Ramachandran Dhanya, Wang Xuemin, Laisk Triin, Zheng Ying, Ingold Nathan, Canson Daffodil M, Kho Pik Fang, Naumann Bianca J, Chapman Carly J, Bousset Kristine, Krause Anna V, Schürmann Peter, Wieland Britta, Hanel Patricia, Hülse Fabienne, Häfner Norman, Runnebaum Ingo, Dubrowinskaja Natalia, Turmanov Nurzhan, Yugay Tatyana, Yessimsiitova Zura Berkutovna, Amant Frédéric, Annibali Daniela, Beckmann Matthias W, Bodelon Clara, Buchanan Daniel D, Chen Chu, Clarke Megan A, Cook Linda S, De Vivo Immaculata, De Wispelaere Wout, Du Mengmeng, Easton Douglas F, Emons Julius, Fasching Peter A, Friedenreich Christine M, Gallagher Grace, Giles Graham G, Goode Ellen L, Harris Holly R, Hunter David J, Kolin David L, Kraft Peter, Lacey James V, Lambrechts Diether, Lu Lingeng, Mutter George L, Naduparambil Jeffin, O'Connell Kelli, Patel Alpa V, Pharoah Paul D P, Rebbeck Timothy R, Ricceri Fulvio, Risch Harvey A, Ruebner Matthias, Sacerdote Carlotta, Scott Rodney J, Setiawan V Wendy, Shu Xiao-Ou, Southey Melissa C, Tham Emma, Tomlinson Ian, Turman Constance, Wentzensen Nicolas, Xu Wanghong, Yu Herbert, Zheng Wei, Spurdle Amanda B, Yarden Yosef, Mägi Reedik, Hillemanns Peter, Glubb Dylan M, Dörk Thilo, O'Mara Tracy A
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
Cancer Research Program, QIMR Berghofer, Brisbane, Queensland, Australia.
EBioMedicine. 2025 Jul 8;118:105830. doi: 10.1016/j.ebiom.2025.105830.
Endometrial cancer is the most common gynaecological cancer in high-income countries. In addition to environmental risk factors, genetic predisposition contributes towards endometrial cancer development but is still incompletely defined.
Building on genome-wide association studies (GWASs) by the Endometrial Cancer Association Consortium, we conducted a GWAS meta-analysis of 17,278 endometrial cancer cases and 289,180 controls, incorporating biobank samples from the UK, Finland, Estonia and Japan.
GWAS analysis identified five additional risk loci (3p25.2, 3q25.2, 6q22.31, 12q21.2, and 17q24.2). Corresponding gene-based analyses supported findings for three of the five loci, at NAV3 (12q21.2), PPARG (3p25.2), and BPTF (17q24.2), as well as two additional candidate risk regions at ATF7IP2 (16p13.2-p13.13) and RPP21 (6p22.1). Validation genotyping in further independent case-control series replicated the most significant locus at 12q21.2 and corroborated risk variants located intronic to NAV3, the gene for Neuron Navigator 3. Downregulation of NAV3 in endometrial cell lines accelerated cell division and wound healing capacity whereas NAV3 overexpression reduced cell survival and increased cell death, indicating that NAV3 acts as a tumour suppressor in endometrial cells.
Our large study extends the number of genome-wide significant risk loci identified for endometrial carcinoma by about one-third and proposes a role of NAV3 as a tumour suppressor in this common cancer.
This study was mainly supported by funding from the Wilhelm Sander Foundation, Germany, and the National Health and Medical Research Council (NHMRC) of Australia. A complete list of funding organisations is provided in the acknowledgements.
子宫内膜癌是高收入国家最常见的妇科癌症。除环境风险因素外，遗传易感性也促使子宫内膜癌的发生，但仍未完全明确。
基于子宫内膜癌协会联盟的全基因组关联研究（GWAS），我们对17278例子宫内膜癌病例和289180例对照进行了GWAS荟萃分析，纳入了来自英国、芬兰、爱沙尼亚和日本生物样本库的样本。
GWAS分析确定了另外五个风险位点（3p25.2、3q25.2、6q22.31、12q21.2和17q24.2）。相应的基于基因的分析支持了五个位点中三个位点的研究结果，分别位于NAV3（12q21.2）、PPARG（3p25.2）和BPTF（17q24.2），以及另外两个候选风险区域ATF7IP2（16p13.2-p13.13）和RPP21（6p22.1）。在进一步独立的病例对照系列中进行的验证基因分型重复了12q21.2处最显著的位点，并证实了位于神经元导航蛋白3（Neuron Navigator 3）基因NAV3内含子中的风险变异。子宫内膜细胞系中NAV3的下调加速了细胞分裂和伤口愈合能力，而NAV3的过表达降低了细胞存活率并增加了细胞死亡，表明NAV3在子宫内膜细胞中起肿瘤抑制作用。
我们的大型研究将已确定的子宫内膜癌全基因组显著风险位点数量增加了约三分之一，并提出了NAV3在这种常见癌症中作为肿瘤抑制因子的作用。
本研究主要由德国威廉·桑德基金会和澳大利亚国家卫生与医学研究委员会（NHMRC）资助。致谢中提供了完整的资助机构列表。
