Abstract 843: Imputation and meta-analysis of five genome-wide association studies identify multiple new loci associated with testicular germ cell tumor
Authors: Wang Zhaoming , Kanetsky Peter A. , McGlynn Katherine A. , Bishop D. Timothy , Chung Charles C. , Dalgaard Marlene D. , Grotmol Tom , Greene Mark H. , Gupta Ramneek , Haugen Trine B. , Litchfield Kevin , Loud Jennifer T. , Mitra Nandita , Nielsen Kasper , Turnbull Clare , Rajpert-DeMeyts Ewa , Vardhanabhuti Saran , Wiklund Fredrik , Schwartz Stephen , Chanock Stephen J. , Nathanson Katherine L. ,   TECAC consortium
Published: August 2015

Genome-wide association studies (GWAS) have already identified 21 genetic loci associated with testicular germ cell tumor (TGCT). Many of the loci contain biologically plausible genes that function in male germ cell maturation and differentiation, as well as KIT-MAPK signaling and chromosomal segregation. We recently formed the international TEsticular CAncer Consortium (TECAC), and pooled data from the three published and one unpublished GWAS (3,556 TGCT cases and 13,969 controls) to identify additional novel susceptibility loci. We imputed across the data set using the 1,000 Genomes Project version 3 and conducted a fixed effects meta-analysis, including the first analysis of the X chromosome. Eleven new loci achieved genome-wide significance level (p&lt;5e-8), mapping to the following regions: 2q14.2, 3q26.2, 4q35.2, 7q36.3, 10q26.13, 15q21.3, 15q22.31, 16q24.2, 17q12, 19p12 and Xq28, most of which harbor biologically plausible genes. The per allele odds ratios associated with these SNPs continue to be higher than those associated with other cancer types, ranging from 1.2 to 1.6. The signal at 17q12 maps to a region which includes HNF1B, a locus already associated with risk of endometrial and prostate cancer. Two of the signals are in the introns of genes known to be involved in embryonal stem cell pluripotency (TFCLP1 - 2q14.2 and ZFPA2/REX1 - 4q35.2), one in the intron of a chromosomal segregation gene (NCAPG - 27q36.3), and one proximate to MEK1 (MAP2K1 - 15q22.31). The identification of these loci provides additional evidence of the importance of the previously implicated biological pathways. Heritability analysis indicated that these eleven new loci explain approximately 7% more familial (father-to-son) risk in addition to ∼26% explained by previously established 21 loci. Our new findings substantially increase the number of known TGCT susceptibility alleles, thus moving the field closer to a comprehensive understanding of the underlying genetic architecture of TGCT, and providing further clues into the biological etiology of TGCT.

Citation Format: Zhaoming Wang, Peter A. Kanetsky, Katherine A. McGlynn, D. Timothy Bishop, Charles C. Chung, Marlene D. Dalgaard, Tom Grotmol, Mark H. Greene, Ramneek Gupta, Trine B. Haugen, Kevin Litchfield, Jennifer T. Loud, Nandita Mitra, Kasper Nielsen, Clare Turnbull, Ewa Rajpert-DeMeyts, Saran Vardhanabhuti, Fredrik Wiklund, Stephen Schwartz, Stephen J. Chanock, Katherine L. Nathanson, TECAC consortium. Imputation and meta-analysis of five genome-wide association studies identify multiple new loci associated with testicular germ cell tumor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 843. doi:10.1158/1538-7445.AM2015-843