Litchfield Kevin, Holroyd Amy, Lloyd Amy, Broderick Peter, Nsengimana Jérémie, Eeles Rosalind, Easton Douglas F, Dudakia Darshna, Bishop D Timothy, Reid Alison, Huddart Robert A, Grotmol Tom, Wiklund Fredrik, Shipley Janet, Houlston Richard S, Turnbull Clare
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Leeds LS9 7TF, UK.
Nat Commun. 2015 Oct 27;6:8690. doi: 10.1038/ncomms9690.
Genome-wide association studies (GWAS) have identified multiple risk loci for testicular germ cell tumour (TGCT), revealing a polygenic model of disease susceptibility strongly influenced by common variation. To identify additional single-nucleotide polymorphisms (SNPs) associated with TGCT, we conducted a multistage GWAS with a combined data set of >25,000 individuals (6,059 cases and 19,094 controls). We identified new risk loci for TGCT at 3q23 (rs11705932, TFDP2, P=1.5 × 10(-9)), 11q14.1 (rs7107174, GAB2, P=9.7 × 10(-11)), 16p13.13 (rs4561483, GSPT1, P=1.6 × 10(-8)) and 16q24.2 (rs55637647, ZFPM1, P=3.4 × 10(-9)). We additionally present detailed functional analysis of these loci, identifying a statistically significant relationship between rs4561483 risk genotype and increased GSPT1 expression in TGCT patient samples. These findings provide additional support for a polygenic model of TGCT risk and further insight into the biological basis of disease development.
全基因组关联研究（GWAS）已确定了睾丸生殖细胞肿瘤（TGCT）的多个风险位点，揭示了一种受常见变异强烈影响的疾病易感性多基因模型。为了鉴定与TGCT相关的其他单核苷酸多态性（SNP），我们对一个超过25000人的合并数据集（6059例病例和19094例对照）进行了多阶段GWAS。我们在3q23（rs11705932，TFDP2，P = 1.5×10⁻⁹）、11q14.1（rs7107174，GAB2，P = 9.7×10⁻¹¹）、16p13.13（rs4561483，GSPT1，P = 1.6×10⁻⁸）和16q24.2（rs55637647，ZFPM1，P = 3.4×10⁻⁹）确定了TGCT的新风险位点。我们还对这些位点进行了详细的功能分析，确定了rs4561483风险基因型与TGCT患者样本中GSPT1表达增加之间的统计学显著关系。这些发现为TGCT风险的多基因模型提供了额外支持，并进一步深入了解了疾病发展的生物学基础。
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