Value of combined phenotypic markers in identifying inheritance of familial adenomatous polyposis.

Familial adenomatous polyposis is an autosomal dominant disease characterised by the development of hundreds of colorectal adenomas in young adults. Occult radio-opaque jaw lesions and pigmented ocular fundus lesions (formerly called congenital hypertrophy of the retinal pigment epithelium) are extraintestinal phenotypic markers for this disorder. We evaluated the usefulness of the combination of these markers for identifying patients who have inherited familial adenomatous polyposis. Forty three affected patients and 12 unaffected first degree relatives from 24 families with familial adenomatous polyposis, including four families without extraintestinal manifestations, were examined for both phenotypic markers. Thirty three of the 43 patients (77%) with familial adenomatous polyposis were positive for both markers, including patients from two families without extraintestinal manifestations. By contrast, only one of 12 (8%) unaffected first degree relatives over 35 years of age had both markers. The sensitivity of the combination of these markers in identifying patients who inherited familial adenomatous polyposis was 77%, the specificity 92%, the predictive value of a positive test 97%, the predictive value of a negative test 52%, and the efficacy 80%. The combined markers had improved efficacy over either marker alone (70% for occult radio-opaque jaw lesions and 67% for pigmented ocular fundus lesions). We conclude that the presence of both occult radio-opaque jaw lesions and pigmented ocular fundus lesions in a person at risk indicates a high probability of inheritance and expression of familial adenomatous polyposis.     

APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous polyposis coli (APC) gene on chromosome 5q. AIMS: This study assessed genotype-phenotype correlations for extraintestinal lesions in FAP. METHODS: Mutations of the APC gene were compared with the occurrence of seven extraintestinal manifestations in 475 FAP patients from 51 families. The frequency of manifestations was adjusted for different ages of patients using person years of exposure. In pedigrees without identified APC gene mutation, analysis of linkage to chromosome 5q and/or assessment of neoplasms for replication errors characteristic of mutation in mismatch repair genes were performed. RESULTS: FAP patients from the 42 families (82%) with identified mutations of the APC gene had more frequent expression of extraintestinal manifestations than affected individuals without identified mutations (risk ratio 1.2-4.0; significant difference for cutaneous cysts). The presence of a cutaneous cyst or extraintestinal cancer significantly increased the likelihood of detection of a mutation in the APC gene (94% and 92% respectively; p < 0.05). In patients without identified APC gene mutation, linkage to the APC gene was found in one large family (lod = 5.1, theta 0.01), and replication error phenotype was absent in all 24 neoplasms from 16 members of these nine pedigrees. Expression of pigmented ocular fundus lesions was strongly associated with mutations in codons 541-1309, but no other extraintestinal manifestations were related to mutation position. Multiplicity of extraintestinal manifestations was high with mutation in codons 1465, 1546, and 2621. CONCLUSIONS: Patients with the colorectal phenotype of FAP but no extraintestinal manifestations may have non-truncating mutations of the APC gene or mutation in a gene other than APC or mismatch repair genes. The site of APC gene mutation is associated with pigmented ocular fundus lesions (codons 542-1309) and predisposition to multiplicity of extraintestinal manifestations (codons 1465, 1546, and 2621).     

Singapore familial adenomatous polyposis (FAP) patients with classical adenomatous polyposis but undetectable APC mutations have accelerated cancer progression

OBJECTIVES: Germline mutation in adenomatous polyposis coli (APC) is detected in up to 80% of familial adenomatous polyposis (FAP) patients worldwide. In this study, we evaluated clinical features and APC mutations of Singapore FAP patients and contrasted genotype-phenotype correlation with Caucasians from other regions of the world and between FAP patients with and without detectable APC mutations. METHODS: We screened 242 members from 57 unrelated FAP families using a combination of cDNA protein truncation test, multiplex ligation-dependent probe amplification, and differential expression techniques. RESULTS: APC germline mutations were detected in 50 families. In contrast to Caucasians, fundic gland polyposis in Singapore patients was associated with APC mutations throughout the coding region and osteomas were also not confined to codon 767-1573. There was also no FAP-associated hepatoblastoma or medullablastoma. APC mutation-negative patients from four families with mixed (adenomatous/hyperplastic/atypical juvenile) polyps were subsequently reclassified as hereditary mixed polyposis syndrome (HMPS) patients. APC mutation-negative patients with classical adenomatous polyposis were negative for MYH, beta-catenin, and Axin 1 mutations. These patients had a significantly older age at diagnosis (P < 0.001) and more colorectal cancers (P= 0.017) than patients with APC mutations. CONCLUSIONS: We achieved a 94% (50/53) APC mutation detection rate via a combination of techniques, suggesting that the current detection rate is probably not exhaustive. Singapore patients have some features similar to and other features distinct from Caucasians. Furthermore, APC mutation-negative patients have accelerated cancer progression that merits closer surveillance.     

Occult radiopaque jaw lesions in familial adenomatous polyposis coli and hereditary nonpolyposis colorectal cancer

The purposes of this study were to determine the association, in 10 pedigrees, between adenomatous polyposis coli, hereditary nonpolyposis colorectal cancer, and occult radiopaque jaw lesions, and to assess whether these radiodensities are predictors for adenomatous polyposis. In seven kindreds with adenomatous polyposis, all patients with polyps had jaw lesions; in one kindred, no jaw lesions were found. In one of two kindreds with hereditary nonpolyposis colorectal cancer, no affected individuals had jaw lesions. In the other, the 1 affected patient with dental radiographs had generalized jaw lesions. Twelve children less than 16 yr old at risk for adenomatous polyposis were observed. Seven children with jaw lesions developed polyps after a mean interval of 4 yr. Five children without jaw lesions were polyp-free during a 5-10-yr follow-up. Thus, occult jaw lesions are consistently found only in some families with adenomatous polyposis coli, providing support for heterogeneity in polyposis syndromes. Jaw lesions are good predictors for polyp development in kindreds with adenomatous polyposis coli and jaw lesions. Their role as markers in hereditary nonpolyposis colorectal cancer needs exploration.     

Genetic and clinical characterisation of familial adenomatous polyposis: a population based study

BACKGROUND: Familial adenomatous polyposis (FAP) is a rare autosomal dominantly inherited disease predisposing to colon cancer and caused by germline mutations in the APC (adenomatous polyposis coli) gene. AIMS: We conducted a population based study to evaluate the prevalence and clinical implications of APC mutations among Finnish FAP kindreds. A possible founder effect in parallel with previous observations in hereditary non-polyposis colon cancer (HNPCC) was addressed. PATIENTS: Affected individuals from 65 kindreds were included. METHODS: The APC gene was screened for mutations using the protein truncation test and heteroduplex analysis. Haplotype analysis was performed with four flanking microsatellite markers. Families that failed to show any mutations were scrutinised with Southern blot hybridisation and allelic expression analysis. RESULTS: Thirty eight different germline mutations in APC were identified in 47 kindreds (72%). The majority of these mutations were novel and unique to each family. Although sharing the classical polyposis phenotype, families without detectable APC mutations differed from mutation positive families in the following respects: firstly, mean age at polyposis diagnosis was higher (38.6 years (48 individuals) v 30.0 years (140 individuals); p=0.001); and secondly, the proportion of kindreds lacking extracolonic disease was higher (6/18 v. 5/47; p=0.04). CONCLUSIONS: Our results may pave the way for predictive testing in mutation positive families and should stimulate further molecular studies in mutation negative families. No founder effect was observed, which is in contrast with HNPCC in the same population.     

APC gene mutations in Chinese familial adenomatous polyposis patients

AIM:To study the characteristics of APC(adenomatous polyposis coli)gene germline mutation in Chinese patients with familial adenomatous polyposis(FAP).METHODS:APC gene from 14 FAP families was amplified by polymerase chain reaction(PCR)and underwent direct sequencing to determine the micromutation type.For the samples without micromutation,the large fragment deletion of APC gene was examined by multiplex ligation-dependent probe amplification(MLPA).RESULTS:There were gene micromutations in 9 families with a...     

Desmoid tumours in familial adenomatous polyposis.

Desmoids are rare, benign fibromatous lesions, which can arise in patients with familial adenomatous polyposis (FAP), a disorder caused by germline adenomatous polyposis coli (APC) gene mutation. This study investigated the risk of desmoids in FAP, the relation between specific APC gene mutations and desmoid formation, and the clinical characteristics of FAP patients with desmoids. Eighty three of 825 FAP patients (10%) from 49 of 161 kindreds (30%) had desmoids. The absolute risk of desmoids in FAP patients was 2.56/1000 person years; comparative risk was 852 times the general population. APC gene mutations were similar in families with and without desmoids. The female/male ratio was 1.4 (p = NS). Previous abdominal surgery was noted in 68% of patients with abdominal desmoids (55% developed within five years postoperatively). Desmoid risk in FAP family members of a desmoid patient was 25% in first degree relatives v 8% in third degree relatives. Desmoids are a comparatively common complication of FAP associated with surgical trauma and familial aggregation. Desmoid development was not linked to specific APC gene mutations and was not found predominantly in women. Studies of chemopreventive therapy, given within five years after abdominal surgery, should be considered in FAP patients with a family history of desmoid disease.     

五个家族性腺瘤性息肉病家系分析

目的分析5个家族性腺瘤性息肉病（FAP）家系,总结常染色体显性遗传规律。 方法对5个FAP家系进行调查分析,取外周血、粪便行全外显子组测序（WES）筛查大肠癌基因,行结肠镜检查并取活体组织进行病理分析。 结果5个家系中,连续几代发生FAP,当父亲或者母亲患FAP后,其子代发生FAP的概率均等（50%）,无性别差异,发病者均存在腺瘤样结肠息肉病基因（APC）突变,未成年人中未见发病,部分患者患有2种以上肿瘤。 结论在有FAP病史的家系中,未成年人一般不发病,成年后均需要进行APC基因检测及结肠镜检查,一旦发现腺瘤需要尽早进行内镜下治疗,避免结直肠癌的发生。     

Multicenter experience with upper gastrointestinal polyps in pediatric patients with familial adenomatous polyposis

BACKGROUND: Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome that includes gastro-duodenal involvement, polyposis, and a propensity to adenocarcinoma necessitating endoscopic surveillance. There are few data describing pediatric upper gastrointestinal FAP resulting in conflicting screening recommendations. OBJECTIVES: To characterize pediatric gastroduodenal FAP and to investigate the association between symptoms at endoscopy and APC mutation analysis with endoscopic-histologic findings warranting surveillance. METHOD: A retrospective chart review was performed, including all children with FAP who underwent upper endoscopy (EGD) at two institutions; (UNMC: 1992-2002, JHH: 1983-2002), all biopsies were reviewed and the APC mutations present in the cohort of patients were correlated to the pattern of severity of endoscopic findings and the frequency of APC mutations identified through commercially available testing for FAP (Labcorp: 1998-2002). RESULTS: Twenty-four patients from 21 families underwent 49 EGDs. Eighty-three percent were asymptomatic at the time of endoscopy. The most common finding was fundic gland polyposis (FGP) (51%), of which 42% and 15% harbored dysplasia and changes indefinite for dysplasia, respectively. Periampullary duodenal adenomata were present in 41% of patients with one patient necessitating ampullectomy. Symptoms at endoscopy were not predictive of premalignant changes. In 15 patients where the APC mutation was known patients with dysplastic FGP, gastric, or duodenal adenoma were more likely to harbor a mutation between codons 1225-1694 than the reference population (p= 0.006). CONCLUSIONS: All pediatric patients with FAP warrant upper gastrointestinal screening and surveillance endoscopy from the time of initial colonoscopy irrespective of referable symptoms. Patients with APC mutation between codon 1225-1694 may be more susceptible to aggressive gastroduodenal involvement in FAP.     

Predictive value of congenital hypertrophy of the retinal pigment epithelium as a clinical marker for familial adenomatous polyposis

One hundred forty-eight members of 53 kindreds with familial adenomatous polyposis (FAP) were examined for congenital hypertrophy of the retinal pigment epithelium (CHRPE) and extracolonic manifestations (ECM) to assess the value of CHRPE as a predictive marker for FAP. Based on eye examination results, the families were divided into 2 groups. In a first group of 34 families, all 61 members diagnosed as having polyps and 13 of the 33 patients at risk had 4 or more lesions distributed in both eyes. By contrast, in a second group of 18 families, all 32 polyposis patients and all 18 members at risk had less than 4 lesions. Extracolonic manifestations were present in 26 of 34 families in the first group and in 11 of 18 families in the second group. Data on one family with ambiguous ancestry were reviewed separately. The existence of 4 or more CHRPE lesions distributed in both eyes seems to be a congenital marker for FAP, present in 65.4 percent of families. When present in a family: 1) it is found in all diagnosed patients in that family, 2) can therefore be considered predictive for the development of polyps in other family members who carry the trait, and 3) if confirmed by longer follow-up, may possibly preclude members without the trait from further evaluation and surveillance.Read at the meeting of The American Society of Colon and Rectal Surgeons, Toronto, Canada, June 11 to 16, 1989.     

The combination of heteroduplex analysis and protein truncation test for exact detection of the APC gene mutations

Familial adenomatous polyposis (FAP) is usually associated with mutation in the adenomatous polyposis coli (APC) gene. To examine the occurrence of these mutations in the number of FAP suspected families from the whole Slovakia effectively, we have applied heteroduplex analysis (HDA) and protein truncation test (PTT) for the analyses of 2-5 base pair deletions and point mutations of the APC gene. In the analyzed exon 15 of the APC gene determined by the primers 15Efor-15Grev for HDA and 15ET7-15J3 for PTT more than 70% of mutations should be deletions [3, 12], which are detectable by HDA. In our collection of 5 FAP families mutations in the APC gene were found in families 10, 27 and 41 using HDA. By PTT test the formation of truncated APC protein in FAP families 2, 10, 16 and 27 were revealed. The necessity of combination of at least HDA and PTT techniques for exact detection of APC mutations in analyzed APC region is discussed.     

Epidemiology of familial adenomatous polyposis in Finland: impact of family screening on the colorectal cancer rate and survival.

The incidence and prevalence rates of familial adenomatous polyposis (FAP) in Finland between 1961 and 1990 were estimated from Finnish polyposis registry data comprising 81 FAP families, including 251 affected patients. In addition, the effect of family screening on the occurrence of colorectal carcinoma was evaluated by comparing the call up and proband groups and calculating the proportion of FAP among all patients with colorectal carcinoma. The incidence of FAP was 0.62 to 2.38 per million and the prevalence increased steadily from 0.88 to 26.3 million during the study period suggesting improving prognosis. Altogether 76 of 116 probands (65.5%) had colorectal carcinoma compared with only five of 76 call up patients (6.6%). Consequently, the life expectancy of the call up patients was significantly better than that of the probands from the age of 31 years and above. However, at most, 0.53% of all colorectal carcinomas were associated with FAP in 1966-70, and the diminishing frequency of this proportion was more a result of an increase in sporadic colorectal carcinomas in Finland than of family screening for FAP. Family screening is very effective in FAP and must always be undertaken when a new proband is diagnosed.     

Colorectal cancer surveillance behaviors among members of typical and attenuated FAP families

OBJECTIVES: Although enhanced colorectal surveillance is recommended for members of familial adenomatous polyposis (FAP) families, little is known about individual-level adherence behavior. This study examined factors associated with recent use of colorectal cancer (CRC) surveillance among FAP patients and their at-risk relatives. METHODS: This cross-sectional study conducted a computer-assisted telephone survey among 150 members of 71 extended families with classic (FAP) or attenuated adenomatous polyposis (AFAP). Participants were enrolled in a university-based hereditary CRC registry or were first-degree relatives of enrollees. Both qualitative and quantitative data were collected and analyzed. RESULTS: Surveillance behavior varied by disease status. Fifty-four percent of 71 participants with a personal history of FAP and 42% of 79 at-risk relatives reported recent use of CRC surveillance recommendations. In multiple logistic regression analysis, lack of patient recall of provider recommendation for an endoscopic examination of the colon (OR 4.8, 95% CI 1.8-13.1), lack of health insurance or no reimbursement for CRC surveillance (OR 3.6, 95% CI 1.2-10.5), and/or the belief that their relative risk of CRC is not increased (OR 3.1, 95% CI 1.2-7.1) were independently associated with not having had a recent colonoscopy or sigmoidoscopy. CONCLUSIONS: Despite the known benefits of CRC surveillance, a substantial proportion of FAP family members did not have a recent colonoscopy or endoscopy. Interventions targeted at both clinicians and patients are needed to improve surveillance behavior. These data are also important in designing decision support tools to assist clinicians in identifying and managing high-risk patients.     

Results of national registration of familial adenomatous polyposis

BACKGROUND AND AIMS: The Danish Polyposis Register was established in 1971 with the aim of improving the poor prognosis of familial adenomatous polyposis (FAP), and in 1975 the register became national. The aim of the present study was to evaluate the prevalence of colorectal cancer and survival rate in FAP patients before and after the establishment of the Danish Polyposis Register. PATIENTS AND METHODS: The Danish Polyposis Register was established by collecting information on probands and construction of their pedigrees. Family members at risk were offered prophylactic endoscopic and molecular genetic examination, and affected individuals were treated by colectomy. RESULTS: At the end of 2001, the Danish Polyposis Register included 434 patients from 165 families. The incidence rate was 1.90x10(-6) and the prevalence rate 4.65x10(-5). Colorectal cancer on the basis of FAP constituted 0.07% of all colorectal cancers in the 1990s. Colorectal cancer was diagnosed in 170/252 probands (67%) and in 5/182 call-up patients (3%) (p<0.001). The cumulative crude survival was 94% in call-up patients compared with 44% in probands (p<0.0001). A comparison of two periods, 1900-1975 and 1976-2001, demonstrated a decreased prevalence of colorectal cancer from 60% to 27% (p<0.0001), and an increased use of colectomy from 52% to 93% (p<0.00001). The cumulative crude survival in FAP showed substantial improvement with time (p<0.00001). CONCLUSION: Since the establishment of the Danish Polyposis Register, the prevalence of colorectal cancer has decreased considerably and the prognosis has improved substantially. The work of the Danish Polyposis Register is probably the main cause of this improvement.     

Heredit?res kolorektales Karzinom

Genetically defined hereditary colorectal cancer affects mostly young patients and their families and accounts for approximately 3?C5% of all colorectal cancers. Early detection and clinical management determine the prognosis and are the responsibility of clinicians. While the classical variant of familial adenomatous polyposis (FAP) is characterized by a distinct phenotype, Lynch syndrome, attenuated FAP (aFAP) and MUTYH-associated adenomatous polyposis (MAP) show phenotypic overlaps which render unequivocal classification difficult. The present article elucidates the clinical manifestations, current surveillance concepts and preventive operative strategies in patients with hereditary tumor predisposition syndromes and their families.     

Clinical and Biologic Features of Adenomatosis Coli in Northern Italy

Background: Familial adenomatous polyposis (FAP) is a hereditary disease characterized by more than 100 adenomas scattered in the large bowel and by various extracolonic manifestations. We proposed a) to establish the frequency of the disorder in Northern Italy, b) to describe the most relevant clinical findings, and c) in a subgroup of 21 patients (from 8 families), to evaluate the spectrum of mutations of the APC gene.

Methods and Results: Patients with FAP diagnosed between 1961 and 1991 were referred to our Study Group from surgery and gastroenterology units of the region Emilia-Romagna. The incidence of FAP was in the order of 1 in 16,500, with about a third of patients being 'single' cases. Colorectal malignancies were present in 75.6% of symptomatic patients but absent in most (93.75%) of the asymptomatic family members ('call-up' individuals). Gastric, duodenal, and jejunal adenomas were found in 8.2%, 30.6% and 53.3% of the investigated patients, respectively. Congenital hypertrophy of the retinal pigment epithelium and occult jaw lesions were seen in 64.7% and 39.5% of FAP patients but only in 0.5% and 2.5% of a matched, by age and sex, control population. These two clinical markers had a specificity of 99% and 97%, although their sensitivity was 64% and 39%. Finally, mutations of the APC gene were detected in 6 families (16 affected individuals) of the 8 families (21 affected individuals) tested; no correlation could be found between genotype and phenotype.

Conclusions: This study confirms that early diagnosis is essential for an appropriate management of FAP patients, although this aim remains elusive in single cases. High-risk individuals are ideal candidates for APC gene mutation analysis, which should be offered to all first-degree relatives of affected patients.     

Familial adenomatous polyposis: genetics and epidemiology

Familial adenomatous polyposis (FAP) is a rare genetic disease characterised by the development of hundreds to thousands of adenomatous polyps along the colon-rectum leading to cancer at a young age, if left untreated. In 1991, the gene responsible for the vast majority of FAP cases, the adenomatous polyposis coli (APC) gene, was identified. In 5-30% of FAP patients, no APC mutation is identifiable by current genetic testing. In 2003, it was shown that 'APC-negative' FAP patients may carry biallelic mutations in a different gene, the MYH gene. Genetics of FAP will be discussed in relation to its present clinical applications. If the hereditable mutation(s) is/are known in a family, it is possible to plan endoscopic surveillance only for those who actually inherited the mutation(s). Also, genetic testing may be of help in the diagnosis of atypical adenomatous polyposis cases and in the clinical management of affected individuals.     

Phenotypic differences in familial adenomatous polyposis based on APC gene mutation status

Background—Familial adenomatous polyposis(FAP) is a clinically well defined hereditary disease caused bygermline mutations within the adenomatous polyposis coli (APC) gene.Although several techniques are applied in the mutation analysis of FAPkindreds about 20-50% of cases remain unclear, with no APC mutationidentified (APC negative).
Aims—To delineate phenotypic differences betweenAPC positive and APC negative patients with respect to colonic andextracolonic disease in order to determine whether additionalmechanisms are involved in the pathogenesis of FAP.
Methods—The entire coding region of the APC genewas analysed using single stranded conformation polymorphism andprotein truncation tests in 50 Swiss FAP families with a total of 161affected individuals. Differences in phenotypic manifestation werestatistically evaluated by Student's t test, Fisher'sexact test, and χ² test.
Results—Thirty six families (72%) were APCpositive. Statistically significant differences between APC positiveand APC negative groups were found for the mean age at diagnosis ofcolonic polyposis (35.2 versus 45.3 years, respectively) and for theoccurrence of stomach polyps (14 patients, all APC positive).Additionally, APC negative patients displayed lower polyp numbers atdiagnosis and less extracolonic manifestations.
Conclusions—FAP kindreds without detected APCgene mutations present with a notably milder disease phenotype comparedwith APC positive families, suggesting that different genetic factors might be involved.

Keywords:familial adenomatous polyposis; adenomatouspolyposis coli gene; mutation; colorectal cancer; extracolonicmanifestations

     

The most frequent APC mutations among Slovak familial adenomatous polyposis patients. Adenomatous polyposis coli

We screened 46 suspected families from whole Slovakia for familial adenomatous polyposis (FAP) cancer predisposition. Individuals were enrolled to the adenomatous polyposis coli (APC) gene mutations mapping program at the base of previous clinical investigation. We have used the following techniques: heteroduplex analysis (HDA), protein truncation test (PTT), single strand conformation polymorphism (SSCP) and sequencing for the identification and detailed positional analysis of APC mutations. Around 90% of all detected mutations were found being truncated. The most frequent mutations from this collection were located within codons 1309 and 1061 of exon 15 and represented 15% and 7%, respectively of all tested families. The expressive phenotype, large amount of colorectal polyps and congenital hypertrophy of the retinal pigment epithelium (CHRPE) were associated to all mutations within codons 1309 and 1060.     

Synchronous primary carcinomas of the ampulla of Vater and ascending colon in a patient with multiple flat adenomas

Multiple primary cancers occurring in the same patients have been reported to represent 1.8–3.9% of all cancers. The majority of all patients reported to have had a combination of simultaneous neoplastic changes in the ampulla of Vater and the colon showed familial adenomatous polyposis (FAP) syndrome. Variants of familial adenomatous polyposis coli are: attenuated adenomatous polyposis coli (AAPC, previously also known as flat adenoma syndrome) and multiple adenoma coli. AAPC is characterized clinically by many, but usually fewer than 100, colonic lesions that are characteristically slightly elevated and plaque-like, with a reddish surface and sometimes central depression. Genetically it represents an extremely rare variant of FAP. Another group of individuals, so-called multiple adenoma patients, have a phenotype similar to AAPC, but most have no demonstrable germ-line adenomatous polyposis coli mutation, as do patients with FAP or AAPC. However, there have been only a few reports that discussed concurrent neoplastic changes in the ampulla of Vater and colon in patients with multiple colonic flat adenomas, but without the florid phenotype of classical FAP. We present rare clinical course of a patient with multiple (more than 60) flat adenomas in the proximal colon and two primary cancers: of the ampulla of Vater and of the ascending colon. This patient and his family history did not show polyposis compatible with FAP or hereditary nonpolyposis colorectal cancer (HNPCC) syndrome.