Pan-Cancer Analysis of Clinical Relevance via Telomere Maintenance Mechanism

Abstract

Understanding the telomere maintenance mechanism (TMM) in immortal cancer cells is vital for TMM-targeted therapies in clinical settings. In this study, we classified four telomere maintenance mechanisms into telomerase, ALT, telomerase + ALT, and non-defined telomere maintenance mechanism (NDTMM) across 31 cancer types using 10,704 transcriptomic datasets from The Cancer Genome Atlas. Our results demonstrated that approximately 50% of the total cohort displayed ALT activity with high telomerase activity in most cancer types. We confirmed significant patient prognoses according to distinct TMMs in six cancer types: adrenocortical carcinoma (ACC), PAAD, HNSC, SARC, GBM, and metastatic cancer. Patients with metastasis had a poor prognosis in the ALT group (p < 0.006) subjected to RAS protein signal transduction. Glioblastoma patients had poor prognosis in NDTMM (p < 0.0043) and showed high levels of myeloid leukocyte activation. Pancreatic adenocarcinoma (p < 0.04) and head and neck squamous cell carcinoma (p < 0.046) patients had a good prognosis in the ALT group with high immune cell activation. Furthermore, we showed that master transcriptional regulators might affect the selection of the TMM pathway and explained why different telomere maintenance mechanisms exist. Furthermore, they can be used to segregate patients and predict responders to different TMM-targeted therapeutics.

Single Cell Analysis of Gastric Cancer Reveals Non-Defined Telomere Maintenance Mechanism

“…This was similar to a study that reported approximately 30–40% and 30% ALT activity in a GC cohort and in tumor cells of another cohort, respectively [ 5 ]. Specifically, in endothelial cells, granulocytes, and macrophages, the number of cells exhibiting ALT and telomerase activities was low and relatively high, respectively.…”

“…By comparing cell type categorization and TMM type in single-cell data subjected to imputation, we determined the TMM types of single cells. TMM types were classified into four categories in order to determine the most prevalent type in each cell, and six pathways were assessed using the gene profile from our previous pan-cancer TMM study [ 5 ].…”

“…The mechanism underlying the maintenance of telomere has been widely investigated in pan-cancer studies [ 4 ]. A previous study using bulk RNA-sequencing (RNA-seq) analysis of pan-cancer data of the Cancer Genome Atlas (TCGA) to classify TMMs into four types was the first to identify non-defined TMM (NDTMM) [ 5 ]. NDTMM is associated with a poor prognosis in glioblastoma [ 6 ].…”

“…In particular, alternative lengthening of telomere (ALT) is associated with poor prognosis of gastric cancer (GC) and a stem-like molecular mechanism [ 8 ]. However, most previous studies used bulk RNA-seq, which limits their relevance and applicability because the specific cell types were not considered [ 5 ]. Each TMM differs in its immortalization process and progression into aggressive drug-resistant cancer cells.…”

A novel telomere-related gene prognostic signature for survival and drug treatment efficiency prediction in lung adenocarcinoma

“…Recently, emerging studies have implied that TMM in cancer is a complicated process that is associated with hundreds of various genes [ 15 ]. These telomere-related genes (TRGs) have also shown significant relevance to the prognosis of several types of cancer.…”