A MicroRNA Based Model That Associates Survival And Treatment Responses To Therapy In Lung Adenocarcinoma

Lung adenocarcinoma(LUAD)is the most common subtype of lung cancer with heterogeneous outcomes and drug responses.To classify patients into different groups and facilitate the suitable therapy,we developed a seven-miRNA signature that is closely associated with survival of patients with LUAD.We first selected 298 miRNAs which actually negatively regulated mRNAs in the TCGA-LUAD cohort and built the miRNA-mRNA pairs based on their regulation relationships.Then we identified 27 miRNAs that can distinguish patients with different overall survival time individually using log-rank test.Consequently,seven miRNAs were selected by Cox’s proportional hazards regression model and a risk-score model was built and validated in the testing set and an independent dataset.Using the Cox regression method,we built a classification model with the seven miRNAs:hsa-mir-194-1,hsa-mir-194-2,hsa-mir-548b,hsa-mir-556,hsa-mir-624,hsa-mir-767 and hsa-mir-3136.We were able to classify LUAD patients into a high-risk group and a low-risk group using this model.Overall survival was significantly different between these two groups in the training set(AUC=0.7149&0.7619;P=1.27e-07&4.58e-07),testing set(AUC=0.709&0.7585;P=1.45e-07&4.38e-06)and an independent validation set(P=0.00784).This seven-miRNA model is independent from age(P=0.9045&0.9383),gender(P=1&0.1968)and stage(P=1&0.2725)which also provide new insights into the current TNM staging system(stage I:P=0.00903&0.0236,stage Ⅱ:P=0.000943&0.0187 and stage Ⅲ:P=0.00124&0.0467)and an alternative system for patient stratification.Strikingly,the prognostic signatures can associate the patients with different therapeutic responses,indicating that high-risk group is more suitable for adjuvant chemotherapy like cisplatin(P=0.0169)when low-risk group significantly suffer from the related treatments like cisplatin(P=0.0565)and vinorelbine(P=0.0243).Our seven-microRNA model provides a distinct and consistent predictor of overall survival among LUAD patients and may provide therapeutic implications for treatment options,such as help identify high-risk LUAD patients who may benefit more from adjuvant therapy like cisplatin and vinorelbine,which may facilitate therapeutic selection for patients with LUAD.