Epimutations and Cancer Susceptibility

Abstract

Abstract Germline genetic testing often fails to detect a mutation in the coding region of the relevant predisposition gene despite a strong clinical suspicion of a hereditary cancer syndrome. In some cases, cancer predisposition is caused by a constitutional epimutation. Epimutations are epigenetic aberrations, typically defined by deoxyribonucleic acid (DNA) methylation, that predispose individuals to cancer through soma‐wide changes in the expression of the afflicted gene. They have been documented in patients with colorectal cancer, chronic lymphocytic leukaemias and some imprinting disorders. The molecular cause of most epimutations is unknown but it is hypothesised that they could be driven by hitherto unidentified genetic alterations in long‐range cis ‐regulatory elements that manifest as DNA methylation or repressive histone modifications at a gene promoter. An understanding of the molecular origin of epimutations may help elucidate the basis of predisposition to cancer. Key Concepts: Constitutional epimutations predispose carriers to early‐onset cancer. A constitutional epimutation inactivates expression from one allele of a gene throughout normal tissues. Primary constitutional epimutations are not inherited in a Mendelian fashion. They are absent in the germline but are present in tissues derived from all three germ layers. Secondary constitutional epimutations cosegregate with an in cis genetic change. In cis DNA elements such as enhancers and insulators regulate gene expression and are potential sites of genetic alterations that give rise to epimutations. Identifying the cause of epimutations will help explain the origin of some cases of familial cancer without a germline DNA mutation.