Abstract 2622: SNP markers in the FGF9 and MAP3K1 region associate with testicular germ cell tumor susceptibility

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Testicular germ cell tumors (TGCT) are the most common cancers in young men, and several lines of evidence point to their substantial genetic component. To date, genome-wide association (GWA) studies have uncovered six TGCT susceptibility loci. Together these loci account for 11-16% of TGCT disease risk to first degree relatives, arguing that additional genetic variation contributing to TGCT susceptibility must exist. Recently we and others indentified variation at DMRT1 associated with TGCT risk. DMRT1 is highly conserved across many species and plays a crucial role in male gonadal development and sex determination. Deletions in DMRT1 lead to male to female (XY) sex reversal. Therefore, we undertook a targeted pathway-based analysis of genes influencing XY sex reversal to identify associations with TGCT risk. Through review of the literature, we identified 27 additional genes in which mutations or deletions are associated with XY sex reversal. Using our existing GWA data in 349 cases and 919 controls, ∼570 risk markers in the 28 candidate loci were evaluated for replication based on a significance threshold of p < 2 x 10−5 for at least two SNP markers. Two markers that mapped near to MAP3K1 and FGF9 meet these criteria. We genotyped the most statistically significant SNP markers in the MAP3K1 ([rs252906][1]; p = 1.89 x 10Δ5) and FGF9 ([rs628137][2]; p = 1.66 x 10Δ5) region in two independent replication sample sets, consisting of 439 cases of TGCT and 960 controls and of 768 cases and 674 controls respectively. In combined analysis, TGCT cases had elevated odds of carriage of the [rs252906][1] major T allele [per-allele odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16, 1.377; P = 5.87 × 10−5] and the [rs628137][2] major G allele (per allele OR = 1.20, 95% CI 1.08, 1.34, P = 5.28 x 10−4 compared with controls. Similarly to KITLG, the susceptibility locus most strongly associated with TGCT risk, FGF9 is associated with proliferation, migration and survival of primordial germ cells, the progenitor cells for human TGCT. MAP3K1 and FGF9 play a crucial role in normal testes development. These finding strengthen the supposition that variation in genes influencing sex determination, and male germ cell development and differentiation play an important role in inherited TGCT susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2622. doi:1538-7445.AM2012-2622 [1]: /lookup/external-ref?link_type=GEN&access_num=rs252906&atom=%2Fcanres%2F72%2F8_Supplement%2F2622.atom [2]: /lookup/external-ref?link_type=GEN&access_num=rs628137&atom=%2Fcanres%2F72%2F8_Supplement%2F2622.atom