Ovarian Cancer Subtypes, Endometriosis Show Genetic Overlap in Study

"This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases," first and corresponding author Sally Mortlock, a researcher at the University of Queensland, and her coauthors wrote in Cell Reports Medicine on Tuesday.

Along with studies pointing to higher-than-usual EOC risk in women with endometriosis, there have been some relatively small genetic studies suggesting genetic overlap between the two conditions, Mortlock explained in an email, noting that for their current study, she and her colleagues searched for causal ties between endometriosis risk and the development of specific EOC subtypes in a large genetic dataset.

"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," she said.

Starting 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 researchers 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.

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.

Despite the genetic overlap between endometriosis and EOC, the authors did not see a significant rise in ovarian cancer risk in women affected by endometriosis compared to those unaffected, Mortlock noted. Still, the shared genetic contributions to both conditions made it possible to get a better look at the biological pathways at play in EOC in general and within specific subtypes.

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 researchers went on to incorporate 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.

Together, the authors suggested that their findings "add to our understanding of disease pathogenesis and yield genomic targets that may facilitate preventive pharmacological intervention by disrupting the link between endometriosis and EOC and promote targeted EOC screening in women with endometriosis."