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 - Funding Information:
This work was supported by the grant from Beijing Municipal Administration of Hospitals, Incubating Program (No. PX 2020016).
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
VL - 52
SP - 638
EP - 653
JO - Acta Biochimica et Biophysica Sinica
JF - Acta Biochimica et Biophysica Sinica
SN - 1672-9145
IS - 6
ER -