Kho Pik Fang, Mortlock Sally, Rogers Peter A W, Nyholt Dale R, Montgomery Grant W, Spurdle Amanda B, Glubb Dylan M, O'Mara Tracy A
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
Hum Genet. 2021 Sep;140(9):1353-1365. doi: 10.1007/s00439-021-02312-0. Epub 2021 Jul 15.
Endometriosis, polycystic ovary syndrome (PCOS) and uterine fibroids have been proposed as endometrial cancer risk factors; however, disentangling their relationships with endometrial cancer is complicated due to shared risk factors and comorbidities. Using genome-wide association study (GWAS) data, we explored the relationships between these non-cancerous gynecological diseases and endometrial cancer risk by assessing genetic correlation, causal relationships and shared risk loci. We found significant genetic correlation between endometrial cancer and PCOS, and uterine fibroids. Adjustment for genetically predicted body mass index (a risk factor for PCOS, uterine fibroids and endometrial cancer) substantially attenuated the genetic correlation between endometrial cancer and PCOS but did not affect the correlation with uterine fibroids. Mendelian randomization analyses suggested a causal relationship between only uterine fibroids and endometrial cancer. Gene-based analyses revealed risk regions shared between endometrial cancer and endometriosis, and uterine fibroids. Multi-trait GWAS analysis of endometrial cancer and the genetically correlated gynecological diseases identified a novel genome-wide significant endometrial cancer risk locus at 1p36.12, which replicated in an independent endometrial cancer dataset. Interrogation of functional genomic data at 1p36.12 revealed biologically relevant genes, including WNT4 which is necessary for the development of the female reproductive system. In summary, our study provides genetic evidence for a causal relationship between uterine fibroids and endometrial cancer. It further provides evidence that the comorbidity of endometrial cancer, PCOS and uterine fibroids may partly be due to shared genetic architecture. Notably, this shared architecture has revealed a novel genome-wide risk locus for endometrial cancer.
子宫内膜异位症、多囊卵巢综合征（PCOS）和子宫肌瘤已被提出作为子宫内膜癌的风险因素；然而，由于存在共同的风险因素和合并症，理清它们与子宫内膜癌之间的关系很复杂。利用全基因组关联研究（GWAS）数据，我们通过评估遗传相关性、因果关系和共享风险位点，探索了这些非癌性妇科疾病与子宫内膜癌风险之间的关系。我们发现子宫内膜癌与PCOS和子宫肌瘤之间存在显著的遗传相关性。对遗传预测的体重指数（PCOS、子宫肌瘤和子宫内膜癌的一个风险因素）进行调整后，子宫内膜癌与PCOS之间的遗传相关性大幅减弱，但不影响与子宫肌瘤的相关性。孟德尔随机化分析表明，仅子宫肌瘤与子宫内膜癌之间存在因果关系。基于基因的分析揭示了子宫内膜癌与子宫内膜异位症以及子宫肌瘤之间共享的风险区域。对子宫内膜癌和遗传相关的妇科疾病进行多性状GWAS分析，在1p36.12发现了一个新的全基因组显著的子宫内膜癌风险位点，该位点在一个独立的子宫内膜癌数据集中得到了验证。对1p36.12处的功能基因组数据进行研究，发现了生物学上相关的基因，包括女性生殖系统发育所必需的WNT4。总之，我们的研究为子宫肌瘤与子宫内膜癌之间的因果关系提供了遗传学证据。它进一步提供证据表明，子宫内膜癌、PCOS和子宫肌瘤的合并症可能部分归因于共享的遗传结构。值得注意的是，这种共享结构揭示了一个新的全基因组子宫内膜癌风险位点。
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