title: A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility.
abstract: Susceptibility to testicular germ cell tumors (TGCT) has a significant heritable component, and genome-wide association studies (GWASs) have identified association with variants in several genes, including KITLG, SPRY4, BAK1, TERT, DMRT1 and ATF7IP. In our GWAS, we genotyped 349 TGCT cases and 919 controls and replicated top hits in an independent set of 439 cases and 960 controls in an attempt to find novel TGCT susceptibility loci. We identified a second marker (rs7040024) in the doublesex and mab-3-related transcription factor 1 (DMRT1) gene that is independent of the previously described risk allele (rs755383) at this locus. In combined analysis that mutually conditions on both DMRT1 single nucleotide polymorphism markers, TGCT cases had elevated odds of carriage of the rs7040024 major A allele [per-allele odds ratio (OR) = 1.48, 95% confidence interval (CI) 1.23, 1.78; P = 2.52 × 10(-5)] compared with controls, while the association with rs755383 persisted (per allele OR = 1.26, 95% CI 1.08, 1.47, P = 0.0036). In similar analyses, the association of rs7040024 among men with seminomatous tumors did not differ from that among men with non-seminomatous tumors. In combination with KITLG, the strongest TGCT susceptibility locus found to date, men with TGCT had greatly elevated odds (OR = 14.1, 95% CI 5.12, 38.6; P = 2.98 × 10(-7)) of being double homozygotes for the risk (major) alleles at DMRT (rs7040024) and KITLG (rs4474514) when compared with men without TGCT. Our findings continue to corroborate that genes influencing male germ cell development and differentiation have emerged as the major players in inherited TGCT susceptibility.
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. pkanetsk@mail.med.upenn.edu
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kanetsky
authors.forename: Nandita
authors.initials: N
authors.lastname: Mitra
authors.forename: Saran
authors.initials: S
authors.lastname: Vardhanabhuti
authors.forename: David J
authors.initials: DJ
authors.lastname: Vaughn
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Ciosek
authors.forename: Richard
authors.initials: R
authors.lastname: Letrero
authors.forename: Kurt
authors.initials: K
authors.lastname: D'Andrea
authors.forename: Madhavi
authors.initials: M
authors.lastname: Vaddi
authors.forename: David R
authors.initials: DR
authors.lastname: Doody
authors.forename: Joellen
authors.initials: J
authors.lastname: Weaver
authors.forename: Chu
authors.initials: C
authors.lastname: Chen
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Starr
authors.forename: Håkon
authors.initials: H
authors.lastname: Håkonarson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Schwartz
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
mesh_terms: D000293:Adolescent; D000328:Adult; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D013736:Testicular Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: C110547:DMRT1 protein; D014157:Transcription Factors