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: Ren-Chin Wu, Ayse Ayhan, Daichi Maeda, Kyu-Rae Kim, Blaise A Clarke, Patricia Shaw, Michael Herman Chui, Barry Rosen, Ie-Ming Shih, Tian-Li Wang
• Journal: The Journal of pathology (J Pathol) Vol. 232 Issue 4 Pg. 473-81 (Mar 2014) ISSN: 1096-9896 [Electronic] England
• PMID: 24338723 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• ARID1A protein, human
• DNA-Binding Proteins
• Nuclear Proteins
• RNA, Messenger
• Transcription Factors
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• TERT protein, human
• Telomerase

Topics

• Adenocarcinoma, Clear Cell (enzymology, genetics, mortality, pathology)
• Adult
• Aged
• Baltimore
• Cell Line, Tumor
• Class I Phosphatidylinositol 3-Kinases
• DNA Mutational Analysis
• DNA-Binding Proteins
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Gene Frequency
• Genetic Predisposition to Disease
• Humans
• Japan
• Kaplan-Meier Estimate
• Middle Aged
• Mutation
• Nuclear Proteins (genetics)
• Ontario
• Ovarian Neoplasms (enzymology, genetics, mortality, pathology)
• Phenotype
• Phosphatidylinositol 3-Kinases (genetics)
• Prognosis
• Promoter Regions, Genetic
• RNA, Messenger (metabolism)
• Republic of Korea
• Telomerase (genetics)
• Transcription Factors (genetics)