Genetic and Epigenetic Dysregulation in Endometrial Carcinoma
Department of Obstetrics and Gynecology, Nippon Medical School Musashi Kosugi Hospital
Endometrial carcinoma arises from the endometrium lining of the uterus and is a common malignancy of the female genital tract. It is generally categorized into two subtypes, types I and II. Type I endometrioid tumors account for 70〜80% of cases, and they occur predominantly in premenopausal and perimenopausal women. Type I tumors are low-grade, early-stage, hormonally sensitive carcinomas; invasion of the uterine wall is minimal, so the prognosis is usually good. By contrast, type II endometrial carcinomas, which are primarily serous, are less common, accounting for only 10〜20% of endometrial carcinomas. Type II tumors occur mostly in older postmenopausal women, are independent of estrogen exposure, and patients with them have a poor prognosis. The Cancer Genome Atlas Research Network performed an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas. The genetic analyses were based on a combination of somatic nucleotide substitutions, microsatellite instability (MSI), and somatic copy number alterations. On the basis of the results, endometrial cancers were classified into four groups: (1) those with unusually high mutation rates and a unique nucleotide change spectrum (POLE [ultramuted] group); (2) those with MSI tumors, most with MLH1 promoter methylation (MSI [hypermuted] group); (3) those with lower mutation frequency comprising most of the microsatellite stable endometrioid cancers (copy number-low [endometrioid] group); and (4) those consisting primarily of serous-like cancers with extensive somatic copy number alterations and a low mutation rate (copy number-high [serous-like] group). In addition, in respect to pathway alterations, endometrial cancer has frequent mutations in the PI3K/AKT pathway. Regarding the epigenetic regulation of endometrial carcinoma, microRNAs (miRNAs) have received a lot of attention in recent years. miRNAs are a large family of small (approximately 22 molecules) non-coding RNAs that negatively regulate protein-coding gene expression post-transcriptionally. Recent studies have revealed dysregulated expressions of several miRNAs, also termed "onco-miRs," in various cancer tissues. Therefore, these onco-miRs could be promising prognostic biomarkers of cancer progression and/or metastasis. For example, in a recent study based on array-based comprehensive analyses, we identified miRNAs and mRNAs significantly dysregulated in endometrioid endometrial carcinomas and demonstrated that miR-200a, miR-200b, and miR-429 are onco-miRs that possibly target PTEN in endometrioid endometrial carcinomas.
Understanding of the genetic and epigenetic alterations of endometrial carcinomas may influence adequate treatments for patients.
日医大医会誌 2017; 13(1), 22-30
endometrial carcinoma, genome, epigenome, microRNA, PTEN
Koichi Yoneyama, MD, PhD, Department of Obstetrics and Gynecology, Nippon Medical School Musashi Kosugi Hospital, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki Kanagawa 211-0063, Japan