TY  - JOUR
AU  - Kuhn, Christina Katharina
AU  - Meister, Jaroslawna
AU  - Kreft, Sophia
AU  - Stiller, Mathias
AU  - Puppel, Sven-Holger
AU  - Zaremba, Anne
AU  - Scheffler, Björn
AU  - Ullrich, Vivien
AU  - Schöneberg, Torsten
AU  - Schadendorf, Dirk
AU  - Horn, Susanne
TI  - TERT expression is associated with metastasis from thin primaries, exhausted CD4+ T cells in melanoma and with DNA repair across cancer entities.
JO  - PLOS ONE
VL  - 18
IS  - 7
SN  - 1932-6203
CY  - San Francisco, California, US
PB  - PLOS
M1  - DKFZ-2023-01367
SP  - e0281487 -
PY  - 2023
AB  - Telomerase reverse transcriptase (TERT) promoter mutations occur frequently in cancer, have been associated with increased TERT expression and cell proliferation, and could potentially influence therapeutic regimens for melanoma. As the role of TERT expression in malignant melanoma and the non-canonical functions of TERT remain understudied, we aimed to extend the current knowledge on the impact of TERT promoter mutations and expression alterations in tumor progression by analyzing several highly annotated melanoma cohorts. Using multivariate models, we found no consistent association for TERT promoter mutations or TERT expression with the survival rate in melanoma cohorts under immune checkpoint inhibition. However, the presence of CD4+ T cells increased with TERT expression and correlated with the expression of exhaustion markers. While the frequency of promoter mutations did not change with Breslow thickness, TERT expression was increased in metastases arising from thinner primaries. As single-cell RNA-sequencing (RNA-seq) showed that TERT expression was associated with genes involved in cell migration and dynamics of the extracellular matrix, this suggests a role of TERT during invasion and metastasis. Co-regulated genes found in several bulk tumors and single-cell RNA-seq cohorts also indicated non-canonical functions of TERT related to mitochondrial DNA stability and nuclear DNA repair. This pattern was also evident in glioblastoma and across other entities. Hence, our study adds to the role of TERT expression in cancer metastasis and potentially also immune resistance.
KW  - Humans
KW  - CD4-Positive T-Lymphocytes: pathology
KW  - Melanoma: genetics
KW  - Melanoma: pathology
KW  - Skin Neoplasms: genetics
KW  - Skin Neoplasms: pathology
KW  - Promoter Regions, Genetic
KW  - Mutation
KW  - DNA Repair: genetics
KW  - Telomerase: genetics
KW  - Telomerase (NLM Chemicals)
KW  - TERT protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37418389
C2  - pmc:PMC10328343
DO  - DOI:10.1371/journal.pone.0281487
UR  - https://inrepo02.dkfz.de/record/277430
ER  -