Dicks Ed M, Tyrer Jonthan P, Ezquina Suzana, Jones Michelle, Baierl John, Peng Pei-Chen, Diaz Michael, Goode Ellen, Winham Stacey J, Dörk Thilo, Van Gorp Toon, De Fazio Ana, Bowtell David, Odunsi Kunle, Moysich Kirsten, Pavanello Marina, Campbell Ian, Brenton James D, Ramus Susan J, Gayther Simon A, Pharoah Paul D P
Department of Public Health and Primary Care, University of Cambridge, UK.
Department of Biomedical Sciences, Cedars-Sinai Medical Centre, Los Angeles, USA.
medRxiv. 2024 Apr 3:2024.04.02.24304968. doi: 10.1101/2024.04.02.24304968.
Rare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to collate exome sequencing data from multiple epithelial ovarian cancer case cohorts and controls in order to systematically evaluate the role of coding, loss-of-function variants across the genome in epithelial ovarian cancer risk. We assembled exome data for a total of 2,573 non-mucinous cases (1,876 high-grade serous and 697 non-high grade serous) and 13,925 controls. Harmonised variant calling and quality control filtering was applied across the different data sets. We carried out a gene-by-gene simple burden test for association of rare loss-of-function variants (minor allele frequency < 0.1%) with all non-mucinous ovarian cancer, high grade serous ovarian cancer and non-high grade serous ovarian cancer using logistic regression adjusted for the top four principal components to account for cryptic population structure and genetic ancestry. Seven of the top 10 associated genes were associations of the known ovarian cancer susceptibility genes , , , , and (false discovery probability < 0.1). A further four genes ( and ) had a false discovery rate of less than 0.1. Of these, was most strongly associated with the non-high grade serous histotype (P = 1.3×10, FDR = 9.1×10). Further support for this association comes from the observation that loss of function variants in this gene are also associated with age at natural menopause and Mendelian randomisation analysis shows an association between genetically predicted age at natural menopause and endometrioid ovarian cancer, but not high-grade serous ovarian cancer.
少数编码DNA修复蛋白的基因中罕见的种系功能丧失变异已被证明与上皮性卵巢癌相关，与高级别浆液性组织学类型的关联更强。本研究的目的是整理来自多个上皮性卵巢癌病例队列和对照的外显子组测序数据，以便系统评估全基因组编码功能丧失变异在上皮性卵巢癌风险中的作用。我们汇总了总共2573例非黏液性病例（1876例高级别浆液性和697例非高级别浆液性）和13925例对照的外显子组数据。对不同数据集应用了统一的变异调用和质量控制过滤。我们使用针对前四个主成分进行调整的逻辑回归，对罕见功能丧失变异（次要等位基因频率<0.1%）与所有非黏液性卵巢癌、高级别浆液性卵巢癌和非高级别浆液性卵巢癌进行逐个基因的简单负担检验，以考虑潜在的人群结构和遗传血统。前10个相关基因中有7个是已知的卵巢癌易感基因、、、、和的关联（错误发现概率<0.1）。另外四个基因（和）的错误发现率小于0.1。其中，与非高级别浆液性组织学类型关联最强（P = 1.3×10，FDR = 9.1×10）。对这种关联的进一步支持来自以下观察结果：该基因中的功能丧失变异也与自然绝经年龄相关，孟德尔随机化分析表明，遗传预测的自然绝经年龄与子宫内膜样卵巢癌相关，但与高级别浆液性卵巢癌无关。
