Browsing by Author "Zhang, Cindy H."
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- 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.
- THOR is a targetable epigenetic biomarker with clinical implications in breast cancerPublication . Apolónio, Joana; Dias, João S.; Fernandes, Mónica T.; Komosa, Martin; Lipman, Tatiana; Zhang, Cindy H.; Leão, Ricardo; Lee, Donghyun; Nunes, Nuno M.; Maia, Ana-Teresa; Morera, José L.; Vicioso, Luis; Tabori, Uri; Castelo-Branco, PedroBreast cancer (BC) is the most frequently diagnosed cancer and a leading cause of death among women worldwide. Early BC is potentially curable, but the mortality rates still observed among BC patients demon‑ strate the urgent need of novel and more efective diagnostic and therapeutic options. Limitless self-renewal is a hallmark of cancer, governed by telomere maintenance. In around 95% of BC cases, this process is achieved by telom‑ erase reactivation through upregulation of the human telomerase reverse transcriptase (hTERT). The hypermethylation of a specifc region within the hTERT promoter, termed TERT hypermethylated oncological region (THOR) has been associated with increased hTERT expression in cancer. However, its biological role and clinical potential in BC have never been studied to the best of our knowledge. Therefore, we aimed to investigate the role of THOR as a biomarker and explore the functional impact of THOR methylation status in hTERT upregulation in BC.
- WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastomaPublication . Zhukova, Nataliya; Ramaswamy, Vijay; Remke, Marc; Martin, Dianna C.; Castelo-Branco, Pedro; Zhang, Cindy H.; Fraser, Michael; Tse, Ken; Poon, Raymond; Shih, David J. H.; Baskin, Berivan; Ray, Peter N.; Bouffet, Eric; Dirks, Peter; Von Bueren, Andre O.; Pfaff, Elke; Korshunov, Andrey; Jones, David T. W.; Northcott, Paul A.; Kool, Marcel; Pugh, Trevor J.; Pomeroy, Scott L.; Cho, Yoon-Jae; Pietsch, Torsten; Gessi, Marco; Rutkowski, Stefan; Bognar, Laszlo; Cho, Byung-Kyu; Eberhart, Charles G.; Conter, Cecile Faure; Fouladi, Maryam; French, Pim J.; Grajkowska, Wieslawa A.; Gupta, Nalin; Hauser, Peter; Jabado, Nada; Vasiljevic, Alexandre; Jung, Shin; Kim, Seung-Ki; Klekner, Almos; Kumabe, Toshihiro; Lach, Boleslaw; Leonard, Jeffrey R.; Liau, Linda M.; Massimi, Luca; Pollack, Ian F.; Ra, Young Shin; Rubin, Joshua B.; Van Meir, Erwin G.; Wang, Kyu-Chang; Weiss, William A.; Zitterbart, Karel; Bristow, Robert G.; Alman, Benjamin; Hawkins, Cynthia E.; Malkin, David; Clifford, Steven C.; Pfister, Stefan M.; Taylor, Michael D.; Tabori, UriTP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% +/- 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% +/- 2% vs. 57.4% +/- 1.8% (p < 0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% +/- 1.5% in lithium treated cells vs. 56.6 +/- 3% (p < 0.01)) accompanied by increased number of.H2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% +/- 8% for lithium treated cells vs. 27% +/- 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.