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.

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.