Hypermethylation of a gene, a common epigenetic modification (epimutation), is associated with transcriptional silencing and can predispose to cancer or other diseases. Robyn Ward and colleagues have found evidence of the germ-line transmission of an MLH1 (a mismatch repair gene) epimutation that causes cancer susceptibility. However, the inheritance pattern is non-Mendelian.

Both epimutations and germ-line sequence mutations in MLH1 cause susceptibility to hereditary nonpolyposis colorectal cancer (HNPCC). Although epimutations usually arise somatically, eight cases of germ-line MLH1 epimutations have been reported previously, but in these cases there was no evidence of intergenerational transmission. However, because germ-line MLH1 epimutations exist, it implies that they could be inherited.

To test this possibility, Ward and colleagues identified two other individuals with MLH1 epimutations and studied their families. To find these individuals, the authors examined the methylation of the MLH1 promoter in 24 patients who had colorectal or endometrial cancer before the age of 50 years and who lacked MLH1 and MSH2 (another mismatch repair gene implicated in HNPCC) sequence mutations. They identified two unrelated women, Patient A and Patient B, who had dense methylation, and therefore transcriptional silencing, of one MLH1 allele in all somatic cells. An analysis of nine first-degree relatives of these patients showed that one of Patient A's four sons had methylation of MLH1 consistent with germ-line transmission. However, his sperm did not carry MLH1 methylation, indicating that the inherited MLH1 epimutation had reverted to normal during spermatogenesis. To complicate matters further, haplotype mapping of the methylated allele carried by Patient A showed that two of her other sons and her sister also carried the same allele, but it was not methylated.

There are several possibilities for why this pattern of inheritance might have occurred. Epimutations might be more efficiently erased during spermatogenesis than during oogenesis. Another possibility is that epimutations are erased during gametogenesis, but re-established owing to cis- or trans-acting genetic factors. Regardless, these data imply that the inheritance of epigenetic mutations can predispose to cancer risk.