title: Pathway-based gene signatures predicting clinical outcome of lung adenocarcinoma.
abstract: Lung adenocarcinoma is often diagnosed at an advanced stage with poor prognosis. Patients with different clinical outcomes may have similar clinico-pathological characteristics. The results of previous studies for biomarkers for lung adenocarcinoma have generally been inconsistent and limited in clinical application. In this study, we used inverse-variance weighting to combine the hazard ratios for the four datasets and performed pathway analysis to identify prognosis-associated gene signatures. A total of 2,418 genes were found to be significantly associated with overall survival. Of these, a 21-gene signature in the HMGB1/RAGE signalling pathway and a 31-gene signature in the clathrin-coated vesicle cycle pathway were significantly associated with prognosis of lung adenocarcinoma across all four datasets (all p-values < 0.05, log-rank test). We combined the scores for the three pathways to derive a combined pathway-based risk (CPBR) score. Three pathway-based signatures and CPBR score also had more predictive power than single genes. Finally, the CPBR score was validated in two independent cohorts (GSE14814 and GSE13213 in the GEO database) and had significant adjusted hazard ratios 2.72 (p-value < 0.0001) and 1.71 (p-value < 0.0001), respectively. These results could provide a more complete picture of the lung cancer pathogenesis.
authors.affiliation: Institute of Biomedical Engineering, National Taiwan University, No.1, Section 1, Jen-Ai Road, Taipei 100, Taiwan.
authors.forename: Ya-Hsuan
authors.initials: YH
authors.lastname: Chang
authors.affiliation: Institute of Biomedical Engineering, National Taiwan University, No.1, Section 1, Jen-Ai Road, Taipei 100, Taiwan.
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Institute of Statistical Science, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, Taiwan.
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, National Taiwan University College of Medicine, No.1, Section 1, Jen-Ai Road, Taipei, Taiwan.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D015331:Cohort Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D020935:MAP Kinase Signaling System; D063868:Patient Outcome Assessment; D011379:Prognosis; D016016:Proportional Hazards Models; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011943:Receptors, Adrenergic, beta