A prognostic signature for lung adenocarcinoma in people who have never smoked

Zhao, W.; Zhang, T.; Hua, X.; Hoang, P. H.; Miraftab, M.; Saha, M.; McElderry, J. P.; Sang, J.; Lee, O. W.; Hartman, C.; Khandekar, A.; Sharma, S.; Colon-Matos, F. J.; Anyaso-Samuel, S.; Wang, D.; Jones, K.; Hutchinson, A.; Hicks, B.; Rosenbaum, J.; Zhong, X.; Yang, Y.; Pesatori, A.; Consonni, D.; Christiani, D. C.; Leung, K. C.; Wong, M. P.; Manczuk, M.; Lissowska, J.; _wi_tkowska, B.; Mukeria, A.; Shangina, O.; Zaridze, D.; Holcatova, I.; Mates, D.; Milosavljevic, S.; Ognjanovic, S.; Savic, M.; Kontic, M.; Gaborieau, V.; Brennan, P.; Arrieta, O.; Bosse, Y.; Edell, E. S.; Schabath, M. B.; Hof

doi:10.1101/2025.08.13.670169

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bioRxiv · 10.1101/2025.08.13.670169

A prognostic signature for lung adenocarcinoma in people who have never smoked

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Abstract

Knowledge of tumor cell dynamics can inform prognosis and treatment yet is largely lacking for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA-seq data from 684 NS-LUAD and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histological data further characterized the subtypes. Steady, marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver genes 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 histological characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the overall classification and strongly predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving NS-LUAD prognostication in clinical settings. SignificanceThe transcriptome of 684 lung adenocarcinomas in people who have never smoked (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 clinically applicable tool for treatment decision making in NS-LUAD patients.

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Zhao, W., Zhang, T., Hua, X., Hoang, P. H., Miraftab, M., Saha, M., McElderry, J. P., Sang, J., Lee, O. W., Hartman, C., Khandekar, A., Sharma, S., Colon-Matos, F. J., Anyaso-Samuel, S., Wang, D., Jones, K., Hutchinson, A., Hicks, B., Rosenbaum, J., Zhong, X., Yang, Y., Pesatori, A., Consonni, D., Christiani, D. C., Leung, K. C., Wong, M. P., Manczuk, M., Lissowska, J., _wi_tkowska, B., Mukeria, A., Shangina, O., Zaridze, D., Holcatova, I., Mates, D., Milosavljevic, S., Ognjanovic, S., Savic, M., Kontic, M., Gaborieau, V., Brennan, P., Arrieta, O., Bosse, Y., Edell, E. S., Schabath, M. B., Hof. 2025-08-16. A prognostic signature for lung adenocarcinoma in people who have never smoked. https://doi.org/10.1101/2025.08.13.670169

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