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
Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.
J Clin Oncol. 2025 Jan 10;43(2):214-225. doi: 10.1200/JCO.23.02708. Epub 2024 Sep 30.
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 () is decisive in determining the course of disease. We therefore investigated whether expression defines the clinical fate of patients with pulmonary carcinoid.
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 expression cutoff was determined in the test cohort on the basis of the distribution of 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, expression exhibited a bimodal distribution in pulmonary carcinoids, separating tumors into -high and low subgroups. A natural cutoff discriminated unfavorable from favorable clinical courses with high accuracy both in the test cohort (5-year overall survival [OS], 0.547 ± 0.132 1.0; < .001) and the validation cohort (5-year OS, 0.788 ± 0.063 0.913 ± 0.048; < .001). In line with these findings, telomerase activity was largely absent in -low tumors, whereas it was readily detectable in high carcinoids. In multivariable analysis considering expression, histology (typical atypical carcinoid), and stage (≤IIA ≥IIB), high expression was an independent prognostic marker for poor survival, with a hazard ratio of 5.243 (95% CI, 1.943 to 14.148; = .001).
Our data demonstrate that high expression defines clinically aggressive pulmonary carcinoids with fatal outcome, similar to neuroblastoma, indicating that activation of may be a defining feature of lethal cancers.
肺类癌的临床病程从惰性疾病到致命性疾病不等，这表明特定的分子改变推动其向完全恶性状态进展。小儿神经母细胞瘤也出现了类似的临床表型谱，其中端粒酶逆转录酶（）的激活在决定疾病进程中起决定性作用。因此，我们研究了表达是否能确定肺类癌患者的临床预后。
通过RNA测序在一个肺类癌测试队列和一个验证队列中检测表达情况（分别为n = 88和n = 105）。根据表达分布在测试队列中确定一个自然的表达临界值，并通过Kaplan-Meier生存估计和多变量分析评估其预后价值。通过端粒重复序列扩增协议检测验证端粒酶活性。
与神经母细胞瘤相似，肺类癌中的表达呈现双峰分布，将肿瘤分为高表达和低表达亚组。一个自然的临界值在测试队列（5年总生存率[OS]，0.547±0.132对1.0；<0.001）和验证队列（5年OS，0.788±0.063对0.913±0.048；<0.001）中都能高度准确地区分不良和良好的临床病程。与这些发现一致，端粒酶活性在低表达肿瘤中基本不存在，而在高表达类癌中很容易检测到。在考虑表达、组织学（典型对非典型类癌）和分期（≤IIA对≥IIB）的多变量分析中，高表达是生存不良的独立预后标志物，风险比为5.243（95%CI，1.943至14.148；=0.001）。
我们的数据表明，高表达定义了具有致命结局的临床侵袭性肺类癌，与神经母细胞瘤相似，表明的激活可能是致命癌症的一个决定性特征。
