Granulosa cell tumours (GCTs) of the ovary account for 90% of sex cord-stromal tumours and have a high recurrence rate up to 50%. A missense mutation in the FOXL2 gene (c.402C>G; pC134W) is a defining feature of GCT and is used as a robust marker for diagnosis. However, other than the FOXL2 mutation the pathogenesis and the driving pathways remain unknown. Determining secondary genetic events in GCTs is essential to understanding and improving prognosis.
In a pilot study, we completed an analysis of whole genome sequencing of ten GCTs and matched normal cases to generate a comprehensive catalogue of coding and non-coding events. We identified a TERT promoter mutation (c.228C>T) in 50% of these cases. TERT is normally inactivated in somatic tissues; however, this promoter mutation has been shown to re-activate transcription of TERT. We validated this TERT mutation in an international cohort of 300 GCTs and found it was present in approximately 25% of cases overall. These TERT promoter mutations have been used to revise the molecular classification of other cancer types such as gliomas. In GCT, we found that this TERT mutation was correlated with a significantly worse survival outcome in patients with primary GCT (p<0.005). Further, we found that this TERT mutation was present in a larger proportion of recurrent cases. Thus, this mutation may denote a novel subtype of GCT with a worse prognosis.
Previous research has shown that TERT activation is evident in over 90% of cancers and is a fundamental step in tumourigenesis that enables unlimited proliferation. This TERT promoter mutation in GCT provides an explanation of how granulosa cells escape atresia and attain immortality. Thus, we hypothesize a mechanism in which the FOXL2 mutation prevents apoptosis and the TERT mutation allows limitless proliferation for oncogenes to transform granulosa cells. However, the current cell models of GCT lack relevant functional pathways and do not recapitulate the biology of these tumours. Therefore, we are developing more suitable cell models to test our hypothesis. We believe that understanding the interaction between these TERT and FOXL2 mutations may lead to novel cancer cell-specific targeted therapies.
Citation Format: Jessica A. Pilsworth, Dawn R. Cochrane, Zhouchunyang Xia, Hugo M. Horlings, Winnie Yang, Melissa K. McConechy, Satoshi Yanagida, Anniina E. Färkkilä, Adele P. Wong, Genny Trigo-Gonzalez, S.W. Grace Cheng, Yikan Wang, Ali Bashashati, Gregg B. Morin, Esther Oliva, Sohrab P. Shah, David G. Huntsman. TERT promoter mutation in granulosa cell tumours of the ovary: Prevalence and prognostic significance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3381. doi:10.1158/1538-7445.AM2017-3381
