LINE-1 methylation is inherited in familial testicular cancer kindreds

BACKGROUND: Testicular germ cell tumors (TGCT) are the most frequent cancers among young men. There is a clear familial component to TGCT etiology, but no high-penetrance susceptibility gene has been identified. Epigenetic aberrations of the genome represent an alternative mechanism for cancer susceptibility; and, studies suggest that epigenetic changes that influence cancer risk can be inherited through the germline. Global DNA hypomethylation has been associated with the risk of cancers of the bladder and head/neck. METHODS: We performed a pilot study of global methylation at long interspersed nuclear elements-1 (LINE-1) in peripheral blood DNA isolated from 466 family members of 101 multiple-case testicular cancer families. RESULTS: Investigating the correlation of LINE-1 methylation levels among parent-child pairs independent of affection status (n = 355) revealed a strong positive association only between mother-daughter (r = 0.48, P = <0.001) and father-daughter pairs (r = 0.31, P = 0.02), suggesting gender-specific inheritance of methylation. Incorporating cancer status, we observed a strong correlation in LINE-1 methylation levels only among affected father-affected son pairs (r = 0.49, P = 0.03). There was a marginally significant inverse association between lower LINE-1 methylation levels and increased TGCT risk, compared with healthy male relatives (P = 0.049). CONCLUSIONS: Our data suggest that heritability of LINE-1 methylation may be gender-specific. Further, the strong correlation between LINE-1 methylation levels among affected father-affected son pairs suggests that transgenerational inheritance of an epigenetic event may be associated with disease risk. Larger studies are needed to clarify these preliminary observations.