UBC Faculty Research and Publications

TERT promoter mutation in adult granulosa cell tumor of the ovary Cochrane, Dawn R.; Xia, Zhouchunyang; Aubert, Geraldine; Färkkilä, Anniina E.M.; Horlings, Hugo M.; Yanagida, Satoshi; Yang, Winnie; Lim, Jamie L.P.; Wang, Yi Kan; Bashashati, Ali; Keul, Jacqueline; Wong, Adele; Norris, Kevin; Brucker, Sara Y.; Taran, Florin-Andrei; Krämer, Bernhard; Staebler, Annette; Oliva, Esther; Shah, Sohrab P.; Kommoss, Stefan; Kommoss, Friedrich; Gilks, C. Blake; Baird, Duncan M.; Huntsman, David G.; Pilsworth, Jessica

Abstract

The telomerase reverse transcriptase (TERT) gene is highly expressed in stem cells and silenced upon differentiation. Cancer cells can attain immortality by activating TERT to maintain telomere length and telomerase activity, which is a crucial step of tumorigenesis. Two somatic mutations in the TERT promoter (C228T; C250T) have been identified as gain-of-function mutations that promote transcriptional activation of TERT in multiple cancers, such as melanoma and glioblastoma. A recent study investigating TERT promoter mutations in ovarian carcinomas found C228T and C250T mutations in 15.9% of clear cell carcinomas. However, it is unknown whether these mutations are frequent in other ovarian cancer subtypes, in particular, sex cordstromal tumors including adult granulosa cell tumors (AGCTs). We performed whole genome sequencing on ten AGCTs with matched normal blood and identified a TERT C228T promoter mutation in 50% of tumors. We found that AGCT with mutated TERT promoter have increased expression of TERT mRNA compared to those with wild-type TERT promoter. AGCT with TERT C228T mutation exhibited significantly longer telomeres compared to AGCT with TERT wild-type promoter. Extension cohort analysis using allelic discrimination revealed the TERT C228T mutation in 51 of 229 primary AGCTs (22%), 24 of 58 recurrent AGCTs (41%), and 1 of 22 other sex cord-stromal tumors (5%). There was a significant difference in overall survival between patients with TERT C228T promoter mutation in the primary tumors and those without it (p = 0.00253, log rank test). In seven AGCTs, we found the TERT C228T mutation present in recurrent tumors and absent in the corresponding primary tumor. Our data suggests that TERT C228T mutations may have an important role in progression of AGCT. Telomeres are conserved, repetitive (TTAGGG) DNA-protein complexes that are added to the ends of chromosomes by the enzyme telomerase to prevent DNA damage and maintain replicative potential. Telomere attrition during DNA replication induces genomic instability that can result in tumorigenesis. Telomerase consists of a catalytic protein subunit known as telomerase reverse transcriptase (TERT) and a functional RNA called telomerase RNA component (TERC). TERT is highly expressed in stem cells and is silenced upon differentiation in somatic cells. Most cancer cells attain proliferative immortality by upregulating the TERT gene to maintain telomere length and telomerase activity. The known mechanisms of telomerase activation include mutations in the TERT promoter, TERT gene amplification, CpG methylation at the TERT promoter, changes in alternative splicing of TERT pre-mRNA and upregulation of transcriptional activators. Approximately 90% of cancers express TERT, while the remaining 10-15% of cancers maintain their telomere length through a telomerase-independent method called alternative lengthening of telomeres. TERT promoter mutations were first reported in familial melanoma and subsequently in sporadic melanoma. There are two hot-spot TERT promoter mutations, C228T and C250T, each generates an identical 11 base pair sequence containing a consensus binding motif for ETS transcription factors, and functions as either a transcriptional activator or repressor to regulate telomerase expression. These two mutations are implicated in the activation of telomerase in other malignances such as central nervous system tumors, hepatocellular carcinomas, bladder cancers and thyroid cancers. A recent study on TERT promoter mutations in gynecological malignancies, including ovarian and uterine carcinomas, reported TERT hot-spot mutations in 15.9% of ovarian clear cell carcinomas. However, it is unknown whether TERT promoter mutations are frequent in sex cord-stromal tumors, including adult granulosa cell tumors (AGCTs). In this study, we evaluated the biological and clinical significance of TERT promoter mutations, specifically C228T, in total of 251 primary ovarian sex cord-stromal tumors.

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