Abstract IA08: Polyposis beyond FAP (and APC)

Abstract

Abstract Familial adenomatous polyposis (FAP) is the most common high-penetrant Mendelian syndrome predisposing to adenomatous polyposis. FAP is caused by monoallelic germline mutations in the gene APC, and shows autosomal dominant inheritance. A somatic mutation in the remaining wild type APC allele results in loss of APC activity, which is one of the initiating events of adenoma development. The high proliferation rate in the colorectum increases the chance that an intestinal epithelium cell obtains this somatic second hit, which explains why FAP patients usually develop hundreds to thousands of adenomatous polyps and, if untreated, inevitably develop colorectal cancer (CRC). Nevertheless, the majority of polyposis patients and families are not explained by mutations in APC. Since the discovery of FAP in 1991, several additional polyposis syndromes have been discovered, usually associated with lower number of polyps and somewhat less elevated risk of CRC. Many of the genes underlying these syndromes play a role in DNA repair and have a wider tumor spectrum. As becomes apparent from the somatic mutation profiles in tumors of these polyposis patients, these DNA repair deficiencies cause increased somatic mutation rates that affect proliferating tissues like the colon, and accelerate the formation of polyps and carcinomas. As an example, polymerase proofreading associated polyposis (PPAP) is a recently discovered autosomal dominant syndrome caused by mutations in the exonuclease domains of the polymerase genes POLE and POLD1. In addition, mutations in the base excision repair genes MUTYH and NTHL1, and the mismatch repair gene MSH3 underlie autosomal recessive polyposis syndromes. Notably, the incidences of these syndromes, particularly those recently discovered, are low. The question therefore arises how many more genes in which mutations cause high-penetrant polyposis still await their discovery. Here, I will present the latest findings on NTHL1-associated polyposis, it's expected incidence and its phenotypic characteristics. Furthermore, I will discuss the possible role of other DNA glycosylase genes of the base excision repair pathway in the development of polyposis and colorectal cancer. Citation Format: Roland P. Kuiper. Polyposis beyond FAP (and APC). [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA08.