Abstract PR13: TERT is frequently mutated in adult-type granulosa cell tumors of the ovary compared to other malignant sex cord-stromal tumors

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, a crucial step of tumorigenesis. Two somatic mutations in the TERT promoter (C228T; C250T) have been identified in multiple cancers, such as melanoma and glioblastoma, as gain-of-function mutations that promote transcriptional activation of TERT. A recent study investigating TERT promoter mutations in ovarian carcinomas found mutations in 15% of clear cell carcinomas. However, it is unknown whether these mutations are prevalent in adult-type granulosa cell tumors (AGCTs) of the ovary, Sertoli-Leydig cell tumors (SLCTs), and other malignant sex cord-stromal tumors. We performed whole-genome sequencing on ten AGCT cases with matched normal and identified the TERT C228T promoter mutation in 50% of cases. We found that AGCT cases with mutated TERT promoter have increased expression of TERT mRNA compared to those with wild-type TERT promoter. All five TERT promoter mutated cases had high levels of TERT mRNA expression, whereas three of the five wild-type TERT cases had no measurable TERT mRNA expression. There was a tendency towards longer telomere lengths in AGCT cases with the TERT promoter mutation relative to those without, although it was not statistically significant. These results suggest that telomerase may be activated by a different method in the cases with no TERT promoter mutations but have TERT mRNA expression. The remaining cases with neither TERT promoter mutations nor TERT mRNA expression likely maintain their telomeres using a telomerase-independent method, such as the alternative lengthening of telomeres pathway. TERT C228T allelic discrimination analysis of 331 AGCTs, 5 SLCTs, and 18 other malignant sex cord-stromal tumors detected the mutation in 56/247 (23%) of primary AGCTs, 22/84 (26%) of recurrent AGCTs, 1/5 (20%) of SLCTs and (0/18) 0% of other malignant sex cord-stromal tumors. The single SLCT case with the TERT promoter mutation was poorly differentiated and harbored the pathognomonic FOXL2 mutation of AGCT, suggesting this SLCT case may actually be an AGCT. In 204 AGCT cases with available survival data, there was a trend towards worse disease-specific survival in patients with the TERT promoter mutation compared to those without; however, statistical significance was not reached (p = 0.128, log-ranked test). In