TY - JOUR
T1 - TERT promoter mutation in adult granulosa cell tumor of the ovary
AU - Pilsworth, Jessica A.
AU - Cochrane, Dawn R.
AU - Xia, Zhouchunyang
AU - Aubert, Geraldine
AU - Färkkilä, Anniina E. M.
AU - Horlings, Hugo M.
AU - Yanagida, Satoshi
AU - Yang, Winnie
AU - Lim, Jamie L. P.
AU - Wang, Yi Kan
AU - Bashashati, Ali
AU - Keul, Jacqueline
AU - Wong, Adele
AU - Norris, Kevin
AU - Brucker, Sara Y.
AU - Taran, Florin-Andrei
AU - Krämer, Bernhard
AU - Staebler, Annette
AU - van Meurs, Hannah
AU - Oliva, Esther
AU - Shah, Sohrab P.
AU - Kommoss, Stefan
AU - Kommoss, Friedrich
AU - Gilks, C. Blake
AU - Baird, Duncan M.
AU - Huntsman, David G.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85042115063&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29449679
U2 - https://doi.org/10.1038/s41379-018-0007-9
DO - https://doi.org/10.1038/s41379-018-0007-9
M3 - Article
C2 - 29449679
SN - 0893-3952
VL - 31
SP - 1107
EP - 1115
JO - Modern Pathology
JF - Modern Pathology
IS - 7
ER -