TERTexpression is associated with metastasis from thin primaries, exhausted CD4+ T cells in melanoma and with DNA repair across cancer entities

Telomerase reverse transcriptase (TERT) promoter mutations occur frequently in cancer, have been associated with increasedTERTexpression and cell proliferation, and could potentially influence therapeutic regimens for melanoma. As the role ofTERTexpression in malignant melanoma and the non-canonical functions of TERT remain understudied, we aimed to extend the current knowledge on both types ofTERTalterations with respect to survival, further clinical and molecular parameters. Using multivariate models,TERTalterations were not consistently associated with survival in melanoma cohorts under immune checkpoint inhibition. The presence of CD4+ T cells increased withTERTexpression and correlated with the expression of exhaustion markers. While the frequency of promoter mutations did not change with Breslow thickness,TERTexpression was increased in metastases arising from thinner primaries. Enrichment analyses of single-cell RNA-seq showedTERTexpression is associated with genes involved in cell migration and dynamics of the extracellular matrix, supporting the role ofTERTduring invasion and metastasis. Co-regulated genes in several bulk tumors and single-cell RNA-seq cohorts also indicated non-canonical functions ofTERTrelated to mitochondrial DNA stability and nuclear DNA repair in line with increasedTERTexpression during chromothripsis (PCAWG cohort) and under hypoxic conditions (PCAWG and SKCM cohorts). Also in glioblastoma (Klughammer and PCAWG cohorts),TERTwas co-expressed with DNA repair genes. Our results thus indicate a relevance ofTERTexpression in melanoma metastasis, T cell dysfunction and DNA repair across cancer entities.SignificanceIn addition to the frequently occurringTERTpromoter mutations, we testTERTexpression with respect to clinical and molecular associates, extending the canonical role ofTERTin melanoma and other cancer entities.