Genetic studies of common cancers have detected a significant component of unattributed heritability, leaving room for other underlying factors. This review focuses on two epigenetic mechanisms whose role in hereditary cancer susceptibility has begun to unfold only recently: constitutional epimutations and micro-RNA-based regulation of gene expression. Both mechanisms may play a role in Lynch syndrome (hereditary non-polyposis colorectal cancer), a Mendelian multi-organ cancer syndrome, predisposition to which is caused by germline defects in the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Lynch syndrome not only serves as a model for cancers arising through deficient DNA mismatch repair (relevant for 10-25% of all colorectal, endometrial, and other cancers), but also highlights the significance of the epigenetic component in cancer development. Knudson’s hypothesis postulates that tumor suppressor gene inactivation requires two hits, with the first one occurring either in somatic cells (sporadic cancer) or in the germline (hereditary cancer), whereas the second hit is always somatic. Cumulative evidence suggests that, besides genetic mutations, either hit may be epigenetic. Methylation at selected tumor suppressor gene promoters accompanies the development of different tumors in Lynch syndrome, and inactivation of the susceptibility genes MLH1 and MSH2 by epigenetic mechanisms may be present already in the germline. Furthermore, germline alterations at micro-RNA loci have been identified in various cancer syndromes, suggesting micro-RNA-based mechanisms of cancer predisposition. A better understanding of the interplay between genetic and epigenetic factors in cancer susceptibility provides the basis for improved diagnostics, prevention and therapy in the respective cancers.
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