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

Area of Science:

• Genetics
• Epigenetics
• Cancer Biology

Background:

• Constitutional epimutations, characterized by hypermethylation of one allele across somatic cells, are recognized causes of cancer predisposition.
• Understanding the origins and inheritance patterns of these epimutations is crucial for evaluating cancer risks within families.

Observation:

• A 29-year-old man presented with early-onset colorectal cancer and a constitutional MLH1 epimutation, marked by allele-specific loss of MLH1 expression.
• This epimutation, present in approximately 50% of alleles, remained stable over 16 years and was inherited from his asymptomatic mother.

Findings:

• The mother carried the same epimutation, but at a low level (less than 5% of somatic cells), without any genetic alteration.
• This case demonstrates that a constitutional epimutation in offspring can arise from low-level somatic mosaicism in an asymptomatic parent.

Implications:

• Low-level mosaicism for epimutations in seemingly unaffected individuals may confer significant cancer risk to their children.
• This highlights the importance of considering epigenetic inheritance in cancer risk assessment for families.