Browsing by Author "Nassiri, Farshad"
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- Analysis of TERT association with clinical outcome in meningiomas: a multi-institutional cohort study.Publication . Gui, Chloe; Wang, Justin Z.; Patil, Vikas; Landry, Alexander P.; Castelo-Branco, Pedro; Singh, Olivia; Tabori, Uri; Aldape, Kenneth; Behling, Felix; Barnholtz-Sloan, Jill S.; Horbinski, Craig; Tabatabai, Ghazaleh; Ajisebutu, Andrew; Liu, Jeff; Patel, Zeel; Yakubov, Rebeca; Kaloti, Ramneet; Ellenbogen, Yosef; Wilson, Christopher; Cohen-Gadol, Aaron; Tatagiba, Marcos; Holland, Eric C.; Sloan, Andrew E.; Chotai, Silky; Chambless, Lola B.; Gao, Andrew; Makarenko, Serge; Yip, Stephen; Nassiri, Farshad; Zadeh, GelarehBackground TERT promoter mutation is a rare biomarker in meningiomas associated with aberrant TERT expression and reduced progression-free survival. Although high TERT expression is characteristic of tumours with TERT promoter mutations, it has also been observed in tumours with wildtype TERT promoters. This study aimed to investigate the prevalence and prognostic association of TERT expression in meningiomas.
- Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancerPublication . Lee, Donghyun D.; Komosa, Martin; Sudhaman, Sumedha; Leão, Ricardo; Zhang, Cindy H.; Apolonio, Joana D.; Hermanns, Thomas; Wild, Peter J.; Klocker, Helmut; Nassiri, Farshad; Zadeh, Gelareh; Diplas, Bill H.; Yan, Hai; Gallinger, Steven; Pugh, Trevor J.; Ramaswamy, Vijay; Taylor, Michael D.; Castelo-Branco, Pedro; Nunes, Nuno Miguel; Tabori, UriAberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allelespecific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer.
- Tert expression in meningiomas predicts progression-free survival independent of tert promoter mutationPublication . Gui, Chloe; Wang, Justin; Patil, Vikas; Landry, Alexander; Castelo-Branco, Pedro; Singh, Olivia; Tabori, Uri; Aldape, Kenneth; Behling, Felix; Barnholtz-Sloan, Jill; Horbinski, Craig; Tabatabai, Ghazaleh; Ajisebutu, Andrew; Liu, Jeff; Patel, Zeel; Yakubov, Rebeca; Kaloti, Ramneet; Ellenbogen, Yosef; Wilson, Christopher; Cohen-Gadol, Aaron; Tatagiba, Marcos; Sloan, Andrew; Holland, Eric; Chambless, Lola; Gao, Andrew; Chotai, Silky; Makarenko, Serge; Yip, Stephen; Nassiri, Farshad; Zadeh, GelarehWhile TERT promoter mutation (TPM) has been es¬tablished as a marker of clinically aggressive meningiomas, this alteration is rare and found in less than 5% of all cases. However, a larger subset of meningiomas may exhibit aberrant TERT expression in the absence of TPMs. This study investigated the effect of TERT gene expression on clinical outcome in meningioma patients. METHODS: Clinical and mo¬lecular data were retrospectively collected on 1241 meningiomas, split into a Toronto discovery cohort and a multi-institutional validation co¬hort. Sanger sequencing and bulk RNA sequencing were used to determine TPM status and TERT gene expression. The effect of TERT expression on progression-free survival (PFS) was assessed using Kaplan-Meier and Cox regression analysis. RESULTS: While meningiomas with TPM showed expectedly higher TERT gene expression compared to wildtype (TP-WT) cases (p<0.0001), TERT expression was still detected in 28.7% (157/547) of TP-WT meningiomas. Meningiomas with TERT expression showed sig¬nificantly worse PFS compared to meningiomas without any TERT expres¬sion. In fact, WHO grade 1 meningiomas with TERT expression had PFS outcomes resembling WHO grade 2 meningiomas lacking TERT expression (p=0.59). In turn, WHO grade 2 meningiomas with TERT expression had clinical outcomes similar to WHO grade 3 meningiomas without TERT ex¬pression (p=0.42). Furthermore, the proportion of meningiomas expressing TERT as well as overall TERT expression levels increased with increasing WHO grade. Multivariable analysis showed that TERT expression was sig-nificantly associated with worse PFS even when controlling for other known predictors of clinical outcome including TPM, CDKN2A/B loss, 1p/22q status and WHO grade (HR 1.85 [95% CI 1.33-2.57], p=0.00024). CON¬CLUSION: TERT expression is a novel independent biomarker of outcome for meningiomas identifiable in up to one-third of cases that may be utilized to reclassify tumors to a higher WHO grade.