Germline and somatic mutations in exon 15 of the APC gene and K-ras mutations in duodenal adenomas in patients with familial adenomatous polyposis.

BACKGROUND: In sporadic colorectal adenomas mutations in the adenomatous polyposis gene (APC) are among the first gene aberrations to appear. In familial adenomatous polyposis (FAP) the patients already have a germline mutation in the APC gene. To investigate the natural history of duodenal adenomas in FAP patients, we examined germline and somatic mutations of the APC gene and K-ras mutations in these lesions. METHODS: Frozen sections from 54 duodenal polyps from 31 FAP patients were used to histologically verify the presence of adenomatous growth in the mucosa; the rest of each biopsy specimen was processed for DNA extraction. APC exon 15 was investigated with the protein truncation test (PTT), using four overlapping polymerase chain reaction (PCR) fragments, and samples showing an APC mutation were thereafter sequenced. The adenomas were examined for K-ras mutations by use of a combination of the 'enriched PCR method' and temporal temperature gradient electrophoresis. RESULTS: APC germline mutations in exon 15 were found in 19 of 31 (61%) patients, whereas somatic mutations were localized to 12 of 54 (22%) duodenal adenomas. In seven adenomas both the germline and the somatic mutations were found, whereas five small adenomas showed somatic mutations only. There was no tendency for more mutations to be detected in large and severely dysplastic adenomas compared with small and mildly dysplastic ones. K-ras mutations were found in four (7%) duodenal adenomas. CONCLUSIONS: The low rate of somatic APC and K-ras mutations in duodenal adenomas may indicate another neoplastic pathway than in FAP adenomas of the large bowel, or that a modifier gene is cosegregating with the disease.     

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).     

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.     

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.     

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.     

Preliminary results of the molecular diagnosis of familial adenomatous polyposis in Cuban families

BACKGROUND AND AIMS: Familial adenomatous polyposis (FAP) is an autosomal dominant condition characterized by multiple adenomatous polyps in the colon and rectum that inevitably develop into adenocarcinomas if the patient's colon is not removed in time. To date more than 500 mutations related to the disease have been identified in the APC (adenomatous polyposis coli) gene. The molecular study of FAP families was initially introduced in Cuba with the aim of identifying the asymptomatic carriers of APC gene mutations in each family. PATIENTS AND METHODS: We studied 23 individuals from 17 Cuban families who had been diagnosed clinically with FAP. Peripheral DNA was extracted from the index case of each family. Exon 15 of the APC gene was screened for germinal mutations using PCR and DNA heteroduplex. RESULTS: Three different germinal mutations were identified in the mutational clustering region of APC gene by sequencing analysis in five FAP unrelated families. Three families carry the most frequent mutation in APC in codon 1309, while the other two families carry mutations in codons 1061 and 1192, respectively. Two asymptomatic carriers of one family were detected, and later the disease was confirmed by colonoscopy in a very early stage while six members at risk were found to be negative. CONCLUSION: For the first time in Cuba molecular diagnosis of FAP was performed and the development of colorectal cancer prevented in asymptomatic carriers.     

Familial adenomatous polyposis: more evidence for disease diversity and genetic heterogeneity

Familial adenomatous polyposis (FAP) is characterised by the presence of profuse colonic carpeting of adenomas throughout the entire colon and rectum. The genetic basis of FAP has been shown to be primarily associated with germline mutations in the APC gene. Notwithstanding, several reports have been published indicating that there is genetic heterogeneity in FAP and that the most likely explanation is the existence of another gene. In this report we further delineate the genotype/phenotype correlation in families that harbour germline mutations in the APC gene and identify some previously unreported changes in the APC gene which predispose to an attenuated disease phenotype. From 53 index patients diagnosed with either FAP or attenuated FAP, 27 harboured changes in the APC gene. The remaining 26 patients were further subgrouped according to their colonic phenotype. There were nine patients with a mixed hyperplastic/adenomatous colonic phenotype and there were 17 patients with an adenomatous colonic phenotype. Evaluation of the disease characteristics of these patients and their families is presented which may aid in the identification of new genes associated with colonic polyposis.     

An unexpected Cowden syndrome case found among members of a large familial adenomatous polyposis kindred

Genetic testing is now considered the standard of care in the management of familial adenomatous polyposis (FAP). Non-carriers of mutations are excluded from endoscopic surveillance. During the systematic screening of the relatives of an affected member with FAP, one non-carrier of APC mutations was unexpectedly found with the typical Cowden syndrome phenotype. One large Algerian family with FAP was screened for an APC germline mutation. Moreover, we also performed a mutation search in the Cowden syndrome member for PTEN, BMPR1A or MADH4 (SMAD4) germline mutations. We identified a mutation in the APC gene that results in a truncated protein (Y935X) in the FAP proband, and subsequently in 12 FAP-affected members. Among the 12 APC mutation-negative members of this family, we found one member with the Cowden disease phenotype. However, the mutation analysis in the PTEN gene and the two other genes involved in juvenile polyposis, namely BMPR1A and MADH4 (SMAD4), in the Cowden syndrome patient failed to show any pathogenic mutation. Genetic testing is a powerful tool that can provide a definitive diagnosis for FAP. However, not all polyposes in the FAP family are adenomatous polyposes.     

Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature

Mutations in the adenomatous polyposis coli (APC) gene cause familial adenomatous polyposis (FAP). Disease severity and the presence of extracolonic manifestations seem to be correlated with the location of the mutation on the APC gene. In this review, large studies describing genotype-phenotype correlations in FAP were evaluated and categorized. Attenuated FAP (AFAP, <100 colorectal adenomas) is correlated with mutations before codon 157, after codon 1595 and in the alternatively spliced region of exon 9. Severe polyposis (>1000 adenomas) is found in patients with mutations between codons 1250 and 1464. Mutations in the remainder of the APC gene cause an intermediate phenotype (hundred to thousands of adenomas). Congenital hypertrophy of the retinal pigment epithelium (CHRPE) and desmoid tumours are associated with mutations between codons 311 and 1444 and after codon 1444, respectively. No consistent correlations were found for upper gastrointestinal tumours. Genotype-phenotype correlations in FAP will be useful in decisions concerning screening and surgical management of FAP.     

Familial adenomatous polyposis patients without an identified APC germline mutation have a severe phenotype

BACKGROUND: Development of more than 100 colorectal adenomas is diagnostic of the dominantly inherited autosomal disease familial adenomatous polyposis (FAP). Germline mutations can be identified in the adenomatous polyposis coli (APC) gene in approximately 80% of patients. The APC protein comprises several regions and domains for interaction with other proteins, and specific clinical manifestations are associated with the mutation assignment to one of these regions or domains. AIMS: The phenotype in patients without an identified causative APC mutation was compared with the phenotype in patients with a known APC mutation and with the phenotypes characteristic of patients with mutations in specific APC regions and domains. PATIENTS: Data on 121 FAP probands and 149 call up patients from 70 different families were extracted from the Danish Polyposis register. METHODS: Differences in 16 clinical manifestations were analysed according to the patient's mutational status. Two sided independent t sample test, two sided chi(2) test, and odds ratios were calculated. RESULTS: Patients without identified APC mutations had a unique and severe phenotype, which was roughly described as: young age at diagnosis and subsequent death in spite of development of few colorectal adenomas; low risk of involvement of the upper gastrointestinal tract, as reflected by a low mean Spigelman stage, and a low risk of fundic gland polyposis. Finally, they had significantly fewer affected family members, although they do not themselves more often represent an isolated case. CONCLUSIONS: The severe phenotype should be considered when counselling FAP families in which attenuated FAP is excluded and in which a causative APC mutation has not been identified.     

Novel germline APC mutations in Swedish patients with familial adenomatous polyposis and Gardner syndrome

BACKGROUND: Familial adenomatous polyposis (FAP) is a familial cancer syndrome in which affected individuals develop multiple adenomatous polyps and are thereby at greatly increased risk of developing colorectal cancer. Gardner syndrome is a variant of FAP, in which the patients also develop extraintestinal tumors, in particular osteomas and desmoid tumors. An attenuated form of the disease (AFAP) is associated with fewer polyps, but still a high risk for colorectal cancer. Germline mutations in the adenomatosis polyposis coli (APC) gene cause FAP and Gardner syndrome and have recently been associated also with the development of AFAP. METHODS: We have analysed the entire APC gene for germline mutations in 7 patients with FAP and in 6 patients with suspected AFAP. Mutation screening was performed by direct sequencing of exons 1-14 and using the protein truncation test for analysis of exon 15. RESULTS: Novel disease-causing germline mutations, all of which resulted in truncation of the APC protein, were identified in 6 of the 7 patients with FAP or Gardner syndrome. No APC mutation was detected in any of the 6 patients with suspected AFAP. CONCLUSIONS: This study reports novel FAP- and Gardner syndrome-causing mutations in the APC gene. The lack of APC mutations in patients with multiple polyps at young age indicates that other genetic defects may cause this phenotype.     

Novel Germline APC Mutations in Swedish Patients with Familial Adenomatous Polyposis and Gardner Syndrome

Background: Familial adenomatous polyposis (FAP) is a familial cancer syndrome in which affected individuals develop multiple adenomatous polyps and are thereby at greatly increased risk of developing colorectal cancer. Gardner syndrome is a variant of FAP, in which the patients also develop extraintestinal tumors, in particular osteomas and desmoid tumors. An attenuated form of the disease (AFAP) is associated with fewer polyps, but still a high risk for colorectal cancer. Germline mutations in the adenomatosis polyposis coli (APC) gene cause FAP and Gardner syndrome and have recently been associated also with the development of AFAP. Methods: We have analysed the entire APC gene for germline mutations in 7 patients with FAP and in 6 patients with suspected AFAP. Mutation screening was performed by direct sequencing of exons 1-14 and using the protein truncation test for analysis of exon 15. Results: Novel disease-causing germline mutations, all of which resulted in truncation of the APC protein, were identified in 6 of the 7 patients with FAP or Gardner syndrome. No APC mutation was detected in any of the 6 patients with suspected AFAP. Conclusions: This study reports novel FAP- and Gardner syndrome-causing mutations in the APC gene. The lack of APC mutations in patients with multiple polyps at young age indicates that other genetic defects may cause this phenotype.     

Serrated adenoma in familial adenomatous polyposis: relation to germline APC gene mutation

BACKGROUND: Serrated adenoma is a precursor of colorectal cancer. AIM: To clarify possible genotype-phenotype correlations of serrated adenomas in familial adenomatous polyposis (FAP). Patients: Eleven patients from eight families with FAP. METHODS: We performed total colonoscopy with multiple biopsies in patients. Neoplasia with a serrated glandular structure was regarded as a serrated adenoma. In each patient, germline mutations of the APC gene were determined. Colonic phenotype was compared with germline mutations of the APC gene. RESULTS: Serrated adenomas were found in three patients. These patients had macroscopic polyps <100 in number. Pedigrees with serrated adenomas had the truncating germline APC mutation at codon 161, 332, or 1556 while in the other pedigrees mutations were found between codons 554 and 1324. CONCLUSIONS: In FAP, serrated adenoma may be a phenotype characteristic of the attenuated form.     

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。     

Clinicopathological features of familial adenomatous polyposis in Korean patients

AIM: To identify prognostic factors and to correlate APC mutations with clinical features, including extracolic manifestations. METHODS: One hundred thirty-five patients who underwent surgical procedures for familial adenomatous polyposis(FAP) were included. FAP was diagnosed when the number of adenomatous polyps was 100. Data related to patient, extracoloic manifestations, cancer characteristics, operative procedure, follow up and surveillance were collected. APC mutation testing was performed in the 30 most recent patients. DNA was extracted from peripheral blood and polymerase chain reaction products using 31 primer pairs on APC gene were sequenced. A retrospective study was performed to investigate a causal relationship between prognosis and feature of patient.RESULTS: The mean age of the 51 patients with colorectal cancer(CRC) was older than that of those without CRC(30.5 vs 36.9, P = 0.002). Older individuals were more likely to have colon cancer at the time of FAP diagnosis [odds ratio, 4.75(95%CI: 1.71-13.89) and 5.91(1.76-22.12) for 40-49 years and age 50 vs age 30). The number of confirmed deaths was 13 and the median age at death was 40 years(range, 27 to 85 years). Ten of the deaths(76.9%) were from CRC. Another cause of two cases of death were desmoid tumors(15.4%). Development of cancer on remnant rectal or ileal mucosa after surgery was not observed. The APC mutation testing revealed 23 pathogenic mutations and one likely pathogenic mutation, among which were four novel mutations. The correlation between mutational status and clinical manifestations was investigated. Mutations that could prodict poor prognosis were at codon 1309 which located on mutation cluster region, codon 1465 and codon 1507.CONCLUSION: Identification of APC mutations should aid in the diagnosis and counseling of family members in terms of early diagnosis and management of FAP.     

A double germline mutations in the APC and p53 genes

Germline mutation in the APC gene is required for the initiation of the development of familial adenomatous polyposis (FAP). According to Fearon and Vogelstein model, further somatic mutations in the K-ras oncogene, DCC gene and p53 tumor suppressor gene are prerequisite for development of colon carcinoma. We have found that the germline mutations in the DNA isolated from lymphocytes of an 18 years old girl with extraordinary expressive phenotype in codons 1060-1061 of the APC gene result in truncation of the APC protein. The mutation in codons 12 and 13 of the K-ras oncogene was not detected, but another germline mutation was found in codon 210 of the p53 gene. Furthermore, no one of these germline mutations was detected in the DNA of peripheral blood lymphocytes of the patient's 21 years old healthy sister. Until now, there has been no evidence about the expressive phenotype due to mutation in codons 1060-1061 of the APC gene; the role of germline missense mutation in codon 210 of the p53 gene in the FAP malignant process remains to be elucidated too. The effect of the combination of germline mutation in two different tumor suppressor genes in the progress of disease is discussed.     

Analysis of K-ras, APC, and beta-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial adenomatous polyposis

BACKGROUND & AIMS: We have previously shown that aberrant crypt foci (ACF) are the putative precursor lesions of colorectal adenomas and subsequent cancer in humans using magnifying endoscopy. The present study was designed to investigate these genetic alterations in ACF biopsy specimens from normal subjects, familial adenomatous polyposis (FAP) or sporadic patients. METHODS: The non-FAP cases included 34 normal subjects, 35 colorectal adenoma patients, and 19 colorectal cancer patients; there were 4 FAP patients. Biopsies were performed on ACF by magnifying endoscopy. K-ras mutations were analyzed by 2-step polymerase chain reaction and restriction fragment length polymorphism, APC mutations by in vitro-synthesized protein assay, and beta-catenin mutations by direct sequencing. Full-length APC and beta-catenin were detected by immunofluorescence. RESULTS: In non-FAP cases, K-ras mutations were detected in 82% (89/106) of nondysplastic ACF and 63% (17/27) of dysplastic ACF. APC mutation and beta-catenin accumulation were not detected in non-FAP ACF, whereas in adenoma of these patients, positivity of APC mutation and beta-catenin accumulation were 78% (24/31), and that of K-ras mutation was 65% (20/31). FAP patients showed K-ras mutations in only 13% (1/8) of dysplastic ACF, which is the predominant form of ACF found in FAP. In FAP patients, somatic APC mutations were found in 100% of dysplastic ACF, as they are in adenoma. The frequency of K-ras mutations was 73% (8 of 11) in FAP adenoma. CONCLUSIONS: The data suggest that in sporadic colorectal carcinogenesis, assuming the biological implication of ACF as a precursor of adenomas, there is a route where K-ras mutation mainly occurs during the formation of ACF, which then become adenomas wherein APC mutation occurs. In FAP, however, somatic mutation of APC predominantly occurs during ACF formation, followed by K-ras mutation.     

Screening for APC Mutations Based on Detection of Truncated APC Proteins

Mutation of the adenomatous polyposis coli (APC)gene is frequently found in colorectal tumors from bothfamilial adenomatous polyposis (FAP) and non-FAPpatients. Analysis of APC mutation is time-consuming and costly due to the large size of the APCgene. As the majority of APC mutations result in thetruncation of gene products, the detection of truncatedAPC proteins may be used as a screening method for APC mutations. The aim of this study is toestablish a practical method of detecting truncated APCproteins for the screening of APC mutations. APCproteins in human colorectal cancer cell lines wereanalyzed by western blotting. Truncated APC proteinswere expressed in all of the colorectal cancer celllines studied. Two species of truncated APC proteinswere expressed in two cell lines. Western blotting is a rapid, reliable screening method for APCmutations and provides information on bothalleles.     

Gastric adenocarcinoma associated with fundic gland polyps in a patient with attenuated familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is a rare autosomal dominant precancerous condition of the colon caused by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. FAP is characterized by the appearance of innumerable adenomatous polyps throughout the large bowel. Fundic gland polyps are the most common gastric lesion in FAP. It is generally believed that fundic gland polyps have little or no potential for malignant transformation in the population at large, and only a few case reports describe the development of high grade dysplasia or gastric adenocarcinoma associated with diffuse fundic gland polyposis in patients with FAP. We report the second case of gastric adenocarcinoma intimately associated with fundic gland polyposis in a family with an attenuated form of FAP. The patient had undergone routine screening per current guidelines because of his known mutation in the APC gene. This suggests that malignant transformation of fundic gland polyps in patients with FAP occur more frequently than previously believed. Current screening recommendations may not be sufficient for patients with FAP or its attenuated forms.     

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