Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer

Abstract

Testicular germ cell tumors (TGCT) have been expected to have a strong underlying genetic component. We conducted a genome-wide scan among 277 TGCT cases and 919 controls and found that seven markers at 12p22 within KITLG (c-KIT ligand) reached genome-wide significance (P < 5.0 x 10(-8) in discovery). In independent replication, TGCT risk was increased threefold per copy of the major allele at rs3782179 and rs4474514 (OR = 3.08, 95% CI = 2.29-4.13; OR = 3.07, 95% CI = 2.29-4.13, respectively). We found associations with rs4324715 and rs6897876 at 5q31.3 near SPRY4 (sprouty 4; P < 5.0 x 10(-6) in discovery). In independent replication, risk of TGCT was increased nearly 40% per copy of the major allele (OR = 1.37, 95% CI = 1.14-1.64; OR = 1.39, 95% CI = 1.16-1.66, respectively). All of the genotypes were associated with both seminoma and nonseminoma TGCT subtypes. These results demonstrate that common genetic variants affect TGCT risk and implicate KITLG and SPRY4 as genes involved in TGCT susceptibility.

Figure 1. Genome wide association results plotted for 277 TGCT patients and 919 controls

The threshold for genome wide significance was P < 5.0 × 10⁻⁸ (top red line) based on Fisher's exact test. Markers that reached significance at P < 5.0 × 10⁻⁶ (bottom green line) based on Fisher's exact test also were considered.

Figure 2. Regional association plots and linkage disequilibrium structure

(a, b) The −log₁₀ of the P-value for the association of each discovery phase marker and TGCT status for segments of chromosomes (a) 12q22 [red line shows P < 5.0 × 10⁻] and (b) 5q31.3 [green line shows P < 5.0 χ 10⁻]. NCBI Build 36 was used for map locations. From each of these regions, two markers were taken into replication and are indicated in blue. Linkage disequilibrium structures for the GWAS data and based on r² are shown.