■綜説
子宮体がんにおけるゲノム・エピゲノムシステムの調節異常
米山 剛一
日本医科大学武蔵小杉病院女性診療科・産科
Genetic and Epigenetic Dysregulation in Endometrial Carcinoma
Koichi Yoneyama
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
Key words
endometrial carcinoma, genome, epigenome, microRNA, PTEN
Correspondence to
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
E-mail：kyone@nms.ac.jp
受付：2016年9月8日 受理：2016年10月26日 |
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