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Attenuated familial adenomatous polyposis manifests as autosomal dominant late-onset colorectal cancer.

ABSTRACT: Colorectal cancer (CRC) risk is well defined for families of patients with classical familial adenomatous polyposis (FAP). However, the risk for those with an attenuated form of FAP is less well characterised. In this study, we estimated CRC risks for carriers of a novel germline mutation in the APC gene that causes attenuated FAP (AFAP). We performed genetic testing on 53 individuals from seven AFAP families harbouring an identical APC:c.288T>A mutation. Using a modified segregation analysis, we estimated relative and absolute CRC risks for mutation carriers. Twenty-three individuals harboured the disease causing mutation. CRC occurred in 28 individuals (mean 61.7 years, range 32-80 years). The estimated CRC relative risks for mutation carriers aged 60-69 and ≥70 years were 19 (95% CI: 1.77-204.08) and 45 (95% CI: 11.32-180.10), respectively, while the absolute CRC lifetime risk for men was 94% (95% CI: 67.5-99.9%), and for women, 84% (95% CI: 50.9-99.0%). This study shows that AFAP can manifest as autosomal dominant late-onset CRC. These findings highlight a subgroup of inherited CRCs that require new criteria for identification and surveillance.

SUBMITTER: Ibrahim A

PROVIDER: S-EPMC4140763 | biostudies-literature |

REPOSITORIES: biostudies-literature

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American founder mutation for attenuated familial adenomatous polyposis.

Project description:Background & aimsSpecific mutations in the adenomatous polyposis coli (APC) gene can lead to an attenuated form of familial adenomatous polyposis (AFAP). Although AFAP mutation carriers have a 69% risk of colorectal cancer by age 80, clinical recognition remains a challenge in some cases because they present with few colonic adenomas and are difficult to distinguish clinically from patients with sporadic polyps.MethodsFamily relationships were established using family history reports, the Utah Population Database, and the public records of the Mormon Church. Genetic analysis of representative family members was performed using a 10,000 single nucleotide polymorphism array platform. Colonoscopy data were available on 120 individuals with the AFAP mutation.ResultsTwo large AFAP kindreds with the identical APC disease-causing mutation (c.426_427delAT) were linked to a founding couple who came to America from England around 1630. Genetic analysis showed that the 2 families share a conserved haplotype of 7.17 Mbp surrounding the mutant APC allele. The data show that 36.6% of the mutation-positive family members have fewer than 10 colonic adenomatous polyps, and 3 (6.8%) of these individuals were diagnosed with colorectal cancer.ConclusionsIn view of the apparent age of this mutation, a notable fraction of both multiple-adenoma patients and perhaps even colon cancer cases in the United States could be related to this founder mutation. The colon cancer risk associated with the mutation makes genetic testing of considerable importance in patients with a personal or family history of either colonic polyps or cancer at a young age.

| S-EPMC2245898 | biostudies-literature

Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or "multiple" colorectal adenomas.

Project description:Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the APC gene (chromosome 5q21). FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyposis (AAPC) have fewer than 100 adenomas. A further group of individuals, so-called "multiple" adenoma patients, have a phenotype like AAPC, with 3-99 polyps throughout the colorectum, but mostly have no demonstrable germ-line APC mutation. Routine mutation detection techniques fail to detect a pathogenic APC germ-line mutation in approximately 30% of patients with classical polyposis and 90% of those with AAPC/multiple adenomas. We have developed a real-time quantitative multiplex PCR assay to detect APC exon 14 deletions. When this technique was applied to a set of 60 classical polyposis and 143 AAPC/multiple adenoma patients with no apparent APC germ-line mutation, deletions were found exclusively in individuals with classical polyposis (7 of 60, 12%). Fine-mapping of the region suggested that the majority (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classical polyposis phenotype. Screening for germ-line deletions in APC mutation-negative individuals with classical polyposis seems warranted.

| S-EPMC122454 | biostudies-literature

Attenuated familial adenomatous polyposis with desmoids caused by an APC mutation.

Project description:We present here a case of attenuated familial adenomatous polyposis (AFAP) with a family history of desmoids and thyroid tumors. This patient had no colonic polyps but did have multiple desmoids. Genetic analysis identified a 4-bp deletion in codon 2644 (c.7932_7935delTTAT: p.Tyr2645LysfsX14) of the adenomatous polyposis coli (APC) gene. In cases with limited numbers of colonic polyps and desmoids, AFAP may be caused by a mutation in the 3' region of APC.

| S-EPMC4785566 | biostudies-literature

Insights into Early Onset Colorectal Cancer through Analysis of Normal Colon Organoids of Familial Adenomatous Polyposis Patients.

Project description:Early onset colorectal cancer (EOCRC) rates have increased in recent decades. While lowering the recommended age for routine colonoscopies to 45 may reduce this burden, such measures do not address those who develop CRC before that age. Additional measures are needed to identify individuals at-risk for CRC. To better define transcriptomic events that precede the development of CRC, we performed RNA-sequencing analysis in colon organoids derived from seven healthy and six familial adenomatous polyposis (FAP) patients. This led to the identification of 2635 significant differentially expressed genes (FDR < 0.05). Through secondary analysis of publicly available datasets, we found that these genes were enriched for significant genes also present in FAP CRC and non-hereditary CRC datasets, including a subset that were unique to EOCRC. By exposing FAP colon organoids to a three-day ethanol treatment, we found that two EOCRC-relevant genes were also targets of CRC related lifestyle factors. Our data provides unique insight into the potential, early mechanisms of CRC development in colon epithelial cells, which may provide biomarkers for patient monitoring. We also show how modifiable lifestyle factors may further alter genes relevant to EOCRC, adding weight to the hypothesis that such factors represent an important contributor to increased EOCRC incidence.

| S-EPMC9454756 | biostudies-literature

Adenomatous Polyposis Coli Gene Mutations in 22 Chinese Pedigrees with Familial Adenomatous Polyposis.

Project description:BACKGROUND Familial adenomatous polyposis (FAP), which has a very high tendency of progression to colorectal cancer, is mainly caused by mutations of the adenomatous polyposis coli (APC) gene. This study systematically screened the APC mutations and observed the correlation of APC mutations with clinical manifestations of FAP. MATERIAL AND METHODS Eighty subjects (probands and their family members of 22 FAP pedigrees) were enrolled, underwent abdominal ultrasound, computed tomography, and colonoscopic examinations, and were assessed for APC mutations between January 2010 and June 2015 at Tianjin Union Medical Center. Peripheral blood was collected from subjects, and DNA was extracted and screened for APC mutations using multiplex ligation-dependent probe amplification for large-fragment deletions or PCR-denaturing high-performance liquid chromatography with DNA sequencing for micromutations. RESULTS Nineteen of 22 FAP pedigrees were found to have mutations of APC, and 17 types APC mutations were identified. All the mutations were heterozygosity with autosomal dominant inheritance. APC mutations included 8 caused by frameshift, 3 by aberrant splicing, 2 by missense mutation, 2 by nonsense mutation, and 2 by large-fragment deletion. Frameshift mutation was the most common type of APC mutation, and Coding DNA Sequence 15 was the most common mutation site. Five novel APC mutations, including 1 with large-fragment deletion, were identified. CONCLUSIONS We systematically screened 17 mutations of APC from 22 Chinese pedigrees with FAP. This study will broaden the spectrum of known APC germline mutations and help understand the types and distribution of APC mutations among Chinese patients with FAP.

| S-EPMC6542301 | biostudies-literature

Familial adenomatous polyposis of the colon.

Project description:Familial adenomatous polyposis (FAP) is a well-defined autosomal dominant predisposition to the development of polyposis in the colon and rectum at unusually early ages. The first symptoms of FAP are diarrhea and blood in the stool. Weight loss and weaknesses occur after the development of advanced tumour. The incidence of the FAP disorder is one per 10000 newborns. There are high levels of heterogeneity with regard to the number and timing of the occurrence of polyps. The classical form of FAP is characterized by the presence of more than 100 polyps, which appear in the second decade of life. The average time of occurrence of polyps is 15 years. The earliest symptoms of polyposis have been observed in a three-year-old child. The polyps are characterized by large potential for the development towards malignant tumour. Malignancy can occur from late childhood onwards. Attenuated adenomatous polyposis coli is characterized by a more benign course of disease in contrast to classical FAP. The occurrence of FAP is associated with mutations in the APC tumour suppressor gene, which was described in 1991. The APC gene is located on chromosome 5q21 and is involved in cell proliferation control. A recessive form of adenomatous polyposis is caused by mutations in the base excision repair gene - MUTYH gene. The MUTYH gene is involved in repairing DNA lesions as a result of oxidative DNA damage. MUTYH associated polyposis (MAP) is a predisposition to the development of polyps of the colon but the number of polyps is lower in comparison to classical FAP. The high risks of cancer observed in these two diseases make them important medical issues. Molecular studies of colonic polyposis have been performed in Poland for over fifteen years. A DNA Bank for Polish FAP patients was established at the Institute of Human Genetics in Poznan in which DNA samples from 600 FAP families have been collected.

| S-EPMC3843547 | biostudies-literature

Celecoxib Colorectal Bioavailability and Chemopreventive Response in Patients with Familial Adenomatous Polyposis.

Project description:Why celecoxib exerts chemopreventive activity in only some familial adenomatous polyposis (FAP) patients remains poorly understood. We conducted a phase II clinical study to identify potential predictive biomarkers for celecoxib chemopreventive activity in FAP. Twenty-seven patients with FAP completed a 6-month oral course of 400 mg of celecoxib twice a day; they underwent colonoscopies before and after celecoxib treatment to assess colorectal polyp tumor burden and to obtain normal and polyp colorectal biopsies to measure celecoxib, 13-S-hydroxyoctadecadienoic acid (13-HODE), 15-HETE, 12-HETE, and LTB4 levels by LC/MS-MS. Celecoxib levels in sera from those patients were also measured before treatment and after 2, 4, and 6 months of treatment. Nineteen of the 27 patients experienced a response to celecoxib, with a ≥ 28% reduction of colonic polyp burden on the basis of a reproducible quantitative assessment of colonoscopy results. Celecoxib levels were significantly lower in polyp tissues than in normal colorectal tissues. Celecoxib levels in sera and normal colorectal tissues were correlated in patients who experienced a response to celecoxib but not in those who did not. Among the measured lipoxygenase products, only 13-HODE levels were significantly lower in polyp tissues than in normal tissues. Our findings demonstrate the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical response in patients with FAP.Prevention relevanceThis study evaluated potential predictive biomarkers for celecoxib chemopreventive activity in patients with FAP. Our findings demonstrated the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical chemopreventive response in patients with FAP. See related Spotlight, p. 205.

| S-EPMC8980107 | biostudies-literature

Seeking insights into early onset colorectal cancer through analysis of normal colon organoids of Familial Adenomatous Polyposis patients

Project description:Here, we generated bulk RNA-seq data on colon organoids derived from both healthy and familial adenomatous polyposis patients. We related findings observed within this dataset to differential expression findings from a publicly available colorectal cancer cohort.

2022-10-13 | GSE207398 | GEO

Familial Adenomatous Polyposis (FAP) and Other Polyposis Syndromes.

Project description:There have been significant advances in our knowledge about the molecular changes that precede and accompany the development of inherited predispositions to colorectal cancer. In this review the clinical relationship to the molecular changes associated with the polyposis syndromes is presented. The aim is to put into context the diverse findings that have been shown to be associated with the development of colorectal cancer in persons who harbor a predisposition to develop disease at unusually early ages. The main focus will be on familial adenomatous polyposis as it serves as a model disease and is the most extensively studied of all of the polyposis syndromes. In addition some information is provided that explains the relationship between a germline change in one gene and what consequences that can have for a particular cell and the development of disease.

| S-EPMC2840009 | biostudies-other

Genetic alteration of colorectal adenoma-carcinoma sequence among gastric adenocarcinoma and dysplastic lesions in a patient with attenuated familial adenomatous polyposis.

Project description:BackgroundFamilial adenomatous polyposis (FAP) is characterized by colorectal polyposis and adenocarcinoma that is frequently accompanied by extracolonic neoplasm. The risk of gastric carcinoma is increasing in Western FAP patients as well as Asian patients.MethodsWe report the case of an FAP patient with fundic gland polyposis who developed gastric adenocarcinoma and metachronous pyloric gland adenomas. These tumors were endoscopically resected, and immunohistochemistry with gastric mucin (i.e., MUC6, MUC5AC) showed that the tumors belonged to the gastric subtype. Somatic mutation profiles were determined by target amplicon sequencing using a next-generation sequencer.ResultsGermline APC variant c.5782delC was found by direct sequencing and somatic KRAS mutations in these tumors were identified by next-generation sequencing. Different KRAS mutation alleles (KRAS p.Gly12Ala, p.Gly12Arg, and p.Gly12Asp) indicated these dysplastic lesions developed from a distinct origin in fundic gland polyposis. Sequential mutations of the APC and KRAS were judged-based on a database search-to be characteristic of the adenoma-carcinoma sequence in colorectal carcinogenesis.ConclusionThe colonic adenoma-carcinoma sequence among gastric adenocarcinoma and dysplastic lesions was indicated in FAP-associated gastric carcinogenesis.

| S-EPMC7507424 | biostudies-literature

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