<i>TERT</i> Expression and Clinical Outcome in Pulmonary Carcinoids
Authors: Lisa Werr, Christoph Bartenhagen, Carolina Rosswog, Maria Cartolano, Catherine Voegele, Alexandra Sexton-Oates, Alex Di Genova, Angela Ernst, Yvonne Kahlert, Nadine Hemstedt, Stefanie Höppner, Audrey Mansuet Lupo, Giuseppe Pelosi, Luka Brcic, Mauro Papotti, Julie George, Graziella Bosco, Alexander Quaas, Laura H. Tang, Kenneth Robzyk, Kyuichi Kadota, Mee Sook Roh, Rachel E. Fanaroff, Christina J. Falcon, Reinhard Büttner, Sylvie Lantuejoul, Natasha Rekhtman, Charles M. Rudin, William D. Travis, Nicolas Alcala, Lynnette Fernandez-Cuesta, Matthieu Foll, Martin Peifer, Roman K. Thomas, Matthias Fischer, Gudrun Absenger, Janine Altmüller, Jean-Philippe Berthet, Frederic Bibeau, Cécile Blanc Fourner, Anne Boland, Christelle Bonnetaud, Marie Brevet, Odd Terje Brustugun, Giovanni Centonze, Lara Chalabreysse, Charlotte Cohen, Jean-Francois Deleuze, Jules L. Derks, Concetta Martina Di Micco, Anne-Marie C. Dingemans, Élie Fadel, Paolo Graziano, Paul Hofman, Veronique 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 Montpréville, Marco Volante, Gavin M. Wright, Francesca Damiola, Séverine Tabone-Eglinger, Nicolas Girard
Journal: Journal of Clinical Oncology (2024)

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 &lt; .001) and the validation cohort (5-year OS, 0.788 ± 0.063 v 0.913 ± 0.048; P &lt; .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.