*4.3. Endometriosis as a Risk Factor for Endometrial Cancer*

With respect to endometriosis itself as a risk factor for other conditions, women with endometriosis have a higher risk of infection, allergy, autoimmune disease, psychiatric conditions, preterm birth, metabolic syndrome, coronary heart disease, and cancer, especially ovarian [158] and breast cancers, and melanoma [159].

A history of endometriosis has been recognized as a precursor lesion of several types of malignancies and endometriosis-associated carcinoma [160,161].

Some investigations suggested no association between endometriosis and EC [28,149, 160,162–164]. One of the recent systematic reviews performed to search for evidence on the association of endometriosis with gynecological cancers also reported no clear association between endometriosis and EC [165]. On the other hand, some studies have reported an association between endometriosis and EC reflecting overlapping risk factors between the

two conditions, including endogenous or exogenous hyperestrogenism and ovulatory dysfunction [160,166]. Another recent epidemiologic study on the association of endometriosis with malignancy reported that patients with endometriosis were significantly more likely to be diagnosed with EC at a younger age than those without endometriosis (mean age at EC diagnosis 57 years vs. 62 years; *<sup>p</sup>* = 5.0 <sup>×</sup> <sup>10</sup>−11) [167]. Moreover, two population-based studies have shown associations between endometriosis and EC [52,168,169].

If we analyze the role of risk factors in the development of endometriosis and EC, some overlapping genetic factors (Figure 1) are worth highlighting. Genetic correlation analyses by Painter et al. (2018) revealed the presence of "weak to moderate, but significant" genetic overlap between endometriosis and EC [52,144]. Namely, in the cross-disease metaanalysis the authors found 13 SNPs that appeared to be involved in replication. These SNPs are the following: rs2475335, rs9865110, rs2278868, rs12303900, rs9349553, rs10008492, rs9530566, rs10459129, rs2198894, rs7042500, rs17693745, rs7515106, and rs1755833 [52,144]. SNP rs2475335, which is located on chromosome 9p23, was most significantly associated with both diseases (*<sup>p</sup>* = 4.9 <sup>×</sup> <sup>10</sup>−<sup>8</sup> ) [52].

To conclude about the link between endometriosis and EC, epidemiological studies have reported conflicting data for an association between the diagnosis of endometriosis and risk of EC [52]. More large-scale investigations are required in order to confirm or refute the link between endometriosis and risk of EC development.
