Oslo and Akershus University College of Applied Sciences, St. Olavs plass, NO-0130 Oslo, Norway.
Hum Reprod. 2012 May;27(5):1525-35. doi: 10.1093/humrep/des075. Epub 2012 Mar 8.
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.
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.
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 <5%), whereas rs2978381 and rs12435857 were associated with an increased risk of TGCT (OR = 1.21 and 1.19, respectively; both FDRs <5%). In the combined case-parent/case-control analysis, rs12435857 and rs10146204 were associated with an increased risk of TGCT (OR = 1.15 and 1.13, respectively; both FDRs <5%), whereas rs10137185 was associated with a reduced risk of TGCT (OR = 0.79, FDR <5%). In addition, we found that three genetic variants in CYP19A1 (encoding aromatase) were statistically significantly associated with the risk of TGCT in the case-parent analysis. The T alleles of the rs2414099, rs8025374 and rs3751592 SNPs were associated with an increased risk of TGCT (OR = 1.30, 1.30 and 1.21, respectively; all FDRs <5%). We found no statistically significant differences in allelic effect estimates between parental inherited genetic variation in the sex hormone pathways and TGCT risk in the offspring, and no evidence of heterogeneity between seminomas and non-seminomas, or between the Norwegian and the Swedish population, in any of the SNPs examined.
Our findings provide support for ERβ and aromatase being implicated in the aetiology of TGCT. Exploring the functional role of the TGCT risk-associated SNPs will further elucidate the biological mechanisms involved.
睾丸生殖细胞肿瘤（TGCT）是年轻男性中最常见的癌症，人们假设子宫内雌激素和雄激素水平的失衡会影响 TGCT 的风险。因此，参与性激素作用的基因中的多态性可能会导致个体对 TGCT 的易感性存在差异。
我们进行了一项挪威-瑞典病例-父母研究。使用 Sequenom MassArray iPLEX Gold，对 20 个性激素通路基因中的 105 个单核苷酸多态性（SNP）进行了基因分型，共涉及 831 个完整的三核苷酸、474 个二核苷酸和 831 个病例单体。为了提高统计效力，将分析扩展到包括 712 个病例单体和 3922 个瑞典对照，从而在一个单独的关联测试中包括三核苷酸、二核苷酸和病例对照样本。使用 UNPHASED 程序进行等位基因关联分析，对带有缺失数据的核家庭进行基于似然的关联检验，并计算比值比（OR）和 95%置信区间（CI）。使用错误发现率（FDR）来调整多重检验。
ESR2 基因（编码雌激素受体β（ERβ））中的 5 个遗传变异与 TGCT 的风险显著相关。在病例-父母分析中，标记物 rs12434245 和 rs10137185 与 TGCT 的风险降低相关（OR 分别为 0.66 和 0.72，均 FDR<5%），而 rs2978381 和 rs12435857 与 TGCT 的风险增加相关（OR 分别为 1.21 和 1.19，均 FDR<5%）。在合并病例-父母/病例对照分析中，rs12435857 和 rs10146204 与 TGCT 的风险增加相关（OR 分别为 1.15 和 1.13，均 FDR<5%），而 rs10137185 与 TGCT 的风险降低相关（OR 为 0.79，FDR<5%）。此外，我们发现 CYP19A1（编码芳香酶）中的 3 个遗传变异与 TGCT 的风险在病例-父母分析中显著相关。rs2414099、rs8025374 和 rs3751592 位点的 T 等位基因与 TGCT 的风险增加相关（OR 分别为 1.30、1.30 和 1.21，均 FDR<5%）。我们没有发现性激素途径中亲代遗传变异与后代 TGCT 风险之间等位基因效应估计值存在统计学显著差异，也没有证据表明在任何研究的 SNP 中，生殖细胞肿瘤与非生殖细胞瘤之间，或挪威人群与瑞典人群之间存在异质性。
我们的研究结果为 ERβ 和芳香酶参与 TGCT 的发病机制提供了支持。探索与 TGCT 风险相关的 SNP 的功能作用将进一步阐明所涉及的生物学机制。
