Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus

Abstract

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

10 Years of GWAS discovery in endometrial cancer: Aetiology, function and translation

“…While endometrial cancer has been found to be genetically correlated with both PCOS and uterine fibroids, Mendelian randomisation analysis only provides evidence for a causal relationship between uterine fibroids and endometrial cancer risk. 20 However, sensitivity analyses in this study suggested potential violation of the Mendelian randomisation assumption that a genetic variant only affects disease through its effect on the exposure. Further assessment of this relationship is recommended when larger GWAS datasets for uterine fibroids are available.…”

“…For example, observational studies have suggested that non-cancerous gynaecological diseases, such as polycystic ovarian syndrome (PCOS) and uterine fibroids, are associated with endometrial cancer. 15 , 16 , 17 , 18 These relationships are supported by genetic correlations 19 , 20 but after adjustment for BMI using GWAS data, the correlation between endometrial cancer and PCOS appears to be at least partly mediated by BMI. 20 Correlation analysis has helped clarify previous inconsistent reports of associations between endometrial cancer and another non-cancerous gynaecological disease, endometriosis, 15 , 16 , 21 , 22 with no evidence of a shared genetic background found using the largest available European GWAS datasets.…”

“… 20 Correlation analysis has helped clarify previous inconsistent reports of associations between endometrial cancer and another non-cancerous gynaecological disease, endometriosis, 15 , 16 , 21 , 22 with no evidence of a shared genetic background found using the largest available European GWAS datasets. 20 On the other hand, ovarian cancer, has been shown to share several epidemiological similarities with endometrial cancer 23 and correlation analysis further supports a relationship between these cancers by demonstrating shared genetics 3919 .…”

“… 38 Meanwhile, meta-analysis of endometrial cancer with PCOS, and uterine fibroids GWAS identified a novel risk region (1p36.12; Table 2 ) that did replicate in an independent dataset. 20 …”

“… 46 The enhancer/promoter chromatin looping data has also been used to assess the four endometrial cancer risk loci recently identified through cross-trait analyses, revealing further candidate target genes. 20 , 38 As these analyses have provided a relatively large number of candidate target genes, even allowing for multiple causal genes at each locus, these genes require prioritisation using additional data.…”