Objective:The proportion of patients with stageⅠlung adenocarcinoma(LUAD)has dramatically increased with the prevalence of low-dose computed tomography use for screening.Up to 30%of patients with stageⅠLUAD experien...Objective:The proportion of patients with stageⅠlung adenocarcinoma(LUAD)has dramatically increased with the prevalence of low-dose computed tomography use for screening.Up to 30%of patients with stageⅠLUAD experience recurrence within 5 years after curative surgery.A robust risk stratification tool is urgently needed to identify patients who might benefit from adjuvant treatment.Methods:In this first investigation of the relationship between metabolic reprogramming and recurrence in stageⅠLUAD,we developed a recurrence-associated metabolic signature(RAMS).This RAMS was based on metabolism-associated genes to predict cancer relapse and overall prognoses of patients with stageⅠLUAD.The clinical significance and immune landscapes of the signature were comprehensively analyzed.Results:Based on a gene expression profile from the GSE31210 database,functional enrichment analysis revealed a significant difference in metabolic reprogramming that distinguished patients with stageⅠLUAD with relapse from those without relapse.We then identified a metabolic signature(i.e.,RAMS)represented by 2 genes(ACADM and RPS8)significantly related to recurrence-free survival and overall survival times of patients with stageⅠLUAD using transcriptome data analysis of a training set.The training set was well validated in a test set.The discriminatory power of the 2 gene metabolic signature was further validated using protein values in an additional independent cohort.The results indicated a clear association between a high risk score and a very poor patient prognosis.Stratification analysis and multivariate Cox regression analysis showed that the RAMS was an independent prognostic factor.We also found that the risk score was positively correlated with inflammatory response,the antigen-presenting process,and the expression levels of many immunosuppressive checkpoint molecules(e.g.,PD-L1,PD-L2,B7-H3,galectin-9,and FGL-1).These results suggested that high risk patients had immune response suppression.Further analysis revealed that anti-PD-1/PD-L1 immunotherapy did not have significant benefits for high risk patients.However,the patients could respond better to chemotherapy.Conclusions:This study is the first to highlight the relationship between metabolic reprogramming and recurrence in stageⅠLUAD,and is the first to also develop a clinically feasible signature.This signature may be a powerful prognostic tool and help further optimize the cancer therapy paradigm.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.81802299 and 81502514)the Fundamental Research Funds for the Central Universities(Grant No.3332018070)+3 种基金the CAMS Innovation Fund for Medical Sciences(Grant Nos.2016-I2M-1-001 and 2017-I2M-1-005)the National Key R&D Program of China(Grant Nos.2018YFC1312100 and 2018YFC1312102)the National Key Basic Research Development Plan(Grant No.2018YFC1312105)the Graduate Innovation Funds of Peking Union Medical College(Grant No.2019-1002-06)。
文摘Objective:The proportion of patients with stageⅠlung adenocarcinoma(LUAD)has dramatically increased with the prevalence of low-dose computed tomography use for screening.Up to 30%of patients with stageⅠLUAD experience recurrence within 5 years after curative surgery.A robust risk stratification tool is urgently needed to identify patients who might benefit from adjuvant treatment.Methods:In this first investigation of the relationship between metabolic reprogramming and recurrence in stageⅠLUAD,we developed a recurrence-associated metabolic signature(RAMS).This RAMS was based on metabolism-associated genes to predict cancer relapse and overall prognoses of patients with stageⅠLUAD.The clinical significance and immune landscapes of the signature were comprehensively analyzed.Results:Based on a gene expression profile from the GSE31210 database,functional enrichment analysis revealed a significant difference in metabolic reprogramming that distinguished patients with stageⅠLUAD with relapse from those without relapse.We then identified a metabolic signature(i.e.,RAMS)represented by 2 genes(ACADM and RPS8)significantly related to recurrence-free survival and overall survival times of patients with stageⅠLUAD using transcriptome data analysis of a training set.The training set was well validated in a test set.The discriminatory power of the 2 gene metabolic signature was further validated using protein values in an additional independent cohort.The results indicated a clear association between a high risk score and a very poor patient prognosis.Stratification analysis and multivariate Cox regression analysis showed that the RAMS was an independent prognostic factor.We also found that the risk score was positively correlated with inflammatory response,the antigen-presenting process,and the expression levels of many immunosuppressive checkpoint molecules(e.g.,PD-L1,PD-L2,B7-H3,galectin-9,and FGL-1).These results suggested that high risk patients had immune response suppression.Further analysis revealed that anti-PD-1/PD-L1 immunotherapy did not have significant benefits for high risk patients.However,the patients could respond better to chemotherapy.Conclusions:This study is the first to highlight the relationship between metabolic reprogramming and recurrence in stageⅠLUAD,and is the first to also develop a clinically feasible signature.This signature may be a powerful prognostic tool and help further optimize the cancer therapy paradigm.
