Endometriosis is a gynecologic condition characterised by the growth of endometrial glands and stroma outside the uterine cavity. It has a well-established association with the risk of ovarian cancer; there is a 3-fold increased risk for the clear cell histotype and a 2-fold increased risk for endometrioid and low-grade serous histotypes. Endometriosis and ovarian cancer are thought to share a pathophysiology in general, and there is some evidence of a genetic link between these conditions. It's possible that the effects of ovarian cancer risk factors differ between women with and without endometriosis. Hysterectomy is associated with a significantly lower risk of ovarian cancer in women with endometriosis but has no association in women without endometriosis. Effect differences by history of endometriosis for other ovarian cancer risk factors are possible and should be evaluated.

The effect of modification by endometriosis status and found no statistically significant differences, possibly due to a small sample size (177 ovarian cancer cases with endometriosis, 184 controls with endometriosis). Thus, we used epidemiologic data from over 22,000 women in the Ovarian Cancer Association Consortium (OCAC) to conduct a comprehensive study of endometriosis as an effect modifier of ovarian cancer risk factors, with over 800 cases and 900 controls having endometriosis. Endometriosis is a chronic gynaecological disease that affects up to 12% of women of reproductive age. The presence of endometriotic lesions outside the uterus characterises the disease, which is associated with pelvic pain and infertility. Lesions are frequently classified based on their location and depth of infiltration into surrounding tissue, and they include superficial peritoneal lesions, deep infiltrating disease, and cysts (endometriomas), which are most commonly found on the ovary.

Ovarian Cancer is the deadliest gynecologic cancer. Because of the rapid development of chemo resistance and the lack of effective early detection strategies, fewer than half of women survive beyond 5 years after diagnosis. To advance understanding of disease aetiology, identify risk factors, and develop early detection methods and effective targeted therapies, more research is required. High-grade serous (HGSOC), low-grade serous (LGSOC), mucinous (MOC), endometrioid (ENOC), and clear cell (CCOC) EOC are the most common histological subtypes. There are also borderline tumours with low malignant potential, most of which have serous (LMPSOC) or mucinous differentiation. The two histotypes most strongly and reproducibly associated with endometriosis are CCOC and ENOC. Concurrent endometriosis is found in 21%-51% of CCOC patients and 23%-43% of ENOC patients. 14, 15, 16 These histotype-associations are supported by data from the Ovarian Cancer Association Consortium, which showed a significant association between endometriosis history and specific histological subtypes of EOC in 7,911 women with invasive EOC.

We used Mendelian randomization (MR) to show that genetic endometriosis risk was causally related to histotype-specific EOC risk and established directionality from endometriosis to EOC risk rather than vice versa. The genetic relationship between endometriosis and EOC histotypes was then examined in order to identify shared risk loci, candidate functional target genes, and pathways. Genetic correlation describes the genetic relationship between two traits and is an estimate of the proportion of variance shared by two traits that can be attributed to genetics. Estimating the genetic correlation between traits helps us understand shared genetic risk factors and biological pathways. We used GWAS summary statistics from meta-analyses and linkage disequilibrium (LD) score regression to estimate the genetic correlation between EOC histotypes and endometriosis (LDSC). Endometriosis and CCOC (rg = 0.71), ENOC (rg = 0.48), and HGSOC (rg = 0.19) had significant (p 0.05) positive genetic correlations (rg). The rg for genetic correlation with LMPSOC was 0.88, but it did not reach statistical significance, and we were unable to estimate rg for LGSOC due to the small sample size for this histotype (1,012 cases). High-definition likelihood inference (HDL) was also used to estimate genetic correlation between diseases, which has been shown to reduce variance by fully accounting for LD.

To identify genetic associations with some evidence of a shared contribution from both diseases, we combined the EOC histotypes and endometriosis susceptibility datasets using two complementary approaches: first, a meta-analysis using approximate Bayes factors computed and combined by the Meta-Analysis with an Approximate Bayes Factor (MetABF) method in both an independent and fixed model, and second, a meta-analysis using the modified Han and Eskin random-effects model (RE2C). We found that genes containing or close to SNPs shared by endometriosis and two EOC histotypes (CCOC and HGSOC) clustered across reproductive tissues such as the ovary, fallopian tube, and uterus. Several pathways were found to be overrepresented among the genes with significant SNPs. Some risk variants and susceptibility genes for endometriosis, ENOC/CCOC, and HGSOC are also shared in the current study, and the extent of germline genetic overlap between endometriosis and ENOC/CCOC is much greater than that between endometriosis and HGSOC. Taken together, this supports previous epidemiological associations between endometriosis and ENOC/CCOC, and suggests a model in which the shared and non-shared components of genetic predisposition and an underlying background of endometriosis likely interact with cellular context-specific somatic mutational profiles and stromal/hormonal microenvironments to give rise to the distinct histological subtypes.

Using genetic data from the largest GWAS meta-analyses of endometriosis and EOC risk currently available, this study used a comprehensive range of statistical genetic approaches to build on existing evidence of an association between endometriosis and EOC. The sample size of some of the less common EOC histotype cohorts, such as LMPSOC, limits the study's ability to identify shared risk loci and target genes. The identification of genetic relationships may also be hampered by phenotypic annotation and endometriosis case heterogeneity affecting the endometriosis GWAS. Several studies have found a link between endometriosis sub-phenotypes and the risk of EOC, specifically endometriomas.

More comprehensive phenotyping and molecular characterization of endometriosis lesions could be used to test genetic associations between potential endometriosis subtypes and risk of certain EOC histotypes, such as determining whether the association between endometriosis and CCOC is driven specifically by endometriomas. Finally, we discovered evidence of a strong genetic correlation and causal relationship between endometriosis and two EOC histotypes, CCOC and ENOC, as well as, to a lesser extent, HGSOC. Further investigation into shared genomic regions revealed various genetic variants, genes, and pathways that are likely to contribute to the causal relationship between the various histotypes. These findings contribute to our understanding of disease pathogenesis and yield genomic targets that may facilitate preventive pharmacological intervention by disrupting the link between endometriosis and EOC, as well as promote targeted EOC screening in endometriosis patients.