Reverse engineering a predictive signature characterized by proliferation, DNA damage, and immune escape from stage I lung adenocarcinoma recurrence

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 and Weygant, Nathaniel (2020): Reverse engineering a predictive signature characterized by proliferation, DNA damage, and immune escape from stage I lung adenocarcinoma recurrence. In: Acta Biochimica et Biophysica Sinica, Vol. 52, No. 6: pp. 638-653

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.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1672-9145
• Language: English