Genetics, genomics and clinical features of adenomatous polyposis

Abstract

Adenomatous polyposis syndromes are hereditary conditions characterised by the development of multiple adenomas in the gastrointestinal tract, particularly in the colon and rectum, significantly increasing the risk of colorectal cancer and, in some cases, extra-colonic malignancies. These syndromes are caused by germline pathogenic variants (PVs) in genes involved in Wnt signalling and DNA repair. The main autosomal dominant adenomatous polyposis syndromes include familial adenomatous polyposis (FAP) and polymerase proofreading-associated polyposis (PPAP), caused by germline PVs in APC and the POLE and POLD1 genes, respectively. Autosomal recessive syndromes include those caused by biallelic PVs in the DNA mismatch repair genes MLH1, MSH2, MSH6, PMS2, MSH3 and probably MLH3, and in the base excision repair genes MUTYH, NTHL1 and MBD4. This review provides an in-depth discussion of the genetic and molecular mechanisms underlying hereditary adenomatous polyposis syndromes, their clinical presentations, tumour mutational signatures, and emerging approaches for the treatment of the associated cancers. Considerations for genetic testing are described, including post-zygotic mosaicism, non-coding PVs, the interpretation of variants of unknown significance and cancer risks associated with monoallelic variants in the recessive genes. Despite advances in genetic testing and the recent identification of new adenomatous polyposis genes, many cases of multiple adenomas remain genetically unexplained. Non-genetic factors, including environmental risk factors, prior oncologic treatments, and bacterial genotoxins colonising the intestine - particularly colibactin-producing Escherichia coli - have emerged as alternative pathogenic mechanisms.

Keywords: APC; Familial adenomatous polyposis; Gastrointestinal polyposis; Hereditary colorectal cancer; MBD4; MMR; MUTYH; NTHL1; POLD1; POLE.

Fig. 1

Adenomatous polyposis syndromes, mode of inheritance, causal genes, affected molecular pathways and associated COSMIC tumour mutational signatures, and possible causes of adenomatous polyposis in patients without germline PVs in known polyposis genes. Abbreviations: CMMRD, constitutional mismatch repair deficiency; CRC, colorectal cancer; FAP, familial adenomatous polyposis; LS, Lynch syndrome; MANS, MBD4-associated neoplasia syndrome; MAP, MUTYH-associated polyposis; MMR, mismatch repair; NTS, NTHL1 tumour syndrome; PPAP, polymerase proofreading-associated polyposis; ED, exonuclease domain