A maternal germline mutator phenotype in a family affected by heritable colorectal cancer

Abstract

Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene,MUTYH, are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner, and some evidence has also linkedMUTYHto elevated incidence of other cancers as well as elevated mutation rates in normal somatic and germline cells. Here, we use whole genome sequencing to measure germline de novo mutation rates in a large extended family affected by pathogenicMUTYHvariation and a history of colorectal cancer. Although this family’s genotype, p.Y179C/V234M (c.536A>G/700G>A on transcript NM_001128425), contains a variant with conflicting functional interpretations, we use anin vitrocell line assay to determine that it partially attenuates MUTYH’s function. In the children of mothers affected by the Y179C/V234M genotype, we identify an elevation of the C>A mutation rate that is weaker than mutator effects previously reported to be caused by other pathogenicMUTYHgenotypes, suggesting that mutation rates in normal tissues may be useful for classifying cancer-associated variation along a continuum of severity. Surprisingly, we detect no significant elevation of the C>A mutation rate in children born to a father with the same biallelicMUTYHgenotype, despite calculating that we should have adequate power to detect such a mutator effect. This suggests that the oxidative stress repaired byMUTYHmay contribute more to female reproductive aging than male reproductive aging in the general population.