A novel locus predicts spermatogenic recovery among childhood cancer survivors exposed to alkylating agents

Exposure to high doses of alkylating agents is associated with increased risk of impaired spermatogenesis among non-irradiated male survivors of childhood cancer, but there is substantial variation in this risk. Here we conducted a genetic study for impaired spermatogenesis utilizing whole genome sequencing data from 167 non-irradiated male childhood cancer survivors of European ancestry from the St. Jude Lifetime Cohort treated with cyclophosphamide equivalent dose (CED)≥4000 mg/m2. Sperm concentration from semen analysis was assessed as the primary outcome. Common variants (MAF>0.05) were adjusted for age at cancer diagnosis, CED, and top principal components. Rare/low-frequency variants (MAF≤0.05) were evaluated jointly by various functional annotations and 4-kb sliding windows. A novel locus at 7q21.3 containing TAC1/ASNS was associated with decreased sperm concentration (rs7784118: P=3.5x10-8). This association was replicated in two independent samples of SJLIFE survivors of European ancestry, including 34 non-irradiated male survivors treated with 0<CED<4000 mg/m2 (P=3.1x10-4) and 24 male survivors treated with CED≥4000 mg/m2 and radiation therapy<40 Gray (P=0.012). No association was observed among survivors not exposed to alkylating agents included in the CED (P>0.29). rs7784118 conferred 3.48- and 9.73-fold increases in risk for clinically defined oligospermia and azoospermia and improved prediction of normospermic, oligospermic, and azoospermic states by 13.7%, 5.3%, and 21.7%. rs7784118 was associated with decreased testosterone level, increased levels of follicle-stimulating and luteinizing hormones, and 8.52-fold increased risk of Leydig cell failure. Additional research is warranted to determine how this SNP influences spermatogenesis and to assess its clinical utility in characterizing high-risk survivors and guiding intervention strategies.