Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines

eLife

Mahmoud Ghandi¹  Kevin Hu²  Franklin W Huang² 

[1] Broad Institute of MIT and Harvard, Cambridge, United States;Broad Institute of MIT and Harvard, Cambridge, United States;Division of Hematology/Oncology, Department of Medicine; Bakar Computational Health Sciences Institute; Institute for Human Genetics; University of California, San Francisco, San Francisco, United States;Helen Diller Family Comprehensive Cancer Center, San Francisco, United States;

关键词: cancer;    telomeres;    genomics;    cell lines;    genetics;    CCLE;    Human;   

DOI  :  10.7554/eLife.66198

来源: eLife Sciences Publications, Ltd

【 摘 要 】

In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer Project, we calculated telomere content across 1299 cancer cell lines. We find that telomerase reverse transcriptase (TERT) expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance genes. Increased dependencies of shelterin members are associated with wild-type TP53 status. Investigating the epigenetic regulation of TERT, we find widespread allele-specific expression in promoter-wildtype contexts. TERT promoter-mutant cell lines exhibit hypomethylation at PRC2-repressed regions, suggesting a cooperative global epigenetic state in the reactivation of telomerase. By incorporating telomere content with genomic features across comprehensively characterized cell lines, we provide further insights into the role of telomere regulation in cancer immortality.

【 授权许可】

CC BY