Kuo-Hao Ho1,2, Tzu-Wen Huang1,3, Ann-Jeng Liu4, Chwen-Ming Shih1,2, Ku-Chung Chen1,2. 1. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. 2. Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. 3. Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. 4. Department of Neurosurgery, Taipei City Hospital Ren-Ai Branch, Taipei 10629, Taiwan.
Abstract
Background: Heterogeneous features of lung adenocarcinoma (LUAD) are used to stratify patients into terminal respiratory unit (TRU), proximal-proliferative (PP), and proximal-inflammatory (PI) subtypes. A more-accurate subtype classification would be helpful for future personalized medicine. However, these stratifications are based on genes with variant expression levels without considering their tumor-promoting roles. We attempted to identify cancer essential genes for LUAD stratification and their clinical and biological differences. Methods: Essential genes in LUAD were identified using genome-scale CRIPSR screening of RNA sequencing data from Project Achilles and The Cancer Genome Atlas (TCGA). Patients were stratified using consensus clustering. Survival outcomes, genomic alterations, signaling activities, and immune profiles within clusters were investigated using other independent cohorts. Findings: Thirty-six genes were identified as essential to LUAD, and there were used for stratification. Essential gene-classified clusters exhibited distinct survival rates and proliferation signatures across six cohorts. The cluster with the worst prognosis exhibited TP53 mutations, high E2F target activities, and high tumor mutation burdens, and harbored tumors vulnerable to topoisomerase I and poly(ADP ribose) polymerase inhibitors. TRU-type patients could be divided into clinically and molecularly different subgroups based on these essential genes. Conclusions: Our study showed that essential genes to LUAD not only defined patients with different survival rates, but also refined preexisting subtypes.
Background: Heterogeneous features of lung adenocarcinoma (LUAD) are used to stratify patients into terminal respiratory unit (TRU), proximal-proliferative (PP), and proximal-inflammatory (PI) subtypes. A more-accurate subtype classification would be helpful for future personalized medicine. However, these stratifications are based on genes with variant expression levels without considering their tumor-promoting roles. We attempted to identify cancer essential genes for LUAD stratification and their clinical and biological differences. Methods: Essential genes in LUAD were identified using genome-scale CRIPSR screening of RNA sequencing data from Project Achilles and The Cancer Genome Atlas (TCGA). Patients were stratified using consensus clustering. Survival outcomes, genomic alterations, signaling activities, and immune profiles within clusters were investigated using other independent cohorts. Findings: Thirty-six genes were identified as essential to LUAD, and there were used for stratification. Essential gene-classified clusters exhibited distinct survival rates and proliferation signatures across six cohorts. The cluster with the worst prognosis exhibited TP53 mutations, high E2F target activities, and high tumor mutation burdens, and harbored tumors vulnerable to topoisomerase I and poly(ADP ribose) polymerase inhibitors. TRU-type patients could be divided into clinically and molecularly different subgroups based on these essential genes. Conclusions: Our study showed that essential genes to LUAD not only defined patients with different survival rates, but also refined preexisting subtypes.
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