Epimutations and Cancer Susceptibility Mathew Aidan Sloane, Prince of Wales Clinical School and Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia Luke Benjamin Hesson, Prince of Wales Clinical School and Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia Robyn Lynne Ward, Prince of Wales Clinical School and Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia 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 epige- netic 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 leu- kaemias and some imprinting disorders. The molecular cause of most epimutations is unknown but it is hypo- thesised that they could be driven by hitherto uni- dentified genetic alterations in long-range cis-regulatory elements that manifest as DNA methylation or repressive histone modifications at a gene promoter. An under- standing of the molecular origin of epimutations may help elucidate the basis of predisposition to cancer. Introduction It is well established that germline genetic mutations in the coding region of tumour suppressor genes cause familial cancer syndromes. Yet not all individuals with a clinical diagnosis of familial cancer have a pathogenic mutation in the disease causing gene. This observation has been explained on the basis that these individuals must harbour new types of alterations, including perturbations of the genomic regions that are regulated by multiple promoters, distant regulatory elements and epigenetic factors (Encode Project Consortium et al., 2012). Epigenetics refers to the structural adaptation of a genomic region, without a change in the deoxyribonucleic acid (DNA) sequence. The state of gene activity is altered through the effects of DNA methylation, histone modifications, noncoding ribonucleic acids (RNAs) and higher-order chromatin structures (Bird, 2007). An epimutation is an aberration in these epigenetic marks, which causes transcriptional silencing of a gene that is normally active, or the expression of a gene that is normally inactive (Hesson et al., 2010). Tumour suppressor genes are often epigenetically inactivated in sporadic cancers (Kulis and Esteller, 2010); however, in this article the focus is specifically on the constitutional epimutations that are present in the somatic tissues derived from all three embryonic germ layers and which predispose to cancer (Hitchins, 2013). Epimutations are rare and account for some imprinting disorders (e.g. Sparago et al., 2004) and to date their role in cancer predisposition has only been well documented in the hereditary bowel cancer condition, Lynch syndrome (Hitchins, 2013) and chronic lymphocytic leukaemia (CLL) (Raval et al., 2007). Epi- mutations explain cancer predisposition in a proportion of patients who test negative for germline sequence altera- tions in known cancer predisposition genes. However, the mechanisms that give rise to epimutations are debated. The authors propose that constitutional epimutations are determined by genetic sequence alterations in cis-reg- ulatory elements and herein Lynch syndrome is used to illustrate the complex relationship between the epigenome, the genome and cancer susceptibility. Instances of epimu- tations with a known mechanism are described, as well as other possible novel mechanisms of epimutations that could account for unexplained familial cancers. See also: Chromatin Structure and Domains; Methylation-medi- ated Transcriptional Silencing in Tumorigenesis Familial Cancers – Is it all in the DNA? Lynch syndrome, familial adenomatous polyposis (FAP), Li–Fraumeni syndrome, familial retinoblastoma and von Advanced article Article Contents . Introduction . Familial Cancers – Is it all in the DNA? . The Many Faces of Epimutations . Possible Alternative Mechanisms to Explain the Origin of Epimutations . Concluding Remarks . Acknowledgement Online posting date: 17 th March 2014 eLS subject area: Genetics & Disease How to cite: Sloane, Mathew Aidan; Hesson, Luke Benjamin; and Ward, Robyn Lynne (March 2014) Epimutations and Cancer Susceptibility. In: eLS. John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0024615 eLS & 2014, John Wiley & Sons, Ltd. www.els.net 1