A Prognostic Signature for Lung Adenocarcinoma in Patients Who Have Never Smoked

作者：Zhao Wei, Tongwu Zhang, Xing Hua, Phuc H. Hoang, Mona Miraftab, Monjoy Saha, John McElderry, Jian Sang, Olivia W. Lee, Caleb Hartman, Azhar Khandekar, Sunandini Sharma, Frank J. Colón-Matos, Samuel Anyaso‐Samuel, Difei Wang, Kristine Jones, Amy Hutchinson, Belynda Hicks, Jennifer Rosenbaum, Xiaoming Zhong, Yang Yang, Angela Cecilia Pesatori, Dario Consonni, David C. Christiani, Kin Chung Leung, Maria Pik Wong, Marta Mańczuk, Jolanta Lissowska, Beata Świątkowska, Anush Mukeriya, Oxana Shangina, Давид Заридзе, Ivana Holcátová, Dana Mateș, Saša Milosavljević, Simona Ognjanovic, Milan Savić, Milica Kontić, Valérie Gaborieau, Paul Brennan, Óscar Arrieta, Yohan Bossé, Eric S. Edell, Matthew B. Schabath, Paul Hofman, Luís Más, Sai Yendamuri, Chih‐Yi Chen, I‐Shou Chang, Chao A. Hsiung, Geoffrey Liu, Juan Miguel Santamaría, Bonnie E. Gould Rothberg, Karun Mutreja, Scott M. Lawrence, Nathaniel Rothman, Ludmil B. Alexandrov, Charles Leduc, Marina K. Baine, Philippe Joubert, Lynette M. Sholl, William D. Travis, Robert Homer, Qing Lan, Stephen J. Chanock, Lixing Yang, Soo‐Ryum Yang, Jianxin Shi, Maria Teresa Landi · 发表于：Cancer Discovery · 年份：2025 · DOI：10.1158/2159-8290.cd-25-0581 · 被引用次数：3 · 研究领域：Lung Cancer Treatments and Mutations、Lung Cancer Diagnosis and Treatment、Ferroptosis and cancer prognosis

Understanding tumor cell dynamics can improve prognosis and treatment but remains limited for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA sequencing data from 684 NS-LUAD cases and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histologic data further characterized the subtypes. "Steady," marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver gene alterations, is linked to prolonged survival and low immune evasion. "Proliferative" shows high proliferation markers, TP53 mutations, and gene fusions. "Chaotic," with high epithelial-to-mesenchymal transition markers, has the worst prognosis, even within stage I tumors. Lacking known molecular or histologic characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the classification and predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving early-stage NS-LUAD prognostication in clinical settings. SIGNIFICANCE: The transcriptome of 684 NS-LUAD identifies three subtypes with different cellular dynamics and genomic and morphologic features. A 60-gene signature accurately stratifies subjects for mortality risk, even in stage I, offering a potential clinically applicable tool for treatment decision-making in patients with NS-...