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Are there genetic similarities between endometriosis and endometrial cancer?

A new international research study describes a genetic basis for overlap between endometriosis and endometrial cancer.

An association between endometriosis and endometrial cancer has been indirectly suggested by epidemiological, biological, and molecular studies, and a new international research study published in Cancer Medicine describes a genetic basis for overlap. 

Endometriosis affects 6% to 10% of reproductive-age women and 35% to 50% of infertile women. Both endometriosis and endometrial cancer are associated with higher levels of estrogen exposure, with a lessened risk related to use of oral contraceptives (OCs) and progesterone-containing hormonal therapies. They share similar symptoms (e.g., pelvic pain) and comorbid conditions (e.g., an increased risk for uterine fibroids and ovarian cancer). Both endometriosis and endometrial cancer also have a genetic component: Twin studies show endometriosis heritability of approximately 50% (51%, 95% CI = 33%-66%) and endometrial cancer heritability of 27% (95% CI = 11%-43%). 

Previously, 19 independent single-nucleotide polymorphisms (SNPs) were found to be associated with endometriosis and nine with endometrial cancer in genomewide association studies (GWAS). However, these SNPs and their genetic locations were not overlapping between the diseases. 

Epidemiological studies, which are hampered by methodological complications such as under- and misdiagnosis of endometriosis, lack of control for confounders, and exclusion criteria, have produced suggestive but conflicting results for a link between the two diseases. 

The current team of researchers from Australia, the United Kingdom, Germany, the United States, Sweden, Belgium, Norway, and Cyprus used data from three GWAS datasets for endometriosis and endometrial cancer containing 462,430 common SNPs to perform a genetic correlation analysis. They also combined the datasets into a cross-disease GWAS metanalysis to assess for SNPs contributing to both diseases.

The authors found a significant weak-to-moderate genetic overlap between endometriosis and endometrial cancer in the genetic correlation analysis, with more SNPs than could expected by chance associated in the same direction of effect. In the cross-disease metanalysis, after adjustment, they found 13 SNPs (see Table) that appeared to be involved in replication. SNP rs2475335, which is located on chromosome 9p23, was most significantly associated with both diseases (P= 4.9 x 10-8). This SNP is housed within the protein tyrosine phosphatase receptor type D (PTPRD) gene. PTPRD deletions and mutations have been found in endometrial tumors. In addition, PTPRD exerts an effect on the STAT3 pathway, which has been identified as relevant to both endometriosis and endometrial cancer. 

The researchers summarized their findings by stating “Our genetic correlation analysis supports recent large epidemiological studies indicating an increased risk of endometrial cancer in women previously diagnosed with endometriosis, while the cross-disease meta-analysis has revealed plausible loci that could increase the risk of both diseases and which should be pursued further in functional studies.” This work, they added, could be a pathway to new diagnostic and treatment options for patients with endometriosis and endometrial cancer.


SNP=single-nucleotide polymorphism