Gene variations in sex hormone pathways and the risk of testicular germ cell tumour: a case–parent triad study in a Norwegian–Swedish population

BACKGROUND Testicular germ cell tumour (TGCT) is the most common cancer in young men, and an imbalance between the estrogen and androgen levels in utero is hypothesized to influence TGCT risk. Thus, polymorphisms in genes involved in the action of sex hormones may contribute to variability in an individual's susceptibility to TGCT. METHODS We conducted a Norwegian–Swedish case–parent study. A total of 105 single-nucleotide polymorphisms (SNPs) in 20 sex hormone pathway genes were genotyped using Sequenom MassArray iPLEX Gold, in 831 complete triads and 474 dyads. To increase the statistical power, the analysis was expanded to include 712 case singletons and 3922 Swedish controls, thus including triads, dyads and the case–control samples in a single test for association. Analysis for allelic associations was performed with the UNPHASED program, using a likelihood-based association test for nuclear families with missing data, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. False discovery rate (FDR) was used to adjust for multiple testing. RESULTS Five genetic variants across the ESR2 gene [encoding estrogen receptor beta (ERβ)] were statistically significantly associated with the risk of TGCT. In the case–parent analysis, the markers rs12434245 and rs10137185 were associated with a reduced risk of TGCT (OR = 0.66 and 0.72, respectively; both FDRs