Molecular Analysis of Endometrial Tumorigenesis: Importance of Complex Hyperplasia Regardless of Atypia

Abstract

Purpose: Endometrial carcinoma (EC) is common in the population and the most frequent extracolonic malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC)/Lynch syndrome. We characterized precursor lesions of endometrioid EC to identify markers of malignant transformation and tumor progression. Experimental Design: Serial specimens of normal endometrium, simple hyperplasia, complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma obtained during a 10-year surveillance of DNA mismatch repair (MMR) gene mutation carriers (together 110 samples) were molecularly profiled and compared with a sporadic reference series of endometrial specimens taken for nonmalignant reasons (62 samples). Results: Among MMR gene mutation carriers, decreased MMR protein expression was present in 7% in normal endometrium, 40% in simple hyperplasia, 100% in complex hyperplasia without atypia, 92% in complex hyperplasia with atypia, and 100% in endometrial carcinoma. Microsatellite instability frequencies were lower (6%, 17%, 67%, 38%, and 64%, respectively). Among 24 tumor suppressor genes, the number of methylated loci increased from normal endometrium to simple hyperplasia to complex hyperplasia (complex hyperplasia without atypia/complex hyperplasia with atypia) in both Lynch syndrome and reference series. The most frequently methylated genes were CDH13, RASSF1A, and GSTP1. In MMR gene mutation carriers, MMR and methylation defects appeared up to 12 years before endometrial carcinoma. Conclusions: Molecular changes in endometrial tissue are detectable several years before endometrial carcinoma in genetically predisposed individuals. Abnormal MMR and methylation classify normal endometrium and simple hyperplasia into one category and complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma into another, suggesting that, contrary to a traditional view, complex hyperplasia without atypia and complex hyperplasia with atypia are equally important as precursor lesions of endometrial carcinoma. (Clin Cancer Res 2009;15(18):5772-83) Endometrial carcinoma is the most common malignant tumor of the female genital organs in industrialized countries (1) and comprises 4% of all cancers in women worldwide (2). Estrogendependent tumors (type I, endometrioid endometrial carcinomas) account for 80% to 85% of cases and non-estrogendependent (type II, nonendometrioid endometrial carcinomas) account for the rest. Type I tumors occur in premenopausal and younger postmenopausal women, are typically low-grade and localized, and have a favorable outcome, whereas type II tumors occur in older postmenopausal women, are of high grade and more advanced stage, and have worse prognosis (1, 2). Type I tumors are considered to form in a background of endometrial hyperplasia. The WHO classifies endometrial hyperplasias as simple or complex, by degree of architectural abnormality, and as having or not having atypia, by cytology (3). Epidemiologic studies suggest that the ri...

Identification of subgroup-specific miRNA patterns by epigenetic profiling of sporadic and Lynch syndrome-associated colorectal and endometrial carcinoma

“…We showed that miR-129-2 methylation stratified endometrial specimens into two groups, one with low methylation (normal endometrium and SH) and another one with a significantly higher methylation (CH and CAH). It remains controversial which lesions should be considered as precursors to EC, and the miRNA data, together with our previous findings of conventional TSGs [27], support the importance of complex hyperplasia, with or without atypia, as a precursor lesion of EC.…”

Strong Correlation Between Molecular Changes in Endometrial Carcinomas and Concomitant Hyperplasia

“…12 Although these patients had a germline predisposition for the development of MSI, the data do suggest that MSI may be present early in endometrial carcinogenesis.…”

Involvement of pelvic inflammation–related mismatch repair abnormalities and microsatellite instability in the malignant transformation of ovarian endometriosis

“…The frequency of MSI-H in ovarian cancer was significantly higher than that in endometriosis. In addition, endometriosis also displayed a high frequency of MSI compared with the normal endometrium, in which its frequency has been reported to be lower than 5% [25]. MMR deficiency has been reported to be an important tumorinitiating mechanism in both endometrial and ovarian carcinomas [26].…”