<i>TERT</i> Expression and Clinical Outcome in Pulmonary Carcinoids.

Abstract

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 (<i>TERT</i>) is decisive in determining the course of disease. We therefore investigated whether <i>TERT</i> expression defines the clinical fate of patients with pulmonary carcinoid. <i>TERT</i> 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 <i>TERT</i> expression cutoff was determined in the test cohort on the basis of the distribution of <i>TERT</i> 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. Similar to neuroblastoma, <i>TERT</i> expression exhibited a bimodal distribution in pulmonary carcinoids, separating tumors into <i>TERT</i>-high and <i>TERT-</i>low subgroups. A natural <i>TERT</i> cutoff discriminated unfavorable from favorable clinical courses with high accuracy both in the test cohort (5-year overall survival [OS], 0.547 ± 0.132 <i>v</i> 1.0; <i>P</i> < .001) and the validation cohort (5-year OS, 0.788 ± 0.063 <i>v</i> 0.913 ± 0.048; <i>P</i> < .001). In line with these findings, telomerase activity was largely absent in <i>TERT</i>-low tumors, whereas it was readily detectable in <i>TERT-</i>high carcinoids. In multivariable analysis considering <i>TERT</i> expression, histology (typical <i>v</i> atypical carcinoid), and stage (≤IIA <i>v</i> ≥IIB), high <i>TERT</i> expression was an independent prognostic marker for poor survival, with a hazard ratio of 5.243 (95% CI, 1.943 to 14.148; <i>P</i> = .001). Our data demonstrate that high <i>TERT</i> expression defines clinically aggressive pulmonary carcinoids with fatal outcome, similar to neuroblastoma, indicating that activation of <i>TERT</i> may be a defining feature of lethal cancers.