Genetic predisposition to colorectal cancer: syndromes, genes, classification of genetic variants and implications for precision medicine

Abstract

This article reviews genes and syndromes associated with predisposition to colorectal cancer (CRC), with an overview of gene variant classification. We include updates on the application of preventive and therapeutic measures, focusing on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and immunotherapy. Germline pathogenic variants in genes conferring high or moderate risk to cancer are detected in 6-10% of all CRCs and 20% of those diagnosed before age 50. CRC syndromes can be subdivided into nonpolyposis and polyposis entities, the most common of which are Lynch syndrome and familial adenomatous polyposis, respectively. In addition to known and novel genes associated with highly penetrant CRC risk, identification of pathogenic germline variants in genes associated with moderate-penetrance cancer risk and/or hereditary cancer syndromes not traditionally linked to CRC may have an impact on genetic testing, counseling, and surveillance. The use of multigene panels in genetic testing has exposed challenges in the classification of variants of uncertain significance. We provide an overview of the main classification systems and strategies for improving these. Finally, we highlight approaches for integrating chemoprevention in the care of individuals with genetic predisposition to CRC and use of targeted agents and immunotherapy for treatment of mismatch repair-deficient and hypermutant tumors. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: VUS; cancer genes; cancer predisposition; cancer syndromes; checkpoint inhibitors; chemoprevention; hereditary colorectal cancer; immuno-oncology; polyposis; variants of uncertain significance.

Figure 1.

Phenotypic classification of nonpolyposis and polyposis CRC syndromes, mode of inheritance, causal genes and affected molecular pathways. Note: Germline AXIN2 autosomal dominant mutations (Wnt pathway) may cause oligodontia-colorectal cancer syndrome characterized by severe permanent tooth agenesis and the presence CRC or precancerous colonic or gastric lesions of variable types (adenomas, hyperplastic polyps) [–134]. Due to the still undefined CRC and polyposis phenotype, it has not been included in the figure. Abbreviations: BER, base excision repair; CMMRD, constitutional mismatch repair deficiency; HMPS, hereditary mixed polyposis syndrome; MAP, MUTYH-associated polyposis; MMR, DNA mismatch repair; PPAP, polymerase proofreading-associated polyposis; SPS, serrated polyposis syndrome.

Figure 2.

Strategy for universal tumor screening for Lynch syndrome in CRC patients (Adapted from Hampel et al. 2018 [29]). The different etiologies of MMR-d CRCs are: i) germline MMR gene mutation; ii) serrated pathway lesions (somatic BRAF mutation and/or MLH1 promoter hypermethylation); iii) double somatic MMR gene mutations; iv) somatic MMR gene mutation secondary to a POLE or POLD1 exonuclease mutation or to biallelic MUTYH mutations. Abbreviations: CRC, colorectal cancer; IHC, immunohistochemistry; MMR, DNA mismatch repair; MMR-d, mismatch repair deficient; MSI, microsatellite instability; MSI-H, high level of microsatellite instability (microsatellite unstable); NGS, next generation sequencing.