Telomerase Reverse Transcriptase Promoter Mutations Identify a Genomically Defined and Highly Aggressive Human Pleural Mesothelioma Subgroup.

Abstract

PURPOSE:

Human malignant pleural mesothelioma (MPM) is characterized by dismal prognosis. Consequently, dissection of molecular mechanisms driving malignancy is of key importance. Here we investigate whether activating mutations in the telomerase reverse transcriptase (TERT) gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns.

EXPERIMENTAL DESIGN:

TERT promoters were sequenced in 182 MPM samples and compared with clinicopathologic characteristics. Surgical specimens from 45 patients with MPM were tested for in vitro immortalization. The respective MPM cell models (N = 22) were analyzed by array comparative genomic hybridization, gene expression profiling, exome sequencing as well as TRAP, telomere length, and luciferase promoter assays.

RESULTS:

TERT promoter mutations were detected in 19 of 182 (10.4%) MPM cases and significantly associated with advanced disease and nonepithelioid histology. Mutations independently predicted shorter overall survival in both histologic MPM subtypes. Moreover, 9 of 9 (100%) mutated but only 13 of 36 (36.1%) wild-type samples formed immortalized cell lines. TERT promoter mutations were associated with enforced promoter activity and TERT mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered. TERT promoter-mutated MPM cases exhibited distinctly reduced chromosomal alterations and specific mutation patterns. While BAP1 mutations/deletions were exclusive with TERT promoter mutations, homozygous deletions at the RBFOX1 and the GSTT1 loci were clearly enriched in mutated cases.

CONCLUSIONS:

TERT promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that TERT promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.

• Authors: Christine Pirker, Agnes Bilecz, Michael Grusch, Thomas Mohr, Barbara Heidenreich, Viktoria Laszlo, Paul Stockhammer, Daniela Lötsch-Gojo, Johannes Gojo, Lisa Gabler, Sabine Spiegl-Kreinecker, Balazs Dome, Ariane Steindl, Thomas Klikovits, Mir Alireza Hoda, Marko Jakopovic, Miroslav Samarzija, Katja Mohorcic, Izidor Kern, Barbara Kiesel, Luka Brcic, Felicitas Oberndorfer, Leonhard Müllauer, Walter Klepetko, Wolfgang M Schmidt, Rajiv Kumar, Balazs Hegedus, Walter Berger
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 14 Pg. 3819-3830 (07 15 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32317288 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• TERT protein, human
• Telomerase

Topics

• Aged
• Biomarkers, Tumor (genetics)
• Cell Line, Tumor
• Cell Survival (genetics)
• Cell Transformation, Neoplastic (genetics)
• Comparative Genomic Hybridization
• DNA Mutational Analysis
• Disease Progression
• Female
• Gene Expression Profiling
• Humans
• Kaplan-Meier Estimate
• Male
• Mesothelioma, Malignant (genetics, mortality, pathology)
• Middle Aged
• Mutation
• Pleura (pathology)
• Pleural Neoplasms (genetics, mortality, pathology)
• Prognosis
• Promoter Regions, Genetic (genetics)
• Retrospective Studies
• Telomerase (genetics)
• Exome Sequencing