hTERT Promoter Methylation: An Epigenetic Cancer Biomarker
2012.10.15
Pedro Castelo Branco The Hospital for Sick Children University of Toronto Toronto, Canada
October 15th 2012, 15h00, CNC Auditorium (2nd floor, old FMUC building, Pólo I)

Host: João Nuno Moreira


Summary:

Purpose: Defining grade of malignancy and disease progression is a major goal in pediatric neurooncology. Since telomerase is a hallmark of cancer, we examined whether promoter methylation of hTERT, the catalytic subunit of telomerase, can be a biomarker for malignancy, response to therapy and patient outcome. Patients and methods: Whole genome methylation arrays (discovery cohort n=280), Sequenom and pyrosequencing of hTERT promoter (validation cohort, n=219) were performed on patient samples and normal tissues. Correlation between hTERT promoter methylation, telomere maintenance and patient outcome was performed.

Results: Using the discovery cohort, we uncovered a specific region upstream-of-the transcription-start-site (UTSS) of hTERT that is hypermethylated in 100% of malignant neoplasms that express hTERT and unmethylated in normal tissues and in low grade tumors lacking hTERT expression. In the validation cohort, this biomarker had positive and negative predictive values of 1.0 and 0.93, respectively. UTSS methylation increased in tumors as they evolved from low to high grade and from primary to metastatic. Furthermore, UTSS methylation was able to identify which low grade neoplasms would progress to malignant cancers. Ependymomas with and without UTSS methylation had 5-year overall survival of 51+/-10% and 95+/-5% respectively (p=0.0008). Finally, UTSS methylation could predict which tumors would respond to targeted therapy with telomerase inhibitor. Conclusion Hypermethylation of a specific region in the hTERT promoter is a cancer signature. It positively correlates with higher hTERT expression, tumor progression and poor prognosis. hTERT UTSS methylation may also represent a diagnostic tool and a therapeutic target for pediatric nervous system tumors.
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Funded by ERDF - European Regional Development Fund through COMPETE 2020 and National Funds via FCT - Fundação para a Ciência e Tecnologia, under projects POCI-01-0145-FEDER-007440 e UIDB/04539/2020.

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