Mitochondrial-associated programmed-cell-death patterns for predicting the prognosis of non-small-cell lung cancer

Abstract

Mitochondria are the convergence point of multiple pathways that trigger programmed cell death (PCD). Mitochondrial-associated PCD (mtPCD) is involved in the pathogenesis of several diseases. However, the role of mtPCD in the prognostic prediction of cancers including non-small-cell lung cancer (NSCLC) remains to be investigated. Here, 12 mtPCD patterns were analyzed in transcriptomics, genomics, and clinical data collected from 4 datasets containing 977 patients. A risk-score assessment system containing 18 genes was established. We found that NSCLC patients with a high-risk score had a poorer prognosis. A nomogram was constructed by incorporating the risk score with clinical features. The risk score was further associated with clinicopathological information, tumor-mutation frequency, and immunotherapy responses. NSCLC patients with a high risk score had more Treg cells infiltration. However, these patients had higher tumor-mutation burden scores and may be more sensitive to immunotherapy. Moreover, receptor-interacting serine/threonine protein kinase 2 (RIPK2) was selected from mtPCD gene model for validation. We found that RIPK2 exhibited oncogenic function, and its expression level was inversely associated with the overall survival of NSCLC. Taken together, our results indicated the accuracy and practicability of the mtPCD gene model and RIPK2 in predicting the prognosis of NSCLC.

Keywords

mitochondrial associated programmed cell death / NSCLC / prognosis / gene signature

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (Nos. 2023YFC3503205 and 2022YFA1103900), the CAMS Innovation Fund for Medical Sciences (CIFMS; No. 2022-I2M-1-009), the National Natural Science Foundation of China (Nos. 82372944, 82073092 and 82273076), the Science and Technology Research Project of Henan Province (No. 222102310636), the Henan Provincial Medical Science and Technology Research Project (No. LHGJ20210183), and the Scientific Research Fund Project of the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital.

Compliance with ethics guidelines

Conflicts of interest Xueyan Shi, Sichong Han, and Guizhen Wang declare that they have no conflict of interest. Guangbiao Zhou is the Executive Deputy Editor-in-Chief of Frontiers of Medicine, who was excluded from the peer-review process and all editorial decisions related to the acceptance and publication of this article. Peer-review was handled independently by the other editors to minimise bias.

The study was approved by the Ethics Committee of Cancer Hospital, Chinese Academy of Medical Sciences and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study. All institutional and national guidelines for the care and use of laboratory animals were followed.

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