Abstract
Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that extends telomeres in cancer cells. It influences tumorigenesis and patient survival. Despite the clinical significance of ALT in tumors, the manner in which ALT is activated and influences prognostic outcomes in distinct cancer types is unclear. In this work, we profiled distinct telomere maintenance mechanisms (TMMs) using 8953 transcriptomes of 31 different cancer types from The Cancer Genome Atlas (TCGA). Our results demonstrated that approximately 29% of cancer types display high ALT activity with low telomerase activity in the telomere-lengthening group. Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe. Five cancer types showed a significant difference in survival in the presence of high ALT activity. Sarcoma patients with elevated ALT had unfavorable risks (p < 0.038) coupled with a high expression of TOP2A, suggesting this as a potential drug target. On the contrary, glioblastoma patients had favorable risks (p < 0.02), and showed low levels of antigen-presenting cells. Together, our analyses highlight cancer type-dependent TMM activities and ALT-associated genes as potential therapeutic targets.
Highlights
Telomeres are repetitive nucleoprotein structures located at the ends of chromosomes [1]
We split the samples into two groups: telomere-lengthening (Long telomere lengths (TLs)) samples and telomere-shortening (Short TL) samples, for each cancer type (Figure 1b)
Our analyses showed that both Telomere maintenance mechanisms (TMMs) pathways might be active in an individual sample, as previously suggested [22,23,24,25,26]
Summary
Telomeres are repetitive nucleoprotein structures located at the ends of chromosomes [1]. They play an essential role in protecting chromosome ends, preventing the DNA damage response (DDR) and maintaining genomic stability [2]. Telomere maintenance mechanisms (TMMs) differ between cancer cells and normal cells. Unlike normal human somatic cells that have a finite proliferation capacity [3], cancer cells have an unlimited capacity to proliferate because of their distinct TMMs [4]. There are two TMM categories in human cancer: telomerase-mediated maintenance, which is observed in 80% of cancers, and alternative lengthening of telomeres (ALT) [5], which is found in ~15% of cancers [6,7]. ALT is based on the homologous recombination (HR)-dependent replication exchange and the synthesis of telomeric templates [8,9]
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