Genetic predisposition to colorectal cancer: Where we stand and future perspectives

Abstract

The development of colorectal cancer (CRC) can be influenced by genetic factors in both familial cases and sporadic cases. Familial CRC has been associated with genetic changes in high-, moderate- and low-penetrance susceptibility genes. However, despite the availability of current gene-identification techniques, the genetic causes of a considerable proportion of hereditary cases remain unknown. Genome-wide association studies of CRC have identified a number of common low-penetrance alleles associated with a slightly increased or decreased risk of CRC. The accumulation of low-risk variants may partly explain the familial risk of CRC, and some of these variants may modify the risk of cancer in patients with mutations in high-penetrance genes. Understanding the predisposition to develop CRC will require investigators to address the following challenges: the identification of genes that cause uncharacterized hereditary cases of CRC such as familial CRC type X and serrated polyposis; the classification of variants of unknown significance in known CRC-predisposing genes; and the identification of additional cancer risk modifiers that can be used to perform risk assessments for individual mutation carriers. We performed a comprehensive review of the genetically characterized and uncharacterized hereditary CRC syndromes and of low- and moderate-penetrance loci and variants identified through genome-wide association studies and candidate-gene approaches. Current challenges and future perspectives in the field of CRC predisposition are also discussed.

Keywords: Hereditary colorectal cancer, Familial colorectal cancer, High penetrance, Low penetrance, Cancer syndromes, Cancer susceptibility, Hereditary cancer genes, Risk variants, Heritability

Core tip: The risk of developing colorectal cancer (CRC) can have genetic influences, especially when there is a family history of the disease. Much of this genetic predisposition to develop cancer is already known, including high-penetrance genes, i.e., those responsible for hereditary cases, and low-penetrance alleles, which are responsible for both sporadic and familial cases. However, despite recent developments in gene identification techniques, the genetic causes of many hereditary cases remain unknown. This review details the hereditary CRC syndromes and their genetic causes, the roles of low- and moderate-risk genetic factors in familial cases and the state-of-the-art in the identification of new causal genes.