TERT promoter mutation in adult granulosa cell tumor of the ovary View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-07

AUTHORS

Jessica A. Pilsworth, Dawn R. Cochrane, Zhouchunyang Xia, Geraldine Aubert, Anniina E. M. Färkkilä, Hugo M. Horlings, Satoshi Yanagida, Winnie Yang, Jamie L. P. Lim, Yi Kan Wang, Ali Bashashati, Jacqueline Keul, Adele Wong, Kevin Norris, Sara Y. Brucker, Florin-Andrei Taran, Bernhard Krämer, Annette Staebler, Hannah van Meurs, Esther Oliva, Sohrab P. Shah, Stefan Kommoss, Friedrich Kommoss, C. Blake Gilks, Duncan M. Baird, David G. Huntsman

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 cord-stromal tumors including adult granulosa cell tumors. We performed whole-genome sequencing on ten adult granulosa cell tumors with matched normal blood and identified a TERT C228T promoter mutation in 50% of tumors. We found that adult granulosa cell tumors with mutated TERT promoter have increased expression of TERT mRNA and exhibited significantly longer telomeres compared to those with wild-type TERT promoter. Extension cohort analysis using allelic discrimination revealed the TERT C228T mutation in 51 of 229 primary adult granulosa cell tumors (22%), 24 of 58 recurrent adult granulosa cell tumors (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 adult granulosa cell tumors, we found the TERT C228T mutation present in recurrent tumors and absent in the corresponding primary tumor. Our data suggest that TERT C228T promoter mutations may have an important role in progression of adult granulosa cell tumors. More... »

PAGES

1107-1115

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41379-018-0007-9

DOI

http://dx.doi.org/10.1038/s41379-018-0007-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1101039077

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29449679


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