title: Frequent somatic mutations of the telomerase reverse transcriptase promoter in ovarian clear cell carcinoma but not in other major types of gynaecological malignancy.
abstract: Up-regulated expression of telomerase reverse transcriptase (TERT) and subsequent maintenance of telomere length are essential in tumour development. Recent studies have implicated somatic gain-of-function mutations at the TERT promoter as one of the mechanisms that promote transcriptional activation of TERT; however, it remains unclear whether this genetic abnormality is prevalent in gynaecological neoplasms. We performed mutational analysis in a total of 525 gynaecological cancers, and correlated TERT promoter mutations with clinicopathological features. With the exception of ovarian clear cell carcinomas, in which mutations were found in 37 (15.9%) of 233 cases, the majority of gynaecological malignancies were wild-type. TERT promoter mutation does not appear to be an early event during oncogenesis, as it was not detected in the contiguous endometriosis associated with ovarian clear cell carcinoma. Ovarian clear cell carcinoma cell lines with TERT promoter mutations exhibited higher TERT mRNA expression than those with wild-type sequences (p = 0.0238). TERT promoter mutation tended to be mutually exclusive with loss of ARID1A protein expression (p = 4.4 × 10(-9) ) and PIK3CA mutation (p = 0.0019) in ovarian clear cell carcinomas. No associations with disease-specific survival were observed for ovarian clear cell carcinoma. The above results, in conjunction with our previous report showing longer telomeres in ovarian clear cell carcinomas relative to other types of ovarian cancer, suggests that aberrations in telomere biology may play an important role in the pathogenesis of ovarian clear cell carcinoma.
authors: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors: Ren-Chin
authors: RC
authors: Wu
authors: Ayse
authors: A
authors: Ayhan
authors: Daichi
authors: D
authors: Maeda
authors: Kyu-Rae
authors: KR
authors: Kim
authors: Blaise A
authors: BA
authors: Clarke
authors: Patricia
authors: P
authors: Shaw
authors: Michael Herman
authors: MH
authors: Chui
authors: Barry
authors: B
authors: Rosen
authors: Ie-Ming
authors: IeM
authors: Shih
authors: Tian-Li
authors: TL
authors: Wang
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D015142:Baltimore; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D009864:Ontario; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D056910:Republic of Korea; D019098:Telomerase / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D019098:Telomerase; D014157:Transcription Factors; C112476:ARID1A protein, human; C484760:PIK3CA protein, human; C509186:TERT protein, human
keywords: ARID1A; PIK3CA; TERT promoter; clear cell carcinoma; telomerase; telomere