The genetics of FAP and FAP-like syndromes

Abstract

The presence of multiple adenomatous polyps in the large bowel confers a high lifetime risk of colorectal cancer. Although many cases of classical familial adenomatous polyposis (> 100 polyps) can be accounted for by mutations in the adenomatous polyposis coli (APC) gene, a large group of patients remains with multiple (5-100) adenomas and in whom there is no detectable APC mutation. Recently two new genetic variants have been found to be associated with multiple colorectal adenomas and cancer, MYH/MUTYH on chromosome 1p and the HMPS/CRAC1 locus on chromosome 15q13-q14. New information also continues to emerge regarding the less common hamartomatous polyposis conditions, Peutz-Jeghers syndrome and Juvenile Polyposis syndrome. In approximately half to two thirds of these families, germline genetic variants can now be uncovered. In this review we draw together some of the most recent information pertinent to the molecular pathogenesis of colorectal polyposis.

Colorectal Cancer Risks in Relatives of Young-Onset Cases: Is Risk the Same Across All First-Degree Relatives?

“…Other syndromes that predispose to CRC are due to mutations in the base-excision repair gene, MYH, and Familial Adenomatous Polyposis due to mutations in the APC gene. 4 It is unclear if the observed familial aggregation risks for CRC is explained just by these known conditions or if this hereditary risk exists also for MSS CRC not related to MYH or APC mutations. Familial cancer risk as assessed in the population-based Swedish Family-Cancer Database was found to be increased in siblings greater than in parents of CRC probands not classified by either DNA MMR status or by germline MYH mutation status.…”

Cross-Species Comparison of Human and Mouse Intestinal Polyps Reveals Conserved Mechanisms in Adenomatous Polyposis Coli (APC)-Driven Tumorigenesis

“…11,12 The vast majority (70 to 90%) of FAP patients have been shown to carry germline APC mutations. 13 More recently, biallelic mutations in the base excision repair gene MYH were found in a subset of polyposis families with attenuated clinical presentation and an autosomal recessive inheritance pattern, often referred to as MAP (MYH-associated polyposis). 14 In view of its initiating role in intestinal cancer, several preclinical models carrying germline mutations in the endogenous mouse Apc tumor supressor gene have been generated, and their phenotype has been characterized.…”

Genetic Bases for Predisposition to Common Multifactorial Disease in Man. Part II

“…Recently, two new genetic variants have been found to be associated with multiple colorectal adenomas and cancer, MYH/MUTYH on chromosome 1p and the HMPS/CRAC1 locus on chromosome 15q13-q14 (9,37,60). Biallelic mutations in the MYH gene are associated with an attenuated familial adenomatous polyposis phenotype.…”