Genetic Overlap Found for Ovarian Cancer Subtypes and Endometriosis

Endometriosis is a chronic gynecological disease affecting up to 12% of reproductive-age women. The disease is characterized by the presence of endometriotic lesions outside the uterus and is associated with pelvic pain and subfertility.

Ovarian cancer is the deadliest gynecologic cancer. Fewer than 50% of women survive beyond five years after diagnosis due to the rapid development of chemoresistance and the absence of effective early detection strategies. Recent genome-wide association studies (GWASs) have provided strong evidence for a genetic contribution to risk of both endometriosis and epithelial ovarian cancer (EOC).

Molecular Bioscientists at the University of Queensland (Brisbane, Australia) and their colleagues estimated the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and EOC histotypes, and identify shared susceptibility loci. They started with more than two dozen SNPs linked to endometriosis through a prior genome-wide association study meta-analysis involving hundreds of thousands of endometriosis cases, EOC cases, or unaffected controls. The investigators identified genetic risk loci linked to both endometriosis and several forms of EOC, particularly clear cell ovarian cancer and endometrioid ovarian cancer. Cases from the high-grade serous ovarian cancer subtype, on the other hand, showed more tenuous genetic ties to endometriosis risk.

Nine genes were associated at genome-wide significance with endometriosis (GREB1, MIR4429, KDR, WNT4, SYNE1, CDKN2B-AS1, CDC42, ID4, PTPRO), 67 with high-grade serous ovarian cancer (HGSOC), one with low-grade serous (LGSOC) (KIAA1024), four for low malignant serous (LMPSOC) (TERT, SLC6A18, MIR4457, CLPTM1L), and 27 for mucinous (MOC) in single-trait gene-based analysis. Genome-wide significant genes for endometriosis were nominally significant for clear cell (CCOC) (GREB1, MIR4429, and WNT4), endometrioid (ENOC) (CDNK2B-AS1), and HGSOC (CDNK2B-AS1, MIR4429, and WNT4).

Both endometriosis and clear cell ovarian cancer involved variants on chromosomes 1, 2, 4, 5, 6, 7, 8, 9, 12, and 17, for example, while high-grade serous ovarian cancer risk was associated with several endometriosis risk loci on chromosomes 2, 9, 10, and 18 that did not appear to be linked to risk of clear cell ovarian cancer or endometrioid ovarian cancer histotypes. Of the 28 loci associated with both endometriosis and EOC, for example, the team highlighted 19 sites containing SNPs that were independently linked to both endometriosis and EOC via the same candidate variants.

The investigators incorporated additional chromatin immunoprecipitation sequence, DNA methylation, endometrial cell single-cell RNA sequence, and other data for subsequent analyses looking at everything from the causal variants, genes, and pathways involved to the functional mechanisms that may play a role in tissues and cell types impacted by endometriosis and EOC.

Sally Mortlock, PhD, a Molecular Bioscientist and first author of the study, said, “We found that individuals carrying certain genetic markers that predispose them to having endometriosis also have a higher risk of certain epithelial ovarian cancer subtypes, namely clear cell and endometrioid ovarian cancer.”

The authors concluded that they had found evidence of a strong genetic correlation and causal relationship between endometriosis and two EOC histotypes, CCOC and ENOC, and to a lesser extent with HGSOC. Further investigation into shared genomic regions revealed different genetic variants, genes, and pathways that likely contribute to the causal relationship with the different histotypes. The study was published on March 15, 2022 in the journal Cell Reports Medicine.

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