Abstract
Endometriosis is a benign condition characterized by the presence of ectopic endometrial tissue. It is still debated whether endometriosis is a disease that can predispose to the pathogenesis of endometrial cancer outside the uterus. Deficiencies in mismatch repair (MMR) genes are a known risk factor for developing endometrioid cancer. Starting from two cases of patients with abnormal MMR endometrioid carcinoma of the uterus and synchronous endometrioid carcinoma in non-ovarian and ovarian endometriosis, we performed a somatic mutation profile and phylogenetic analysis of the lesions in order to identify if they were metastasis or primary de novo tumors. In the first case, we identified de novo activating mutations in PIK3CA and KRAS in endometrioid cancer lesions but not in endometriosis. Although the acquisition of a de novo mutation in ESR1 and a decrease in mutant allele fraction (MAF) from the endometrial tumor to the localizations in the endometriosis lesions, the clonal relationship was confirmed by the limited number of heteroplasmic mutations in D-loop mitochondrial DNA region. In the other case, the clonal behavior was demonstrated by the overlap of MAF at each site. Our data support the hypothesis of a retrograde dissemination of tumor cells, moving from the primary carcinoma in the endometrium to ectopic sites of endometriosis where localizations of tumor arise.
Highlights
Endometriosis is a relatively common disease, characterized by the presence of ectopic endometrial tissue outside the uterus [1]
Molecular analysis was performed to search for variants in mismatch repair (MMR) genes on genomic DNA extracted from peripheral blood
Since somatic mutations are a widespread event in “normal” tissue and most endometriotic lesions harboring cancer-associated genes do not necessarily lead to malignant transformation [17], environmental features protective against malignant transformation or that buffer the effects of such mutations may prevent the progression from endometriosis to gynecologic cancers [16]
Summary
Endometriosis is a relatively common disease, characterized by the presence of ectopic endometrial tissue outside the uterus [1]. Ovarian endometriosis has been reported to be associated with an increased risk of epithelial ovarian cancer, representing the direct precursor of clear-cell and endometrioid ovarian carcinomas [5]. Genomic characterization by The Cancer Genome Atlas (TCGA) classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high [8]. Another classification of endometrial cancer differentiates tumors into two subtypes: type I is characterized by a favorable prognosis and represented mostly by endometrioid adenocarcinoma, associated with an unopposed estrogen stimulation, often preceded by endometrial hyperplasia; type II has significantly poorer 5-year survival predominantly represented by non-endometrioid histology, mostly arising in an atrophic endometrium and deriving from intraepithelial carcinoma as a precancerous lesion [9]. Since the evidence of activity of immune checkpoint inhibitors in patients with advanced mismatch repair (MMR)deficient endometrial cancer [10] and considering that Lynch syndrome may account for about 3% of all endometrial cancers [11], it is recommended to screen all endometrial cancer patients with the use of immunohistochemical tests for MLH1, MSH2, MSH6, and PMS2 [12]
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