TERT
Expression and Clinical Outcome in Pulmonary Carcinoids
Authors: Werr Lisa , Bartenhagen Christoph , Rosswog Carolina , Cartolano Maria , Voegele Catherine , Sexton-Oates Alexandra , Di Genova Alex , Ernst Angela , Kahlert Yvonne , Hemstedt Nadine , Höppner Stefanie , Mansuet Lupo Audrey , Pelosi Giuseppe , Brcic Luka , Papotti Mauro , George Julie , Bosco Graziella , Quaas Alexander , Tang Laura H. , Robzyk Kenneth , Kadota Kyuichi , Roh Mee Sook , Fanaroff Rachel E. , Falcon Christina J. , Büttner Reinhard , Lantuejoul Sylvie , Rekhtman Natasha , Rudin Charles M. , Travis William D. , Alcala Nicolas , Fernandez-Cuesta Lynnette , Foll Matthieu , Peifer Martin , Thomas Roman K. , Fischer Matthias ,   on behalf of the Lung NEN Network, Absenger Gudrun , Altmüller Janine , Berthet Jean-Philippe , Bibeau Frederic , Fourner Cécile Blanc , Boland Anne , Bonnetaud Christelle , Brevet Marie , Brustugun Odd Terje , Centonze Giovanni , Chalabreysse Lara , Cohen Charlotte , Deleuze Jean-Francois , Derks Jules L. , Di Micco Concetta Martina , Dingemans Anne-Marie C. , Fadel Élie , Graziano Paolo , Hofman Paul , Hofman Veronique , Lacomme Stéphanie , Lund-Iversen Marius , Metovic Jasna , Milione Massimo , Moonen Laura , Muscarella Lucia Anna , Nürnberg Peter , Olaso Robert , Meyer Vincent , Perrin Corinne , Planchard Gaetane , Popper Helmut , Rousseau Nathalie , Roz Luca , Sabella Giovanna , Sparaneo Angelo , Speel Ernst Jan M. , Thivolet-Béjui Françoise , Thomas de Montpréville Vincent , Volante Marco , Wright Gavin M. , Damiola Francesca , Tabone-Eglinger Séverine , Girard Nicolas 
Published: September 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
< .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.