Possible involvement of hMLH1, p16(INK4a) and PTEN in the malignant transformation of endometriosis

Endometriosis is a common gynecologic disease, which generally follows a benign course. Notwithstanding, several clinical and histologic studies as well as molecular data show that endometriosis could be a precursor of sporadic endometrioid and clear cell carcinomas at extrauterine loci. Several reports have implicated alterations of the hMLH1 and p16(ink4a) (p16) genes, in particular hypermethylation of the promoter region, and of the PTEN gene, principally genetic mutations, in endometrial and ovarian cancers and have indicated that these alterations are already present in precancer conditions. In this report, we analyzed the methylation status of hMLH1 and p16 and the protein expression of PTEN and hMLH1 in 46 cases of endometriosis stages III and IV to better define the possible involvement of these genes in the malignant transformation of endometriosis. We found abnormal methylation of hMLH1 in 4 of the 46 cases (8.6%). In addition, these cases had no detectable hMLH1 protein expression. Regarding patients with hMLH1 alterations, 2 were classified as stage IV and 2 showed coexistent endometriosis and carcinoma. Only 1 case of endometriosis (2.17%), classified as atypical, showed abnormal methylation of p16. Reduced PTEN protein expression was detected in 7 of 46 cases (15.21%): 5 were clinically classified as stage IV, and the other 2 presented both cancer and hypermethylated hMLH1. Our preliminary study suggests that reduced expression of both hMLH1 and PTEN may be involved in the malignant evolution of endometriosis and should be used as markers of neoplastic transformation in aggressive endometriosis with elevated tumor markers.