The genetic basis of colonic adenomatous polyposis syndromes

Abstract

Colorectal cancer (CRC) is one of the most common forms of cancer worldwide and familial adenomatous polyposis (FAP) accounts for approximately 1% of all CRCs. Adenomatous polyposis syndromes can be divided into; familial adenomatous polyposis (FAP) -classic FAP and attenuated familial adenomatous polyposis (AFAP), MUTYHassociated polyposis (MAP), NTHL1-associated polyposis (NAP) and polymerase proofreading-associated polyposis (PPAP). The polyposis syndromes genetics and clinical manifestation of disease varies and cases with clinical diagnosis of FAP might molecularly show a different diagnosis. This review examines different aspects of the adenomatous polyposis syndromes genetics and clinical manifestation of disease; in addition the genotype-phenotype and modifier alleles of FAP will be discussed. New technology has made it possible to diagnose some of the APC mutation negative patients into their respective syndromes. There still remain many molecularly undiagnosed adenomatous polyposis patients indicating that there remain causative genes to be discovered and with today's technology these are expected to be identified in the near future. The knowledge about the role of modifier alleles in FAP will contribute to improved pre-symptomatic diagnosis and treatment. New novel mutations will continually be discovered in genes already associated with disease and new genes will be discovered that are associated with adenomatous polyposis. The search for modifier alleles in FAP should be made a priority.

APC and MUTYH Analysis in FAP Patients: A Novel Mutation in APC Gene and Genotype-Phenotype Correlation

“…Certainly, APC and MUTYH are not the only genes predisposing to the familial polyposis. Indeed, recent literature indicates that also other genes may be involved, like NTHL1 , POLD1 and POLE genes, even though they are able to explain only a small proportion of cases [ 35 , 36 ]. Moreover, new candidate genes are continually discovered by exome sequencing and are currently subject to further investigation before their use in the diagnosis of these patients [ 37 ].…”

CD36 – a plausible modifier of disease phenotype in familial adenomatous polyposis

“…The disease spectrum observed in patients with germline causative variants in APC has been associated with a genotype/phenotype correlation where some variants are linked to severe and others milder forms of the disease [ 9 ]. Notwithstanding, phenotype differences in patients with the same mutation are still observed and modifiers of disease severity still await discovery.…”

“…Many reports have confirmed the severity of codon 1309 variants but not all patients with this mutation present with similar disease characteristics, with some patients displaying extremely severe polyposis whereas others have significantly less dense polyposis. These evidence suggests that there are other factors (genetic and/or environmental) influencing disease expression [ 5 , 9 ].…”

A proposed therapeutic algorithm for colorectal cancer prevention, based on endoscopic polypectomies in patients with multiple colonic polyps

“…The issue of polyps and polypectomy in gastroenterology has been at the forefront of many scientific papers over the past years (1,2), but few reports have addressed the issue from the general surgeon`s perspective (3).…”

“…For both sexes the occurrence of cancer takes place at a higher age than the appearance of polyps, suggesting that early detection and removal of polyps may prevent their malignancy; in men, the spread is about 8 years (61 years polyps vs 69 years CRC) and in women less than 2 years (64 years polyps vs 66 years CRC). Figure 3 illustrates the variation of the "age" parameter in relation to the presence of CRC and the sex of the patients, observing the higher age difference in male patients (1) with malignant tumors versus the polyps and female patients (2) where the difference between the presence of CRC and polyps is much smaller (Figure 3). Figure 4.…”