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Brief Report
October 2015

Mosaic Epigenetic Inheritance as a Cause of Early-Onset Colorectal Cancer

Author Affiliations
  • 1Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia
  • 2Department of Paediatrics, University of Adelaide, South Australia, Australia
  • 3Sonic Healthcare, Macquarie Park, New South Wales, Australia
  • 4Brian Wilson Chancellery, University of Queensland, Brisbane, Queensland, Australia
JAMA Oncol. 2015;1(7):953-957. doi:10.1001/jamaoncol.2015.1484

Importance  Constitutional hypermethylation of 1 allele throughout the soma (constitutional epimutation) is an accepted mechanism of cancer predisposition. Understanding the origin and inheritance of epimutations is important for assessing cancer risk in affected families.

Observations  We report a 29-year-old man with early-onset colorectal cancer who showed a constitutional MLH1 epimutation (approximately 50% of alleles methylated and allele-specific loss of MLH1 expression) that was stable over a 16-year period. The epimutation was inherited without a genetic alteration from his asymptomatic mother. She showed methylation on the same allele but in less than 5% of her somatic cells.

Conclusions and Relevance  These findings indicate that low-level somatic mosaicism for an epimutation in an asymptomatic parent can produce a nonmosaic constitutional epimutation in a child. Asymptomatic low-level methylation in some individuals may be associated with substantial cancer risk to their offspring.