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Human molecular genetics
Aug 01, 2011;20 (15): 3109-17.

A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility.

Peter A Kanetsky, Nandita Mitra, Saran Vardhanabhuti, David J Vaughn, Mingyao Li, Stephanie L Ciosek, Richard Letrero, Kurt D'Andrea, Madhavi Vaddi, David R Doody, Joellen Weaver, Chu Chen, Jacqueline R Starr, Håkon Håkonarson, Daniel J Rader, Andrew K Godwin, Muredach P Reilly, Stephen M Schwartz, Katherine L Nathanson
Author Information
  1. Peter A Kanetsky: Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. pkanetsk@mail.med.upenn.edu
PMID: 21551455 DOI: 10.1093/hmg/ddr207

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.

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Grants

  1. R01 CA114478/NCI NIH HHS
  2. R01CA085914/NCI NIH HHS
  3. P30 CA006927/NCI NIH HHS
  4. R01CA114478/NCI NIH HHS
  5. CA093283/NCI NIH HHS
  6. 5P30CA016520/NCI NIH HHS

MeSH Term

Adolescent
Adult
Genome-Wide Association Study
Genotype
Humans
Male
Neoplasms, Germ Cell and Embryonal
Testicular Neoplasms
Transcription Factors
Young Adult

Chemicals

DMRT1 protein
Transcription Factors
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
Article has an altmetric score of 2

Word Cloud

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