Abstract 811: Mosaic chromosome Y loss is not associated with testicular germ cell tumor risk

Background Testicular germ cell tumors (TGCTs) affect approximately 6 in 100,000 men with peak incidence in men 15 to 40 years of age. Established risk factors include family history of disease, undescended testis, contralateral TGCT, impaired fertility, and 21 GWAS susceptibility loci. Recent evidence suggests a 1.6 Mb deletion in the AZFc region (“gr/gr” deletion) of chromosome Y previously associated with male infertility is also associated with two- and three-fold increased risks of sporadic and familial TGCT, respectively. Furthermore, population-based studies have suggested mosaic chromosome Y loss in blood-derived DNA may be associated with increased risk of various solid tumors. Our aim was to investigate if mosaic loss across the entire Y chromosome is a TGCT risk factor. Methods We obtained blood and buccal-derived DNA from two studies: the NCI Familial Testicular Cancer Study (FTC, Cases = 172, Controls = 163) and NCI9s US Servicemen9s Testicular Tumor Environmental and Endocrine Determinants Study (STEED, Cases = 506, Controls = 611). We designed a quantitative polymerase chain reaction (qPCR) with 15 probes spanning the Y chromosome to assess Y loss. Samples were run in triplicate across three batches and normalized to a standard curve. We quantified probe signals as a target to reference (T/R) ratio, and averaged ratios across the 15 probes to yield an overall Y chromosome signal. Results On average, men with TGCT had slightly lower mean T/R ratios compared with control men lacking TGCT (1.02 vs. 1.03). Multivariate logistic regression models adjusted for study batch effects detected no significant relationship between mean Y chromosome T/R ratio and TGCT risk (OR = 0.34, 95% CI = 0.10-1.17, P = 0.09). A similar null relationship was observed when using a threshold of 1.5 standard deviations below the mean T/R ratio to dichotomize between mosaic Y loss and no mosaic Y loss (OR = 0.59, 95% CI = 0.21-1.63, P = 0.31). Conclusion Our study suggests that mosaic chromosome Y loss, as measured by 15 probes spanning the Y chromosome, is not associated with either sporadic or familial TGCT risk. Further studies aimed at investigating the AZFc region of the Y chromosome are needed to better assess whether this locus is directly associated with TGCT risk or is indirectly associated by means of a shared relationship with impaired fertility. Citation Format: Mitchell J. Machiela, Casey L. Dagnall, Anand Pathak, Jennifer T. Loud, Stephen J. Chanock, Mark H. Greene, Katherine A. McGlynn, Douglas R. Stewart. Mosaic chromosome Y loss is not associated with testicular germ cell tumor risk. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 811.