Mosaic chromosome Y loss and testicular germ cell tumor risk

Studies have suggested mosaic loss of chromosome Y (mLOY) in blood-derived DNA is common in older men. Cohort studies investigating mLOY and mortality have reported contradictory results. Previous work found a 1.6 Mb deletion of the AZFc region on the Y chromosome (the “gr/gr” deletion) is associated with both male infertility and increased risk of testicular germ cell tumors (TGCT). We investigated whether mosaic loss across the entire Y chromosome was associated with TGCT. We obtained blood and buccal-derived DNA from two case-control studies: the NCI Familial Testicular Cancer Study (FTC; cases=172, controls=163) and the NCI US Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study (STEED; cases=506, controls=611). We utilized 15 quantitative polymerase chain reactions (qPCR) spanning the Y chromosome to assess mLOY. Multivariate logistic regression models adjusted for study batch effects detected no significant overall relationship between mean chromosome Y T/R ratio and TGCT (OR=0.34, 95% CI=0.10–1.17, P=0.09). When restricted to familial TGCT cases, a significantly lower T/R ratio was observed in cases compared with controls (0.993 vs 1.014, P-value=0.01). Our study suggests mLOY, as measured by 15 probes spanning the Y chromosome, could be associated with familial TGCT, but larger studies are required to confirm this observation.