TY - JOUR
T1 - Reverse engineering a predictive signature characterized by proliferation, DNA damage, and immune escape from stage i lung adenocarcinoma recurrence
AU - Yao, Jiannan
AU - Xue, Xinying
AU - Qu, Dongfeng
AU - Westphalen, C. Benedikt
AU - Ge, Yang
AU - Zhang, Liyang
AU - Li, Manyu
AU - Gao, Tianbo
AU - Chandrakesan, Parthasarathy
AU - Vega, Kenneth J.
AU - Peng, Jun
AU - An, Guangyu
AU - Weygant, Nathaniel
N1 - Publisher Copyright:
© 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PY - 2020/4/29
Y1 - 2020/4/29
N2 - 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.
AB - 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.
KW - biomarker
KW - immunity
KW - lung adenocarcinoma
KW - pancreatic adenocarcinoma
KW - prognosis
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U2 - 10.1093/abbs/gmaa036
DO - 10.1093/abbs/gmaa036
M3 - Article
C2 - 32395755
AN - SCOPUS:85087532782
SN - 1672-9145
VL - 52
SP - 638
EP - 653
JO - Acta Biochimica et Biophysica Sinica
JF - Acta Biochimica et Biophysica Sinica
IS - 6
ER -