Attenuated Familial Adenomatous Polyposis - Springer Link

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James M. Church, M.D., Editor

Attenuated Familial Adenomatous Polyposis An Evolving and Poorly Understood Entity Gerald S. Hernegger, M.D., Harvey G. Moore, M.D., Jose G. Guillem, M.D., M.P.H. From the Colorectal Service, Department of Surgery, Memorial-Sloan Kettering Cancer Center, New York, New York rectal cancer, increased awareness of attenuated familial adenomatous polyposis should improve diagnosis, surveillance, and treatment strategies in this unique subset of familial polyposis syndromes. [Key words: AFAP; FAP; Familial adenomatous polyposis; Attenuated familial adenomatous polyposis; Colorectal neoplasms]

PURPOSE: Familial adenomatous polyposis is a well-described, autosomal dominant, inherited syndrome characterized by diffuse polyposis of the colon and rectum as well as various upper gastrointestinal and extraintestinal manifestations. A subset of patients present with fewer colorectal polyps, later age of onset of polyps and cancer, and a predilection toward involvement of the proximal colon. This variant of familial adenomatous polyposis is known as attenuated familial adenomatous polyposis. The purpose of this review is to summarize current knowledge regarding this poorly understood entity and propose guidelines for diagnosis, surveillance, and surgical management. METHODS: The MEDLINE database was searched from 1985 onward using the keywords, “attenuated familial adenomatous polyposis,” “AFAP,” “adenomatous polyposis coli gene,” and “APC gene.” Additional articles were identified through the reference sections of retrieved papers. All papers that pertained to attenuated familial adenomatous polyposis or mutations in the APC gene producing an attenuated phenotype were included. RESULTS: Attenuated familial adenomatous polyposis is transmitted in an autosomal dominant fashion. Several distinct mutations within the APC gene have been associated with an attenuated phenotype, but variability of disease expression within kindreds possessing identical mutations makes classification difficult. Polyps are diagnosed at a mean age of 44 years, with cancer diagnosed at a mean of 56 years of age. Frequent involvement of the proximal colon necessitates the use of colonoscopy for surveillance, and infrequent involvement of the rectum supports the role of a total abdominal colectomy and ileorectal anastomosis. CONCLUSIONS: Although currently recognized as a distinct clinical entity, attenuated familial adenomatous polyposis may be part of a spectrum of disease that includes familial adenomatous polyposis and is caused by different mutations within the APC gene. Because of its unique characteristics, yet apparent overlap with familial adenomatous polyposis and hereditary nonpolyposis colo-

Hernegger GS, Moore HG, Guillem JG. Attenuated familial adenomatous polyposis: an evolving and poorly understood entity. Dis Colon Rectum 2002;45:127–136.

F

amilial adenomatous polyposis (FAP) is a welldescribed, autosomal dominant, inherited syndrome with a near-100 percent penetrance. Although the phenotypic hallmark of FAP has traditionally been described as greater than 100 colorectal polyps, a subset of patients presents with fewer colorectal polyps, later age of onset of both polyps and colorectal cancer, and a more proximal colonic distribution than in classic FAP (Table 1). This variant of FAP is referred to as attenuated familial adenomatous polyposis (AFAP). The natural history and, therefore management, of these two variations in presentation differs. In this review we present the history, genetic background, clinical features, and current management guidelines of this poorly understood and evolving entity.

EVOLUTION OF A SYNDROME In 1985 Muto et al.1 coined the term “flat adenoma” to describe a slightly elevated mucosal lesion, less than twice the thickness of the surrounding normal mucosa, with a reddish surface and a central umbilication. These flat lesions were generally less than 1 cm in size. Histologically, adenomatous tubules were noted to spread laterally between normal crypts near the luminal surface, resulting in flat, rather than pol-

Presented in part at the meeting of the Collaborative Group of the Americas for Inherited Colorectal Cancer, Philadelphia, Pennsylvania, October 3 to 4, 2000. Supported in part by the Grace J. Fippinger Foundation and the William Bianco Trust. Address reprint requests to Dr. Guillem: 1275 York Avenue, Room C-986, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.

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Table 1. Features of Attenuated Familial Adenomatous Polyposis Less than 100 colorectal polyps Proximal distribution of polyps and cancers Late age-of-onset (polyps at 44; CRC at 56 years) Autosomal dominant inheritance Associated with an APC Mutation Associated with ECM CRC ⫽ colorectal cancer; ECM ⫽ extracolonic manifestation.

ypoid growth. Also emphasized was a higher incidence of high-grade dysplasia in these flat lesions than in typical polypoid adenomas. Henry Lynch et al.2 later described a family with hereditary nonpolyposis colorectal cancer (HNPCC) with flat adenomas (range, 2–70 polyps) and a rightsided predominance of polyps. Also noted was a later age of onset of colorectal cancer than is typical of patients with HNPCC. Lynch suspected that this presentation likely represented a variant of HNPCC, or possibly a new, distinct syndrome. The demonstration of autosomal dominant transmission of flat adenomas in two colorectal cancerprone families led Lynch et al. to propose the term “hereditary flat adenoma syndrome.” Patients from these families had fewer polyps than seen in FAP, but more polyps than generally found in patients with HNPCC.3 Numerous investigations followed to determine the genetic basis of the syndrome. In a large kindred phenotypically consistent with the hereditary flat adenoma syndrome, linkage analysis was used to map the responsible mutation to the long arm of chromosome 5, near the APC gene locus.4 Subsequently, four different germline mutations were identified at the APC locus in kindreds with a diagnosis consistent with AFAP.5,6 In 1995 Lynch et al. concluded that AFAP represented a phenotypically distinct variant of classic FAP and was transmitted in an autosomal dominant fashion.7

THE APC GENE: GENOTYPIC AND PHENOTYPIC CORRELATIONS The APC gene is located on Chromosome 5q21, consisting of 15 exons, and includes 2843 codons. The APC gene functions as a tumor suppressor gene and encodes for a 300 kDa protein.7 The APC protein product associates with ␤-catenin and thereby prevents its interaction with T-cell-factor/Lymphoid enhancer factor (Tcf/Lef). With an abnormal APC protein product, the binding to ␤-catenin does not occur,

Dis Colon Rectum, January 2002

leaving Tcf/Lef free to associate with ␤-catenin, forming a DNA-sequence-specific transcription complex in target cells that produces proliferative effects through the transcription of specific cell cycle stimulating sequences.8,9 This proliferative response may represent the first step toward tumorigenesis. Identification and characterization of the APC gene set the stage for genotype-phenotype correlative studies.10–14 To date, at least 34 distinct mutations have been identified within the APC gene locus in individuals manifesting the AFAP phenotype (Table 2). Several mutations are located at the 5' end of the gene within exons 3 and 4. These 5' mutations are clustered within ten codons of the mutations associated with classic FAP.15–20 Mutations producing an AFAP phenotype have also been identified in exon 6,19,21 exon 9,7,20,22–26 and intron 9.27 In addition, several mutations causing AFAP have been identified at the 3' end of the gene.16,20,28–36 A full deletion of the entire APC gene region has also been associated with AFAP.37 As in classic FAP, APC mutations in AFAP tend to be single base pair changes or frameshift mutations that result in premature stop codons and thus truncated proteins. Depending on the specific location of AFAP mutations, varying phenotypic expression has been noted. Mutations at the 3' end of the APC gene and within exon 9 are associated with fewer adenomas, whereas those at the 5' end result in a more variable number of colorectal adenomas and more severe upper gastrointestinal manifestations.20 The basis for the broad genotype-phenotype variability within AFAP may be related to interactions with nonhereditary or environmental factors as well as mutations in nearby genes linked to the APC gene. Alternatively, mutations in other genes not linked to the APC gene or in the wild-type allele may play a role.5 More recent evidence suggests that the nature of the somatic “second hit” predicted by the Knudson two-hit hypothesis is dependent on the inherited germline mutation. Certain combinations of mutations confer different “selective advantages” and result in phenotypic variability. This interdependence between germline and somatic mutations has been demonstrated in both FAP-related38 and sporadic colorectal cancers.39 It has become increasingly clear that the phenotypic range of specific APC mutations forms a continuum of clinical manifestations and that divisions between classic and attenuated forms of FAP may be arbitrary (Fig. 1).

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Table 2. Mutations of the APC Gene Associated with an Attenuated Polyposis Phenotype No.

Exon

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

3 3 Intron 3 4 4 4 4 4 4 4 4 4 4 6 6 9

17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

Mutation

Effect

Codon

Sub G to A Sub T to A Trans C to T Del 551 Sub C to T Sub T to C Trans C to T

Stop Stop Stop Stop Stop Stop Stop Stop Stop Stop Splicing out Ex 3 Stop Stop Stop Stop Stop

137 140 146 149 151 156 157 169 163 184 232 233 332

9 9 9

Del 988 Ins A Del 2 A

Stop at nucleotide 1014 Stop Stop

364 367

9 9 Intron 9 15 15 15 15 15 15 15 15 15 15 15 Entire allele

Del 2 A Del AT Sub G to T Del 2 A Del C Del 4 bp Ins 2 bp Del 4 bp Del 4 bp Del A Del A Del C Del TCTA Del 4 bp

Stop Stop Stop at nucl 1358 Stop Stop Stop Stop Frameshift Truncated peptide Stop Stop Stop at nucleotide 6218 Stop Stop

Trans C to T Sub G to A

Del AT Del C

CLINICAL PRESENTATION Colorectal Pathologic Features. The majority of patients present with less than 100 (generally between 1 and 50) adenomas, primarily located proximal to the splenic flexure and often morphologically flat. Review of the reports summarized in Table 2 indicates that polyps are diagnosed at a mean age of 44 years, and cancers at a mean of 56 years. Thus, diagnosis of polyps and cancers in AFAP is generally 10 to 15 years later than in FAP. However, because these data are based on when these lesions are detected and not necessarily when they arise the true age of development of polyps and cancers in AFAP is unclear. Certainly, lack of recognition of AFAP by patients and physicians results in fewer patients presenting for

93 99

398 436 1062 1597 1862 1924 1962 1979 1987 2044 2047 2643 2662

References Giardiello et al.15 (1997) Dobbie et al.16 (1996) Spirio et al.17 (1999) Giardiello et al.15 (1997) Spirio et al.18 (1993) Giardiello et al.15 (1997) Dobbie et al.19 (1994) Giardiello et al.15 (1997) Spirio et al.18 (1993) Dobbie et al.19 (1994) Soravia et al.20 (1998) Dobbie et al.19 (1994) Smith-Raven et al.21 (1994) Soravia et al.20 (1998) Su et al.22 (2000) Soravia et al.20 (1998) van der Luijt et al.23 (1995) Curia et al.24 (1998) Ficari et al.25 (2000) Young et al.26 (1998) Lynch et al.7 (1995) Varesco et al.27 (1994) Scarano et al.28 (1999) Friedl et al.29 (1996) van der Luijt et al.30 (1996) Eccles et al.31 (1996) Scott et al.32 (1996) Brensinger et al.33 (1998) Dobbie et al.16 (1996) Scott et al.34 (1995) Soravia et al.20 (1998) Couture et al.35 (2000) Matsubara et al.36 (2000) Pilarski et al.37 (1999)

voluntary surveillance, perhaps contributing to a delay in diagnosis in these patients. A striking feature of AFAP is the variability in number of polyps within members of the same kindred. Some affected members have few polyps, while other have several hundred.17,20,29,33 This variability presents difficulties in classifying a kindred as AFAP or FAP. Similar to FAP, colorectal cancers in patients with AFAP are generally accompanied by synchronous adenomas.7 Extracolonic Manifestations. Several extracolonic manifestations typically noted in FAP have also been noted in patients with AFAP. These include upper gastrointestinal lesions such as duodenal or gastric adenomas, periampullary tumors, and gastric fundic

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Figure 1. Genotype/phenotype correlation of the APC gene. FAP ⫽ familial adenomatous polyposis; CHRPE ⫽ congenital hypertrophic retinal pigment epithelium.

gland polyps.6 Fundic gland polyps are nearly always associated with AFAP and may precede the development of colorectal adenomas.6 In rare cases, dysplastic changes and adenocarcinoma of the stomach have been reported to arise from fundic gland polyps in patients with AFAP.40,41 Other associated malignancies have included gastric adenocarcinoma, breast cancer, and hepatoblastoma.3,7 Although commonly noted in FAP, congenital hypertrophic retinal pigment epithelium, osteomas, and desmoids have rarely been reported in patients with AFAP. When noted, they are primarily in patients with mutations at the 3' end of the APC gene.32,33

DIAGNOSIS The diagnosis of AFAP is more difficult than that for classic FAP because of the wide variability of phenotypic expression and overall lack of awareness of this syndrome.42 In addition, screening with flexible sigmoidoscopy, the recommended modality for classic FAP, is inadequate, because the majority of colonic lesions in patients with AFAP are right-sided. Presence of extracolonic manifestations associated with AFAP and FAP, such as upper gastrointestinal or periampullary adenomas and cancers, should spark consideration of these diagnoses. The finding of fundic

gland polyps on upper endoscopy in any patient with a personal or family history of colorectal cancer should prompt a more detailed family history, pedigree determination, and consideration of genetic testing.7 In these patients, evaluation of the lower gastrointestinal tract should be initially performed with colonoscopy. Finally, in patients presenting with newly diagnosed colorectal polyps and cancers and a suggestive family history, detailed pedigrees should be generated and the diagnosis of AFAP should be considered. Genetic testing may be offered if clinically indicated. For asymptomatic at-risk individuals belonging to known FAP or AFAP kindreds, genetic testing should ideally be performed between the ages of 10 and 15 years to determine the presence or absence of an APC mutation. If APC status has not been established in the kindred, an affected family member should be tested first to establish the presence of a germline APC mutation and assure that the test will be informative in the asymptomatic at-risk family members. Currently, genetic testing may be performed with the protein truncation test (PTT), which assays for the presence of foreshortened proteins generated by an in-vitro synthesized protein assay.43 The PTT identifies a mutation in approximately 80 percent of FAP

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kindreds. Certain types of mutations, such as missense mutations, may be missed by the assay. In addition, mutations at the 5' and 3' extremes of the APC gene, where AFAP mutations often exist, are sometimes missed. In at-risk patients belonging to a kindred in which a mutation has been previously identified, the PTT will be informative and a negative PTT is nearly 100 percent accurate. In individuals with a negative test but for whom a high index of suspicion of AFAP exists, direct DNA sequencing of the exons most often involved in AFAP may be performed on an individual basis. Another option is single-stranded conformation analysis.44 However, in patients from kindreds without a known mutation, the PTT will be uninformative, and a negative test reported as “no mutation detected” may be misinterpreted, leading to a false-negative result.45,46 Patients possessing mutations associated with AFAP or belonging to FAP families with a variable number of adenomas with right-sided predominance should have an initial screening with complete colonoscopy. Some difficulty may arise in classifica-

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tion even with full colonoscopy because of inability to appreciate minute polyps that, if recognized, would satisfy the criteria of classic FAP. This error may be minimized by use of the dye-spray technique.47 All definitions and recommendations in the present article, however, are based on results of natural endoscopy.

MANAGEMENT Surveillance Strategy. Clinical surveillance in patients with AFAP can be based on the results of genetic testing (Fig. 2). For individuals who test positive for a mutation associated with AFAP, we recommend a baseline colonoscopy and esophagoduodenoscopy (EGD) at the time of genetic testing or by the age of 15 years. The importance of early endoscopy relates to the phenotypic variability seen within kindreds possessing identical mutations and the potential consequences of missing an early age-of-onset polyposis phenotype such as classic FAP. Endoscopic findings consistent with classic FAP should be managed ac-

Figure 2. Management of attenuated familial adenomatous polyposis (AFAP) based on results of genetic testing. FAP ⫽ familial adenomatous polyposis; EGD ⫽ esophagoduodenoscopy; HNPCC ⫽ hereditary nonpolyposis colorectal cancer.

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cording to currently available guidelines. Patients with an APC mutation but negative endoscopic examinations can undergo repeat colonoscopy and EGD at age 20 and then annually thereafter. Patients who have colonoscopic findings consistent with AFAP may undergo polypectomy when feasible, followed by continued yearly surveillance. Patients with adenomas too numerous to clear endoscopically, or for whom endoscopic surveillance is not technically possible, should be considered for surgical management as outlined below. For patients with uninformative test results, the same recommendations apply, except that subsequent colonoscopy and EGD may be performed at two-year intervals. The risk of developing disease in these patients is unknown and varies between zero and approximately 80 to 90 percent. Because of similarities between the presentation of HNPCC and AFAP, the diagnosis of HNPCC should be considered in patients with a suggestive family history and no previously demonstrable mutation of the APC gene. Testing for microsatellite instability and mismatch repair (MMR) gene mutations may therefore be undertaken if clinically indicated. Likewise, patients suspected of HNPCC with microsatellite instabilitynegative tumors should be considered for APC testing. In patients with true-negative APC test results (a mutation has been demonstrated in an affected member but not in an at-risk member), a colonoscopy should be performed at the time of genetic testing or by the age of 15. Although the PTT is nearly 100 percent accurate in this setting, endoscopic evaluation serves as confirmation of a negative test. Because polyps occur later in AFAP individuals than in classic FAP, a second colonoscopy at age 20 should be considered to detect late-appearing polyps. If both examinations are negative, no further surveillance is necessary, and the patient may undergo future colorectal cancer screening as an average-risk individual. Findings consistent with AFAP or FAP should be managed as above. Colorectal Surgical Management. Patients with AFAP are at increased risk for the development of colorectal cancer, although the exact risk remains unknown at this time. However, it seems from what we currently know that patients with AFAP do not have the near certainty of developing colorectal cancer that classic patients with FAP have. Thus, the indications for prophylactic colectomy differ between these two entities. In patients with few adenomas,


colonoscopic polypectomy is sufficient to clear the affected bowel segments. The ten-year gap between the diagnosis of polyps and cancer, similar to classic FAP, suggests that the adenoma-carcinoma sequence is not accelerated in these individuals, and thus surveillance every one to two years should not impose any undue risk to the patient. When multiple polyps are clustered within a single segment of the colon, especially the cecum, resection may be the safest option.48 When resection is required, a total abdominal colectomy can be performed with an ileorectal anastomosis. Because the rectal segment is generally uninvolved in these patients, total proctocolectomy with ileal pouch-anal anastomosis does not seem to be required. The rectal segment does need continued surveillance, however, because this mucosa is still at risk.7,42 Total abdominal colectomy with ileorectal anastomosis may also be required in patients who are difficult to examine fully by colonoscopy and thus unable to undergo proper surveillance. Recent evidence suggests that certain nonsteroidal anti-inflammatory medications may play a role in management of polyposis in these patients. Both sulindac and celecoxib have been shown to reduce polyp burden in patients with FAP.49,50 However, it is important to realize that suppression of colonic polyps does not eliminate malignant potential, because colorectal cancers have developed in patients with FAP receiving sulindac.51,52 Management of Upper Gastrointestinal Manifestations. Patients with AFAP develop duodenal adenomas and periampullary carcinomas like their classic FAP counterparts. Management of these manifestations should therefore not differ from that described for FAP.53

FUTURE DIRECTIONS AFAP is now recognized as a distinct clinical entity. However, whether such a distinction is warranted remains to be answered, because AFAP may well turn out to be part of a larger entity based on APC alterations. More accurate information is required in regard to the true risk of colorectal cancer development in these individuals, to stratify risk and identify patients who require prophylactic colectomy. It is anticipated that large cooperative genotypic-phenotypic correlative studies based on precise mutational analysis and accurate long-term follow-up will shed light on this evolving entity.

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REFERENCES 1. Muto T, Kamiya J, Sawada T, et al. Small “flat adenoma” of the large bowel with special reference to its clinicopathologic features. Dis Colon Rectum 1985;28:847–51. 2. Lynch HT, Smyrk T, Lanspa SJ, et al. Flat adenomas in a colon cancer-prone kindred. J Natl Cancer Inst 1988;80: 278 – 82. 3. Lynch HT, Smyrk TC, Lanspa SJ, et al. Phenotypic variation in colorectal adenoma/cancer expression in two families. Hereditary flat adenoma syndrome. Cancer 1990;66:909 –15. 4. Leppert M, Burt R, Hughes JP, et al. Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med 1990;322:904 – 8. 5. Spirio L, Otterud B, Stauffer D, et al. Linkage of a variant or attenuated form of adenomatous polyposis coli to the adenomatous polyposis coli (APC) locus. Am J Hum Genet 1992;51:92–100. 6. Lynch HT, Smyrk TC, Lanspa SJ, et al. Upper gastrointestinal manifestations in families with hereditary flat adenoma syndrome. Cancer 1993;71:2709 –14. 7. Lynch HT, Smyrk T, McGinn T, et al. Attenuated familial adenomatous polyposis (AFAP). A phenotypically and genotypically distinctive variant of FAP. Cancer 1995; 76:2427–33. 8. Shih IM, Yu J, He TC, Vogelstein B, Kinzler KW. The beta-catenin binding domain of adenomatous polyposis coli is sufficient for tumor suppression. Cancer Res 2000;60:1671– 6. 9. Rubinfeld B, Souza B, Albert I, et al. Association of the APC gene product with beta-catenin. Science 1993;262: 1731– 4. 10. Church JM. Anatomy of a gene: functional correlations of APC mutation. Semin Colon Rectal Surg 1998;9: 49 –52. 11. Bodmer WF, Bailey CJ, Bodmer J, et al. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 1987;328:614 – 6. 12. Groden J, Thliveris A, Samowitz W, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991;66:589 – 600. 13. Kinzler KW, Nilbert MC, Su LK, et al. Identification of FAP locus genes from chromosome 5q21. Science 1991; 253:661–5. 14. Joslyn G, Carlson M, Thliveris A, et al. Identification of deletion mutations and three new genes at the familial polyposis locus. Cell 1991;66:601–13. 15. Giardiello FM, Brensinger JD, Luce MC, et al. Phenotypic expression of disease in families that have mutations in the 5' region of the adenomatous polyposis coli gene. Ann Intern Med 1997;126:514 –9. 16. Dobbie Z, Spycher M, Mary JL, et al. Correlation between the development of extracolonic manifestations

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

133

in FAP patients and mutations beyond codon 1403 in the APC gene. J Med Genet 1996;33:274 – 80. Spirio L, Green J, Robertson J, et al. The identical 5' splice-site acceptor mutation in five attenuated APC families from Newfoundland demonstrates a founder effect. Hum Genet 1999;105:388 –98. Spirio L, Olschwang S, Groden J, et al. Alleles of the APC gene: an attenuated form of familial polyposis. Cell 1993;75:951–7. Dobbie Z, Spycher M, Hurliman R, et al. Mutational analysis of the first 14 exons of the adenomatous polyposis coli (APC) gene. Eur J Cancer 1994;11:1709 –13. Soravia C, Berk T, Madlensky L, et al. Genotypephenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 1998;62:1290 –301. Smith-Ravin J, Pack K, Hodgson S, Tay SK, Phillips R, Bodmer W. APC mutation associated with late onset of familial adenomatous polyposis. J Med Genet 1994;31: 888 –90. Su L-K, Barnes CJ, Yao W, Yi Q, Lynch PM, Steinbach G. Inactivation of germline mutant APC alleles by attenuated somatic mutations: a molecular genetic mechanism for attenuated familial adenomatous polyposis. Am J Hum Genet 2000;67:582–90. van der Luijt RB, Vasen HF, Tops CM, Breukel C, Fodde R, Meera Khan P. APC mutation in the alternatively spliced region of exon 9 associated with late onset familial adenomatous polyposis. Hum Genet 1995;96: 705–10. Curia MC, Esposito DL, Aceto G, et al. Transcript dosage effect in familial adenomatous polyposis: model offered by two kindreds with exon 9 APC gene mutations. Hum Mutat 1998;11:197–201. Ficari F, Cama A, Valanzano R, et al. APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis. Br J Cancer 2000;82:348 –53. Young J, Simms LA, Tarish J, et al. A family with attenuated familial adenomatous polyposis due to a mutation in the alternatively spliced region of APC exon 9. Hum Mutat 1998;11:450 –5. Varesco L, Gismondi V, Presciuttini S, et al. Mutation in a splice-donor site of the APC gene in a family with polyposis and late age of colonic cancer death. Hum Genet 1994;93:281– 6. Scarano MI, De Rosa M, Panariello L, et al. Familial adenomatous polyposis coli: five novel mutations in exon 15 of the adenomatous polyposis coli (APC) gene in Italian patients. Mutations in brief no. 225. Online. Hum Mutat 1999;13:256 –7. Friedl W, Meuschel S, Caspari R, et al. Attenuated familial adenomatous polyposis due to a mutation in the 3' part of the APC gene. A clue for understanding the function of the APC protein. Hum Genet 1996;97: 579 – 84. van der Luijt RB, Meera Khan P, Vasen HF, et al. Germ-

134

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

HERNEGGER ET AL line mutations in the 3' part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli. Hum Genet 1996;98:727–34. Eccles DM, van der Luijt R, Breukel C, et al. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet 1996;59: 1193–201. Scott RJ, Froggatt NJ, Trembath RC, Evans DG, Hodgson SV, Maher ER. Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3' APC gene mutation. Hum Mol Genet 1996;5:1921– 4. Brensinger JD, Laken SJ, Luce MC, et al. Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene. Gut 1998;43:548 –52. Scott RJ, van der Luijt R, Spycher M, et al. Novel germline APC gene mutation in a large familial adenomatous polyposis kindred displaying variable phenotypes. Gut 1995;36:731– 6. Couture J, Mitri A, Lagace R, et al. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet 2000;57:205–12. Matsubara N, Isozaki H, Tanaka N. The farthest 3' distal end APC mutation identified in attenuated adenomatous polyposis coli with extracolonic manifestations. Dis Colon Rectum 2000;43:720 –1. Pilarski RT, Brothman AR, Benn P, Shulman Rosengren S. Attenuated familial adenomatous polyposis in a man with an interstitial deletion of chromosome arm 5q. Am J Med Genet 1999;86:321– 4. Lamlum H, Ilyas M, Rowan A, et al. The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson’s ‘two-hit’ hypothesis. Nat Med 1999; 5:1071–5. Rowan AJ, Lamlum H, Ilyas M, et al. APC mutations in sporadic colorectal tumors: a mutational “hotspot” and interdependence of the “two hits.” Proc Natl Acad Sci U S A 2000;97:3352–7. Zwick A, Munir M, Ryan CK, et al. Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli. Gastroenterology 1997;113:659 – 63. Hofgartner WT, Thorp M, Ramus MW, et al. Gastric adenocarcinoma associated with fundic gland polyps in a patient with attenuated familial adenomatous polyposis. Am J Gastroenterol 1999;94:2275– 81. Lynch HT, Smyrk TC. Classification of familial adenomatous polyposis: a diagnostic nightmare [editorial]. Am J Hum Genet 1998;62:1288 –9. Powell SM, Petersen GM, Krush AJ, et al. Molecular diagnosis of familial adenomatous polyposis. N Engl J Med 1993;329:1982–7.


44. Rabelo R, Foulkes W, Gordon PH, et al. Role of molecular diagnostic testing in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer families. Dis Colon Rectum 2001;44:437– 46. 45. Giardiello FM, Brensinger JD, Petersen GM, et al. The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. N Engl J Med 1997; 336:823–7. 46. Frazier ML, Su LK, Amos CI, Lynch PM. Current applications of genetic technology in predisposition testing and microsatellite instability assays. J Clin Oncol 2000; 18:70S-4S. 47. Wallace MH, Frayling IM, Clark SK, Neale K, Phillips RK. Attenuated adenomatous polyposis coli: the role of ascertainment bias through failure to dye-spray at colonoscopy. Dis Colon Rectum 1999;42:1078 – 80. 48. Lynch HT, Watson P. AFAP: variety is the spice of life. Gut 1998;43:451–2. 49. Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000;342:1946 –52. 50. Giardiello FM, Hamilton SR, Krush AJ, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993;328: 1313– 6. 51. Lynch HT, Thorson AG, Smyrk T. Rectal cancer after prolonged sulindac chemoprevention. A case report. Cancer 1995;75:936 – 8. 52. Niv Y, Fraser GM. Adenocarcinoma in the rectal segment in familial polyposis coli is not prevented by sulindac therapy. Gastroenterology 1994;107:854 –7. 53. Guillem JG, Smith AJ, Calle JP, Ruo L. Gastrointestinal polyposis syndromes. Curr Probl Surg 1999;36: 217–323.

Invited Commentary To the Editor—Doctors Hernegger, Moore, and Guillem have provided us with an excellent overview of a difficult but important syndrome. They have highlighted the difficulties it presents in definition, diagnosis, and management, but some of their statements deserve further comment. In their conclusion the authors refer to attenuated familial adenomatous polyposis (AFAP) as a “distinct clinical entity.” This is hardly the case. It is not distinct genetically because a large number of different APC mutations can be expressed as AFAP. It is not distinct clinically because patients with less than 100 adenomas may have familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), or multiple sporadic adenomas. It is not even distinct in a familial sense, because members of a FAP family may vary widely in the severity of their polyposis. The

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definition of AFAP, multiple but less than 100 synchronous colorectal adenomas, is an arbitrary one that suffers from its imposition of a finite number on a disease with a spectrum of subtle variations. Suggestions for the use of dye spray colonoscopy threaten to take even this definition away.1 Perhaps we should not get too hung up on AFAP as a syndrome, but rather realize that some patients with FAP have a mild expression of the colonic polyposis. Certainly this mild form of the colonic disease is most common with mutations at either end of the gene, and in many cases the polyps are predominantly right sided. However, the underlying disease remains FAP. The authors have pointed out how the unique features of AFAP influence diagnosis and management. Patients present relatively late, genetic testing may be less informative and more complex, and screening should be with colonoscopy rather than sigmoidoscopy. These are important points. The potential confusion of AFAP with HNPCC and sporadic adenomas deserves to be underlined. We do not know how many sporadic adenomas can occur at once, how many make AFAP, and how often a germline mismatch repair gene mutation is manifest by multiple polyps. The presence of extracolonic manifestations of FAP is an important clue to the correct diagnosis, whereas analysis of adenomas for microsatellite instability will help exclude HNPCC. Dye spray colonoscopy has a role here in revealing the tiny adenomas that confirm the diagnosis of FAP. The recommendation that relatives shown definitively not to have a germline APC mutation be examined by colonoscope at 15 and 20 years of age is debatable and something not usually recommended for “standard” FAP where the stakes are higher but the clinical presentation more obvious. It implies that the protein truncation test is not to be trusted. If this is the case, why stop colonoscopy at age 20 in a syndrome where polyps occur late? More data are needed on the incidence of false-negative genetic testing and the pattern of clinical presentation in patients with AFAP. At present we are happy to tell relatives who test negative when their affected relatives test positive that they do not have FAP and can be excluded from surveillance. Management of patients with AFAP is complex because nonsurgical options are available and because the syndrome includes patients with two forms of the disease. Patients with mutations at the 5' end of APC are at minimal risk for desmoid disease, whereas patients with mutations in exon 15 are at high risk.

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This risk of desmoids, often manifest in other relatives who have had an operation, may encourage deferment of surgery. The alternative to colectomy, endoscopic polypectomy with or without chemoprevention, is risky, especially when the patient has been shown to carry a germline APC mutation. Colonoscopic surveillance does not prevent cancer in all patients with HNPCC2 and must be reserved for truly compliant patients who realize the risks. Attenuated familial adenomatous polyposis is the name given to the clinical situation of patients with FAP who have more adenomas than occur in the general population but fewer than are usually found with most germline APC mutations. Hernegger, Moore, and Guillem have done us a service by bringing this variant to our attention and by focusing our attention on its more controversial aspects.

REFERENCES 1. Wallace MH, Frayling IM, Clark SK, Neale K, Phillips RK. Attenuated adenomatous polyposis coli: the role of ascertainment bias through failure to dye-spray at colonoscopy. Dis Colon Rectum 1999;42:1078 – 80. 2. Jarvinen HJ, Aarnio M, Mustonen H, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000;118:829 –34.

James Church, M.D. Cleveland, Ohio

The Authors Reply To the Editor—We appreciate Dr. Church’s kind remarks regarding our review of attenuated familial adenomatous polyposis (AFAP). Like Dr. Church, we also believe that familial adenomatous polyposis represents a spectrum of disease presentation that includes AFAP and may be based, in part, on unique mutations of the APC gene. This is evident when one notes the variability in numbers of colorectal polyps found in affected members of kindreds with the same APC mutations. However, we believe that although the definition of AFAP may be based on an arbitrary number of colorectal polyps, certain clinical features of AFAP warrant attention, because they form the basis for modifications in treatment strategies designed for “classic” FAP. Dr. Church has called into question two of our recommendations and we welcome the opportunity to address them. First, Dr. Church feels that endoscopic management of patients with AFAP is a “risky”

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strategy. As pointed out by Lynch and Watson,1 colonoscopic polypectomy may be a valuable alternative to colectomy in selected patients with AFAP, whereas this would not be a consideration for a patient with FAP with greater than 100 polyps. The apparent ten-year interval between the development of polyps and invasive cancer in AFAP reassures us that even in the presence of an APC mutation, careful patient selection and colonoscopic clearance of the colorectal mucosa every one to two years should not place the patient at increased risk for the development of colorectal cancer. Second, Dr. Church believes that our recommendations for patients with true-negative protein truncation test (PTT) results may be overly aggressive and perhaps unnecessary. However, we are not alone in our cautious approach, because others also routinely perform confirmatory endoscopy, even in the presence of true-negative PTT results.2,3 In fact, at certain institutions, flexible sigmoidoscopy is recommended at age 18, 25, and 35 years in individuals belonging to FAP families, yet having a negative PTT result. In patients belonging to AFAP families, this strategy necessitates colonoscopy rather than flexible sigmoidoscopy because of the concern of proximal disease in the absence of distal pathology. Because of the variability in disease manifestation within kindreds possessing identical mutations, at-risk patients from “AFAP families” may or may not develop the attenu-


ated polyposis phenotype seen in other family members. Thus, we recommend colonoscopy at the time of genetic testing or by age 15, to identify an early, aggressive polyposis more typical of classic FAP. Because the incidence of polyps begins to rise by age ten in patients with FAP and polyps seem to develop on average ten years later in AFAP, we have chosen to repeat colonoscopy at age 20 to detect these laterappearing polyps. Perhaps experience will determine whether a repeat colonoscopy is indicated at a later age or not at all. We anticipate that large-scale genotype/phenotype correlative studies as well as epidemiologic studies examining environmental-genetic interactions will shed light on what continues to be a poorly understood variant of FAP.

REFERENCES 1. Lynch HT, Watson P. AFAP: variety is the spice of life [letter]. Gut 1998;43:451–2. 2. King JE, Dozois RR, Lindor NM, Ahlquist DA. Care of patients and their families with familial adenomatous polyposis. Mayo Clin Proc 2000;75:57– 67. 3. Lynch HT, Lynch JF. Genetics of colonic cancer. Digestion 1998;59:481–92.

Jose G. Guillem, M.D., M.P.H. Gerald S. Hernegger, M.D. Harvey G. Moore, M.D. New York, New York