Dawning of the epigenetic era in hereditary cancer.

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Abstract

Lynch syndrome, defined as the autosomal dominant predisposition to colorectal, endometrial and additional cancers due to heterozygous germline mutations within the mismatch repair genes MLH1, MSH2, MSH6 and PMS2, was the first hereditary cancer syndrome to be recognized. It has probably also been the most intensively studied high-risk cancer syndrome in terms of its clinical manifestations and genetic etiologies and provides an exemplary model for the rapid and continual translation of research-based findings into routine clinical policies and practices for the benefit of patients. It is unsurprising then that the intersection between epigenetics and cancer predisposition was first exemplified by the finding of constitutive epimutations of the MLH1 and MSH2 genes as an alternative cause for Lynch syndrome in the absence of a conventional germline mismatch repair mutation. However, the role of epigenetic aberrations in the pathogenesis of Lynch syndrome may extend beyond etiology. As we enter a new era of epigenomics in disease pathogenesis, this commentary asks provocative questions on the role that epigenetic aberrations may play in cancer development the context of Lynch syndrome. We also highlight the need for rapid incorporation of clinically-relevant epigenetic-based findings into routine clinical practice to maximize the benefits seen by patients.