<i>TERT</i> Expression and Clinical Outcome in Pulmonary Carcinoids
Abstract
PURPOSE The clinical course of pulmonary carcinoids ranges from indolent to fatal disease, suggesting that specific molecular alterations drive progression toward the fully malignant state. A similar spectrum of clinical phenotypes occurs in pediatric neuroblastoma, in which activation of telomerase reverse transcriptase ( TERT ) is decisive in determining the course of disease. We therefore investigated whether TERT expression defines the clinical fate of patients with pulmonary carcinoid. METHODS TERT expression was examined by RNA sequencing in a test cohort and a validation cohort of pulmonary carcinoids (n = 88 and n = 105, respectively). A natural TERT expression cutoff was determined in the test cohort on the basis of the distribution of TERT expression, and its prognostic value was assessed by Kaplan-Meier survival estimates and multivariable analyses. Telomerase activity was validated by telomere repeat amplification protocol assay. RESULTS Similar to neuroblastoma, TERT expression exhibited a bimodal distribution in pulmonary carcinoids, separating tumors into TERT -high and TERT- low subgroups. A natural TERT cutoff discriminated unfavorable from favorable clinical courses with high accuracy both in the test cohort (5-year overall survival [OS], 0.547 ± 0.132 v 1.0; P < .001) and the validation cohort (5-year OS, 0.788 ± 0.063 v 0.913 ± 0.048; P < .001). In line with these findings, telomerase activity was largely absent in TERT -low tumors, whereas it was readily detectable in TERT- high carcinoids. In multivariable analysis considering TERT expression, histology (typical v atypical carcinoid), and stage (≤IIA v ≥IIB), high TERT expression was an independent prognostic marker for poor survival, with a hazard ratio of 5.243 (95% CI, 1.943 to 14.148; P = .001). CONCLUSION Our data demonstrate that high TERT expression defines clinically aggressive pulmonary carcinoids with fatal outcome, similar to neuroblastoma, indicating that activation of TERT may be a defining feature of lethal cancers.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (79)
Lisa Werr
Christoph Bartenhagen
Carolina Rosswog
Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Cologne, Germany
Maria Cartolano
Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany
Catherine Voegele
Rare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research on Cancer/World Health Organisation (IARC/WHO), Lyon, France
Alexandra Sexton-Oates
Rare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research on Cancer/World Health Organisation (IARC/WHO), Lyon, France
Alex Di Genova
Rare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research on Cancer/World Health Organisation (IARC/WHO), Lyon, France
Angela Ernst
Institute of Medical Statistics and Computational Biology, Medical Faculty, University of Cologne, Cologne, Germany
Yvonne Kahlert
Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Cologne, Germany
Nadine Hemstedt
Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Cologne, Germany
Stefanie Höppner
Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Cologne, Germany
Audrey Mansuet Lupo
Department of Pathology, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, Paris Cité University, Paris, France
Giuseppe Pelosi
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
Luka Brcic
Diagnostic and Research Institute of Pathology, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz
Mauro Papotti
Department of Oncology, University of Turin, Torino, Italy
Julie George
Graziella Bosco
Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Alexander Quaas
Laura H. Tang
Kenneth Robzyk
Sloan Kettering Institue, Memorial Sloan Kettering Cancer Center, New York, NY
Kyuichi Kadota
Mee Sook Roh
Rachel E. Fanaroff
University of Maryland School of Maryland, Baltimore, MD
Christina J. Falcon
Memorial Sloan Kettering Cancer Center, New York, NY
Reinhard Büttner
Sylvie Lantuejoul
Department of Biopathology, Léon Bérard Centre, Lyon, France
Natasha Rekhtman
Charles M. Rudin
William D. Travis
Nicolas Alcala
Rare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research on Cancer/World Health Organisation (IARC/WHO), Lyon, France
Lynnette Fernandez-Cuesta
Rare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research on Cancer/World Health Organisation (IARC/WHO), Lyon, France
Matthieu Foll
Rare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research on Cancer/World Health Organisation (IARC/WHO), Lyon, France
Martin Peifer
Roman K. Thomas
Matthias Fischer
Gudrun Absenger
Janine Altmüller
Jean-Philippe Berthet
Frédéric Bibeau
Cécile Blanc Fourner
Anne Boland
Christelle Bonnetaud
Marie Brevet
Odd Terje Brustugun
Section of Oncology, Drammen Hospital, Vestre Viken HF, Drammen, Norway
Giovanni Centonze
Lara Chalabreysse
Charlotte Cohen
Jean-François Deleuze
Jules L. Derks
Concetta Martina Di Micco
Anne-Marie C. Dingemans
Élie Fadel
Paolo Graziano
Paul Hofman
Véronique Hofman
Stéphanie Lacomme
Marius Lund-Iversen
Jasna Metovic
Massimo Milione
Laura Moonen
Lucia Anna Muscarella
Peter Nürnberg
Robert Olaso
Vincent Meyer
Corinne Perrin
Gaetane Planchard
Helmut Popper
Nathalie Rousseau
Luca Roz
Giovanna Sabella
Angelo Sparaneo
Ernst Jan M. Speel
Françoise Thivolet-Béjui
Vincent Thomas De Montpreville
Marie Lannelongue Hospital, Le Plessis-Robinson, France
Marco Volante
Gavin M. Wright
Francesca Damiola
Séverine Tabone-Eglinger
Nicolas Girard
Institut Curie, Institut du Thorax Curie-Montsouris, Paris