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Translational Cancer Mechanisms and Therapy

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

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 and Walter Berger
Christine Pirker
1Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
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Agnes Bilecz
22nd Institute of Pathology, Semmelweis University, Budapest, Hungary.
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Michael Grusch
1Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
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  • ORCID record for Michael Grusch
Thomas Mohr
1Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
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Barbara Heidenreich
3Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
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  • ORCID record for Barbara Heidenreich
Viktoria Laszlo
4Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University Vienna, Austria.
5Department of Tumor Biology, National Koranyi Institute of Pulmonology, Semmelweis University, Budapest, Hungary.
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Paul Stockhammer
4Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University Vienna, Austria.
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Daniela Lötsch-Gojo
1Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
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Johannes Gojo
1Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
6Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
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Lisa Gabler
1Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
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Sabine Spiegl-Kreinecker
7Department of Neurosurgery, Neuromed Campus, Kepler University Hospital, Johannes Kepler University, Linz, Austria.
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Balazs Dome
4Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University Vienna, Austria.
5Department of Tumor Biology, National Koranyi Institute of Pulmonology, Semmelweis University, Budapest, Hungary.
8Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary.
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Ariane Steindl
4Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University Vienna, Austria.
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  • ORCID record for Ariane Steindl
Thomas Klikovits
4Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University Vienna, Austria.
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  • ORCID record for Thomas Klikovits
Mir Alireza Hoda
4Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University Vienna, Austria.
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Marko Jakopovic
9Department for Respiratory Diseases Jordanovac, University Hospital Center, University of Zagreb, Zagreb, Croatia.
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Miroslav Samarzija
9Department for Respiratory Diseases Jordanovac, University Hospital Center, University of Zagreb, Zagreb, Croatia.
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Katja Mohorcic
10University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.
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Izidor Kern
10University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.
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Barbara Kiesel
11Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
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Luka Brcic
12Medical University of Graz, Diagnostic and Research Institute of Pathology, Graz, Austria.
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Felicitas Oberndorfer
13Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
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Leonhard Müllauer
13Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
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Walter Klepetko
4Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University Vienna, Austria.
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Wolfgang M. Schmidt
14Center for Anatomy and Cell Biology, Neuromuscular Research Department, Medical University of Vienna, Vienna, Austria.
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Rajiv Kumar
3Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
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Balazs Hegedus
22nd Institute of Pathology, Semmelweis University, Budapest, Hungary.
4Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University Vienna, Austria.
15Department of Thoracic Surgery, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany.
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  • For correspondence: walter.berger@meduniwien.ac.at Balazs.Hegedues@rlk.uk-essen.de
Walter Berger
1Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
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  • For correspondence: walter.berger@meduniwien.ac.at Balazs.Hegedues@rlk.uk-essen.de
DOI: 10.1158/1078-0432.CCR-19-3573 Published July 2020
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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.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2020;26:3819–30

  • Received October 30, 2019.
  • Revision received March 13, 2020.
  • Accepted April 17, 2020.
  • Published first April 21, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 26 (14)
July 2020
Volume 26, Issue 14
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Telomerase Reverse Transcriptase Promoter Mutations Identify a Genomically Defined and Highly Aggressive Human Pleural Mesothelioma Subgroup
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 and Walter Berger
Clin Cancer Res July 15 2020 (26) (14) 3819-3830; DOI: 10.1158/1078-0432.CCR-19-3573

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Telomerase Reverse Transcriptase Promoter Mutations Identify a Genomically Defined and Highly Aggressive Human Pleural Mesothelioma Subgroup
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 and Walter Berger
Clin Cancer Res July 15 2020 (26) (14) 3819-3830; DOI: 10.1158/1078-0432.CCR-19-3573
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