TERT Expression and Clinical Outcome in Pulmonary Carcinoids.

IF 42.1 1区 医学 Q1 ONCOLOGY
Journal of Clinical Oncology Pub Date : 2025-01-10 Epub Date: 2024-09-30 DOI:10.1200/JCO.23.02708
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
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引用次数: 0

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.

肺癌中 TERT 的表达与临床预后
目的:肺类癌的临床病程从轻微到致命不等,这表明特定的分子改变推动了向完全恶性状态的发展。小儿神经母细胞瘤也有类似的临床表型,其中端粒酶逆转录酶(TERT)的激活在决定疾病进程方面起着决定性作用。因此,我们研究了TERT的表达是否决定了肺类癌患者的临床命运:方法:我们通过RNA测序检测了肺类癌试验队列和验证队列(分别为88人和105人)中TERT的表达。根据TERT表达的分布情况,确定了测试队列中TERT表达的自然临界值,并通过卡普兰-梅耶生存率估计和多变量分析评估了其预后价值。端粒酶活性通过端粒重复扩增协议检测进行验证:结果:与神经母细胞瘤相似,TERT表达在肺类癌中呈双峰分布,将肿瘤分为TERT高和TERT低两组。在测试组群(5年总生存率[OS],0.547 ± 0.132 v 1.0;P < .001)和验证组群(5年总生存率,0.788 ± 0.063 v 0.913 ± 0.048;P < .001)中,自然TERT分界线能高度准确地区分不利和有利的临床病程。与这些发现一致的是,端粒酶活性在TERT低的肿瘤中基本不存在,而在TERT高的类癌中很容易检测到。在考虑了TERT表达、组织学(典型类癌v非典型类癌)和分期(≤IIA v ≥IIB)的多变量分析中,TERT高表达是生存率低的独立预后标志,危险比为5.243(95% CI,1.943至14.148;P = .001):我们的数据表明,TERT的高表达定义了临床侵袭性肺类癌的致命结局,这与神经母细胞瘤类似,表明TERT的激活可能是致命癌症的一个决定性特征。
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来源期刊
Journal of Clinical Oncology
Journal of Clinical Oncology 医学-肿瘤学
CiteScore
41.20
自引率
2.20%
发文量
8215
审稿时长
2 months
期刊介绍: The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.
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