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Prognostic implications of autophagy-associated gene signatures in non-small cell lung cancer.

ABSTRACT: Autophagy, a highly conserved cellular proteolysis process, has been involved in non-small cell lung cancer (NSCLC). We tried to develop a prognostic prediction model for NSCLC patients based on the expression profiles of autophagy-associated genes. Univariate Cox regression analysis was used to determine autophagy-associated genes significantly correlated with overall survival (OS) of the TCGA lung cancer cohort. LASSO regression was performed to build multiple-gene prognostic signatures. We found that the 22-gene and 11-gene signatures could dichotomize patients with significantly different OS and independently predict the OS in TCGA lung adenocarcinoma (HR=2.801, 95% CI=2.252-3.486, P<0.001) and squamous cell carcinoma (HR=1.105, 95% CI=1.067-1.145, P<0.001), respectively. The prognostic performance of the 22-gene signature was validated in four GEO lung cancer cohorts. Moreover, GO, KEGG, and GSEA analyses unveiled several fundamental signaling pathways and cellular processes associated with the 22-gene signature in lung adenocarcinoma. We also constructed a clinical nomogram with a concordance index of 0.71 to predict the survival possibility of NSCLC patients by integrating clinical characteristics and the autophagy gene signature. The calibration curves substantiated fine concordance between nomogram prediction and actual observation. Overall, we constructed and verified a novel autophagy-associated gene signature that could improve the individualized outcome prediction in NSCLC.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6932887 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Prognostic implications of autophagy-associated gene signatures in non-small cell lung cancer.

Liu Yang Y Wu Ligao L Ao Haijiao H Zhao Meng M Leng Xue X Liu Mingdong M Ma Jianqun J Zhu Jinhong J

Aging 20191207 23

Autophagy, a highly conserved cellular proteolysis process, has been involved in non-small cell lung cancer (NSCLC). We tried to develop a prognostic prediction model for NSCLC patients based on the expression profiles of autophagy-associated genes. Univariate Cox regression analysis was used to determine autophagy-associated genes significantly correlated with overall survival (OS) of the TCGA lung cancer cohort. LASSO regression was performed to build multiple-gene prognostic signatures. We fo ...[more]

PMID: 31811814

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Project description:BackgroundCure and long-term survival for non-small cell lung cancer (NSCLC) remains hard to achieve. Cellular senescence, an emerging hallmark of cancer, is considered as an endogenous tumor suppressor mechanism. However, senescent cancer cells can paradoxically affect the surrounding tumor microenvironment (TME), ultimately leading to cancer relapse and metastasis. As such, the role of cellular senescence in cancer is highly controversial.MethodsIn 155 formalin-fixed paraffin-embedded (FFPE) samples from surgically resected NSCLC patients with pathological tumor-node-metastasis (pTNM) stages I-IV (8th edition), cellular senescence was assessed using a combination of four immunohistochemical senescence markers, i.e., lipofuscin, p16INK4a, p21WAF1/Cip1 and Ki67, and correlated to clinicopathological parameters and outcomes, including overall survival (OS) and disease-free survival (DFS).ResultsA tumoral senescence signature (SS) was present in 48 out of 155 NSCLC patients, but did not correlate to any clinicopathological parameter, except for p53 mutation status. In a histologically homogenous patient cohort of 100 patients who fulfilled the following criteria: (I) one type of histology, i.e., adenocarcinoma, (II) without known epidermal growth factor receptor (EGFR) mutation, (III) curative (R0) resection and (IV) no neoadjuvant systemic therapy or radiotherapy, the median OS and DFS for patients with a tumoral SS (n=30, 30.0%) compared to patients without a tumoral SS (n=70, 70.0%) was 53 versus 141 months (P=0.005) and 45 versus 55 months (P=0.25), respectively. In multiple Cox proportional hazards (Cox PH) model analysis correcting for age, pTNM stage I-III and adjuvant therapy, a tumoral SS remained a significant prognostic factor for OS (HR =2.03; P=0.014).ConclusionsThe presence of a tumoral SS particularly based on high p16INK4a expression significantly affects OS in NSCLC adenocarcinoma. In this light, adjuvant senolytic therapy could be an interesting strategy for NSCLC patients harboring a tumoral SS, ultimately to improve survival of these patients.

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Prognostic implications of autophagy-associated gene signatures in non-small cell lung cancer.

Publications

Prognostic implications of autophagy-associated gene signatures in non-small cell lung cancer.

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