TERTpromoter mutation in adult granulosa cell tumor of the ovary

Autor: Pilsworth, Jessica A., 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, van Meurs, Hannah, Oliva, Esther, Shah, Sohrab P., Kommoss, Stefan, Kommoss, Friedrich, Gilks, C. Blake, Baird, Duncan M., Huntsman, David G.
Zdroj: Modern Pathology; July 2018, Vol. 31 Issue: 7 p1107-1115, 9p
Abstrakt: The telomerase reverse transcriptase (TERT) gene is highly expressed in stem cells and silenced upon differentiation. Cancer cells can attain immortality by activating TERTto maintain telomere length and telomerase activity, which is a crucial step of tumorigenesis. Two somatic mutations in the TERTpromoter (C228T; C250T) have been identified as gain-of-function mutations that promote transcriptional activation of TERTin multiple cancers, such as melanoma and glioblastoma. A recent study investigating TERTpromoter 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 TERTC228T promoter mutation in 50% of tumors. We found that adult granulosa cell tumors with mutated TERTpromoter have increased expression of TERTmRNA and exhibited significantly longer telomeres compared to those with wild-type TERTpromoter. Extension cohort analysis using allelic discrimination revealed the TERTC228T 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 TERTC228T 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 TERTC228T mutation present in recurrent tumors and absent in the corresponding primary tumor. Our data suggest that TERTC228T promoter mutations may have an important role in progression of adult granulosa cell tumors.
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