Wang Xuemin, Kho Pik Fang, Ramachandran Dhanya, Bafligil Cemsel, Amant Frederic, Goode Ellen L, Scott Rodney J, Tomlinson Ian, Evans D Gareth, Crosbie Emma J, Dörk Thilo, Spurdle Amanda B, Glubb Dylan M, O'Mara Tracy A
Cancer Research Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Gynaecology Research Unit, Hannover Medical School, 30625 Hannover, Germany.
iScience. 2023 Apr 7;26(5):106590. doi: 10.1016/j.isci.2023.106590. eCollection 2023 May 19.
To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of , a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer.
为了检测新的子宫内膜癌风险变异，我们在多性状全基因组关联研究（GWAS）分析中利用了来自子宫内膜癌风险因素的信息。我们首先使用孟德尔随机化评估已确定和疑似子宫内膜癌风险因素与子宫内膜癌之间的因果关系。经过多变量分析，五个独立风险因素（腰围、睾酮水平、性激素结合球蛋白水平、初潮年龄和自然绝经年龄）被纳入多性状贝叶斯GWAS分析。我们鉴定出三个与子宫内膜癌风险相关的潜在新位点，其中一个（7q22.1）在独立的子宫内膜癌GWAS数据集中得到重复，并且在荟萃分析中达到全基因组显著性。该位点可能通过改变睾酮水平影响子宫内膜癌风险。与此一致，我们观察到子宫内膜癌风险信号与参与睾酮代谢的基因的表达之间存在共定位。因此，我们的研究结果提示了激素疗法预防或治疗子宫内膜癌的机会。
