous prostate showed telomerase activity (272, 276, 277). These observations have several implications. Considering the high prevalence of telomerase activity in PCa and in nonmalignant tissue directly adjacent to PCa, telomerase activity in these adjacent lesions might represent undiscovered or unsampled PCa. Because pathological characterization evaluates the top surface of a tissue block only, assessment of telomerase activity could provide a more sensitive means than conventional histology for the detection of cancer cells in a subset of the benign-appearing tissues (277). Also, the finding of telomerase activity in BPH lesions adjacent to PCa might implicate that these lesions have submicroscopic cancerous changes. The presence of telomerase in a high proportion of the PIN lesions supports the hypothesis that this lesion is a precursor of PCa and harbors early molecular alterations leading to malignancy.
III. Etiology of Familial Clustering of Prostate Carcinoma
After the initial reports of the existence of a familial/ hereditary form of PCa, several studies have tried to identify potential etiological factors contributing to increased risk of PCa in those families. A limited number of studies have investigated whether hormonal levels tend to be familial or inherited (18, 107). However, it is difficult to interpret the results of these studies because both genetic and environmental factors may affect hormone levels. In addition, the relevance of the results reported is also in some doubt, as the potential role of some of the hormones examined in PCa is not evident (18, 107). Genes that are believed to play a potential role in the prostate hormone-signaling cascade include those encoding the AR, the VDR, and the 5-aR enzyme type 2. Polymorphisms in these genes may influence receptor/enzyme activity and consequently alter the risk of PCa. Unfortunately, the contribution of such allelic variants to familial clustering of PCa has currently not been reported. Until recently, efforts to identify genes involved in familial clustering of PCa have focused primarily on TSGs, of which only BRCA1 was found to be of potential interest. Inherited mutations in this highly penetrant dominant gene have been shown to predispose women to breast and ovarian cancer (280). Interestingly, in a study of seven Icelandic breast cancer families, two of which showed evidence of linkage to BRCA1, PCa was found to be the second most frequent malignancy after breast cancer (281). Among presumed paternal carriers of mutant BRCA1 gene alleles, 44% had a history of PCa. Ford et al. (282) examined 33 BRCA1-linked families and estimated a relative risk of PCa of 3.33 (95% confidence interval: 1.8 – 6.2) among men carrying BRCA1 mutations compared with the general population. To more directly assess the potential role of BRCA1 mutations in the etiology of PCa, Langston et al. (283) screened for germline BRCA1 mutations in 49 men from families with clustering of either breast or prostate cancer and 145 controls. One germline BRCA1 mutation as well as five rare sequence variants were identified in PCa samples. The fact that
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none of the sequence variants was identified in the population-based control group suggests that one or more of these variants may ultimately be shown to represent alleles predisposing to PCa (283). Based on the above mentioned data, it seems likely that BRCA1 gene mutations may affect PCa risk, but the contribution of germline BRCA1 mutations to the overall incidence of PCa appears to be small and may be limited to specific subgroups of patients (283). Other groups have tried to identify specific PCa-susceptibility genes by linkage analysis. The high lifetime incidence of PCa in males, along with an estimated 91% of the cases being sporadic in etiology (284), results in a significant problem with phenocopies in familial clusters of PCa: individuals whose PCas result from very different causes (285). The late age of onset (,0.1% of PCa cases are diagnosed under the age of 40) leads to general lack of available samples from an affected individual’s ancestors (285). These obstacles are complicated by the absence of known clinical features (other than age of onset) that might allow subgrouping of PCa families to reflect potential genetic heterogeneity (22). Also, it is difficult to find families that contain large numbers of affected members (285). Despite the difficulties encountered with identifying PCa susceptibility loci, several groups have evaluated informative families for genetic alterations that increase the risk of PCa. Recently, these efforts have resulted in the identification of a potential susceptibility locus for PCa; ’hereditary prostate cancer-1’ (HPC1) (285). In this study, two-point analysis of 66 North American families found suggestive linkage with D1 s218 (LOD score 2.75), a microsatellite marker located on the long arm of chromosome 1 (1q24q25). Analysis of 25 additional Swedish families narrowed the region of linkage to an interval of ;15 centimorgans defined by markers D1 s2883 and D1 s422. An admixture test for homogeneity estimated that 34% of the families analyzed were linked to this interval (285). Gra`nberg et al. (286) subsequently demonstrated that the age at time of diagnosis significantly contributed to the results of linkage analysis. In this study, the proportion of families linked to HPC1 was 66% for the 14 families with the earliest average ages at diagnoses, but decreased to 7% for the families with the latest age at diagnosis. These findings have provided additional evidence of a locus on chromosome 1q24-q25 that predisposes men to develop early-onset PCa. In addition, an independent study by Eeles et al. (287) showed that the proportion of families linked to 1q24-q25 was 0% for those with 3 or fewer PCa cases, but was 20% for those with 4 or more PCa cases. Thus, HPC1 was shown to contribute more significantly to larger PCa clusters, and the majority of small clusters of 3 or fewer PCa cases were likely to be due to other gene(s), to chance, or to environmental factors. Given both the complex nature of this disease and the significance of identifying a hereditary PCa susceptibility locus, several other groups have attempted to verify these initial results. The data of Smith et al. (285) were confirmed by related studies (288, 289) based on different data sets and by two unrelated studies (287, 290). However, another two studies (291, 292) were not able to find evidence for linkage of PCa to 1q24-q25. Conflicting evidence regarding linkage to a chromosomal region is not unexpected in a common disease such as PCa and may be explained by several reasons.
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It may represent a false-positive or false-negative linkage result or sample differences in the presence of locus heterogeneity (291). In the presence of locus heterogeneity, it might be difficult to replicate a linkage that is correct but that represents an infrequent locus (291). Despite obvious similarities between the studies regarding average age at diagnosis and average number of living affected men genotyped per family (285, 291), some differences can be shown to exist. The data set of Smith et al. (285), for example, contained two African-American families that contributed approximately one-half of the LOD score for the North American pedigree studies. This group therefore suggested including additional African-American families to further explore the hypothesis that alterations in the 1q24-q25 region may increase risk of PCa in specific racial/ethnic populations (285). Another study (291) did not include African-American families because of higher PCa incidence and mortality rates in this group. In conclusion, it is anticipated that identification of PCa susceptibility genes will provide critical information regarding the genetic mechanisms not only for hereditary PCa but also for the more common sporadic disease. Such studies will greatly benefit from locating families with large clusters of cases with early-age onset of PCa. To date, the genes that might be associated with altered risk of PCa include the BRCA1 gene and the more recently identified HPC1 region of LOH at 1q24-q25. Because identification and evaluation of potential PCa susceptibility loci receive worldwide attention, it is likely that more definitive conclusions regarding the role of HPC1 in prostate carcinogenesis or other, yet to be discovered susceptibility loci, will be provided in the near future.
IV. Human Papillomavirus and Prostate Carcinoma
The mechanisms by which viruses may induce tumorigenesis include failure of the host immune response to viral infection or interactions between viral and host DNA resulting in genomic instability and accumulation of genetic alterations, which may then increase viral gene expression (293). Interaction of viral proteins with specific cellular proteins may also relate to the above mentioned events. For example, the E7 protein of human papillomavirus (HPV) types 16 and 18 binds the protein of the retinoblastoma gene, thereby blocking its normal function (294). Similarly, the HPV protein ubiquitin-ligase E6 is able to induce a rapid degradation of TP53 resulting in an inadequate response to DNA damage (293, 295). Using Southern blot analysis and PCR, McNicol and Dodd (296) revealed that 14 (52%) of 27 PCa specimens were either HPV-16 or HPV-18 positive. Ibrahim et al. (297) found HPV-16 in 6 (15%) of 40 PCa samples using PCR. In this study, the presence of HPV was confirmed by in situ hybridization in one specimen only. Anwar et al. (145) showed that 28 (41%) of 68 PCa specimens contained HPV DNA of types 16, 18, or 33, and Rotola et al. (298) found HPV types 6, 11, or 16 in 6 (75%) of 8 PCa samples. Three studies have found HPV DNA in a considerable number of BPH samples (48 of 95; 51%) (145, 296, 298). Similar rates of HPV positivity
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in benign and cancerous specimens may be due to a stimulatory effect on viral growth rates related to the higher rate of cell proliferation present in both of these conditions (299). In addition, high proliferation rates in BPH lesions may result from contamination with HPV-colonized prostatic urethral or anogenital mucosa (297). Detection of HPV could also be technique specific, in that a variation in the annealing temperatures for the PCR used to detect the virus genomes could lead to spuriously positive results (300, 301). In view of the above mentioned consideration, it is not surprising that the initial high prevalence of HPV in PCa (overall 54/143 PCa samples; 38%) contrasts with more recent negative results, some of which have taken precautions to avoid contamination. In the 8 studies reported after 1992, 330 PCa samples were analyzed, 58 (18%) of which contained HPV DNA (143, 228, 300, 302–306). Moreover, McNicol and Dodd (296) looked at transcription of HPV-16 E6/E7 protein in PCa samples from their previous study that were known to be HPV positive by PCR analysis (307). Evidence of transcription was found in only 3 of 7 PCa samples and in 5 of 10 BPH samples (307). Another observation that contradicts a relation between HPV and PCa is that HPV infection has been mostly associated with squamous carcinoma, whereas PCa is predominantly an adenocarcinoma. To date, two prostatic squamous cell carcinomas have been evaluated that did not reveal HPV DNA by PCR (25). Thus, despite the potential mechanisms of HPV-associated carcinogenesis, there seems to be no preferential association of oncogenic HPV types to malignant transformation of prostatic cells.
V. Morphological Diversity of Prostate Carcinoma
Morphologically, PCa is particularly intriguing regarding its propensity to display multiple tumors in the same prostate and the various histological growth patterns in a given carcinoma. For example, Ruijter et al. (308) found in a total of 61 prostatectomy specimens resected for clinically localized PCa 155 anatomically distinct foci of carcinoma (mean, 2.5 lesions per patient). Only 17 prostate specimens (28%) contained a single tumor, and as many as 42% of the prostates harbored three carcinoma lesions or more. These multiple PCa lesions represent either completely independent, genetically unrelated events or a ’field effect’ whereby a carcinogenic insult results in the independent transformation of a field of adjacent epithelial cells (309). Also, one malignant transforming event may have occurred and the progeny of a single cancer cell spread through the prostate, giving rise to topographically distinct but genetically related tumors. An alternative explanation is that a germline genetic alteration occurred that predisposes a given patient to the evolution of multiple cancer lesions in the same prostate. To date, there is no agreement as to which of these mechanisms are operative in human PCa. In addition to multifocality, PCa lesions often display various histological patterns of tumor growth (308, 310). PCas are graded according to the Gleason system, which considers the degree of glandular differentiation and growth pattern in relation to the prostatic stroma (310). Gleason (310) made a deliberate attempt to subdivide the two ends of the spectrum
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of histological malignancy, leading to five histological growth patterns. Ruijter et al. (308) found that 42% of 155 tumors were histologically composed of two or more histological growth patterns. Heterogeneity seems to be inherent to PCa; this can be inferred from other types of analysis, such as p53 gene mutation (222), DNA ploidy (311), E-cadherin expression (226), ras gene mutations (215), and detection of allelic imbalance (198). It is plausible that morphological heterogeneity is the result of tumor mulifocality. With the passage of time, the volume of carcinoma lesions will increase. This inevitably brings multifocal processes of varying grades closer together, finally culminating in the collision and fusion of lesions. Interestingly, individual lesions from prostates harboring multiple carcinomas were of relative low histological grade and displayed only minimal grade heterogeneity (308). However, the overall grade heterogeneity and histological grade of all tumors from a given case with multifocal disease was not different from prostates in which only a single tumor was present (308). This can be interpreted as indirect evidence that growth and fusion of tumor lesions relates to the evolution of grade heterogeneity. Similarly, by carefully determining the topographical distribution of grades within tumors, one might find examples of collision, but not fusion, of different growth patterns of carcinoma. However, once overgrowth of one component arising over another has occurred, the individual contributions of progression vs. multifocality are impossible to determine. Moreover, intratumoral heterogeneity may also occur as the result of a multitude of epigenetic aberrations including metabolic, enzymatic, and molecular perturbations that influence cell structure and function. These structural and functional alterations, combined with tumor cell-host tissue interactions, may induce an endless range of phenotypes. Thus, the precise mechanisms through which the various morphological grades arise are currently unknown and merit further study. One approach is a longitudinal analysis of the progression of prostate cancer by the use of sequential biopsies, but these cannot consider multicentricity. Alternatively, a DNA fingerprint from each of the tumor lesions or areas within a given carcinoma may ultimately reveal a genetic relationship, i.e., clonal or nonclonal origin of tumor multifocality and heterogeneity. Detailed information about the existence and extent of PCa multifocality and heterogeneity has not only influenced our thinking about the natural history of PCa, but has also revealed clinical consequences, such as biopsy sampling error. Needle biopsies are taken from the prostate by ultrasound or digital rectal guidance. Unfortunately, using either of these techniques, it is currently impossible to consistently identify regions of PCa that will adversely influence the patient’s prognosis. Consequently, six needle biopsies are taken in a random systematic fashion from ill-defined regions on the posterior surface of the prostate (312). This approach has been shown to significantly underestimate histological grade (308) as well as the aggressiveness of PCa based on the specific molecular changes (226). For example, an exact concordance between biopsy and prostatectomy grade was present in only 50% of the cases, and biopsy grade underestimated the prostatectomy grade in 40% of the cases (308). Of even more clinical
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importance, 23% of the poorly differentiated PCa present in prostatectomy specimens were missed by biopsy sampling. Also, the sensitivity of biopsies to provide samples of abnormal E-cadherin expression or accumulation of p53 protein from a given prostate with aberrant marker expression was 15% and 60%, respectively (226). This sampling error by biopsy is, at least in part, due to the multifocality and heterogeneity of PCa; i.e., sampling accuracy from the prostate depends not only on which tumor, but also which area in a given tumor is biopsied. Similar disappointing results are anticipated for other prognostic factors when applied to biopsy specimens. Moreover, all of the molecular biological data obtained from PCas should be interpreted in the context of the heterogeneity that is so characteristic for this type of cancer. VI. Concluding Remarks
This commentary has reviewed a series of genetic and phenotypic alterations that are potentially involved in prostate carcinogenesis. We have emphasized the familial and racial distribution data, because these might provide more detailed information on which of the factors play an important role in malignant transformation. Figure 7 summarizes the current state of knowledge regarding the multistep nature of prostate carcinogenesis. Using this information one might ultimately be able to construct a risk profile based on a combination of several genetic and phenotypic alterations.
FIG. 7. Summary of factors potentially involved in the subsequent stages of prostate carcinoma progression.
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With such a risk profile, it might be possible to discriminate men whose disease will remain clinically controlled from those who will develop life-threatening PCa. Moreover, one might ultimately be able to design therapeutic approaches other than empirically based. The exact place of all the new markers in the diagnostic armamentarium is not always completely clear and should be determined further in well controlled, prospective clinical evaluations, in which methods are standardized. However, we must concede that the diagnostic assessment of PCa and the prediction of its prognosis is limited by the inherent heterogeneity of the disease and the circumstances under which we study it.
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4th International Workshop on Resistance to Thyroid Hormone May 23–25, 1999 Reboucas Convention Center Sa˜o Paulo, BRAZIL For further information contact: Geraldo Medeiros-Neto, MD, FACP Thyroid Unit, Hospital das Clinicas Av Eneas C Aguiar 155-8A B1-3 05403-900 Sa˜o Paulo, BRAZIL Phone (55) (11) 212-5711 FAX (55) (11) 211-5194 email:
[email protected]
