Reverse engineering a predictive signature characterized by proliferation, DNA damage, and immune escape from stage I lung adenocarcinoma recurrence. (12th May 2020)

• Record Type: Journal Article
• Authors: Yao, Jiannan; Xue, Xinying; Qu, Dongfeng; Westphalen, C Benedikt; Ge, Yang; Zhang, Liyang; Li, Manyu; Gao, Tianbo; Chandrakesan, Parthasarathy; Vega, Kenneth J; Peng, Jun; An, Guangyu; Weygant, Nathaniel
• Is Part Of: Acta biochimica et biophysica Sinica. Volume 52:Number 6(2020)
• Page Start: 638
• Page End: 653
• Publication Date: 2020-05-12
• Subjects: lung adenocarcinoma -- pancreatic adenocarcinoma -- biomarker -- prognosis -- immunity; Biochemistry -- Periodicals; Biophysics -- Periodicals; 572.05
• DOI: 10.1093/abbs/gmaa036
• Languages: English
• ISSNs: 1672-9145

Abstract

Abstract: Identifying early-stage cancer patients at risk for progression is a major goal of biomarker research. This report describes a novel 19-gene signature (19-GCS) that predicts stage I lung adenocarcinoma (LAC) recurrence and response to therapy and performs comparably in pancreatic adenocarcinoma (PAC), which shares LAC molecular traits. Kaplan–Meier, Cox regression, and cross-validation analyses were used to build the signature from training, test, and validation sets comprising 831 stage I LAC transcriptomes from multiple independent data sets. A statistical analysis was performed using the R language. Pathway and gene set enrichment were used to identify underlying mechanisms. 19-GCS strongly predicts overall survival and recurrence-free survival in stage I LAC ( P =0.002 and P <0.001, respectively) and in stage I–II PAC ( P <0.0001 and P <0.0005, respectively). A multivariate cox regression analysis demonstrated the independence of 19-GCS from significant clinical factors. Pathway analyses revealed that 19-GCS high-risk LAC and PAC tumors are characterized by increased proliferation, enhanced stemness, DNA repair deficiency, and compromised MHC class I and II antigen presentation along with decreased immune infiltration. Importantly, high-risk LAC patients do not appear to benefit from adjuvant cisplatin while PAC patients derive additional benefit from FOLFIRINOX compared with gemcitabine-based regimens. When validated prospectively, this proof-of-concept biomarker may contribute to tailoring treatment, recurrence reduction, and survival improvements in early-stage lung and pancreatic cancers.