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.
Highlights
The telomere maintenance (TMM) mechanism is used by cancer cells to promote immortality [1]
Little is known about the non-defined telomere maintenance mechanism (NDTMM), but it has been reported in several cancer types, including glioblastoma [7], osteosarcoma [8], and metastases of cutaneous melanoma [9]
NDTMM has only been reported in certain cancer types [1], our results showed that NDTMM could function in all cancer types
Summary
The telomere maintenance (TMM) mechanism is used by cancer cells to promote immortality [1]. As the research on telomerase [2] and alternative lengthening of telomeres [3] in human cancer is being actively conducted, interest in the role of TMM in the immortality of tumor cells (which is one of the hallmarks of cancer) is increasing. It has been studied in cancer cell lines with tumors of relevant origin based on TERT isoform expression patterns [4]. The role of telomere homeostasis in metastatic cancer is unknown, and targeting TMM in aggressive metastatic tumors with a poor prognosis can be a good strategy
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