Identification of mutational signature for lung adenocarcinoma prognosis and immunotherapy prediction

There is no robust genomic signature to predict the prognosis of patients with early-stage lung adenocarcinoma (LUAD). It was known that clonal heterogeneity was closely associated to tumour progression and prognosis prediction. Herein, using stage I patients from The Cancer Genome Atlas, we identified the clonal/subclonal events of each gene and preselected a set of genes with prognosis-specific mutation patterns based on a robust published transcriptomic prognostic signature. Subsequently, we constructed a mutational prognostic signature (MPS), whose prognostic performance was independently validated in two datasets of stage I samples. The predicted high-risk patients had significantly higher immune cell infiltration, along with higher expression of cytotoxic and immune checkpoint genes, and an integrated dataset with 88 samples confirmed that high-risk patients could benefit from immunotherapy. The developed MPS can identify the high-risk patients with stage I LUAD and improve individualised treatment planning of high-risk patients who might benefit from immunotherapy. KEY MESSAGES: We creatively developed a prognostic signature (57-MPS) based on clonal diversity. The high-risk samples displayed an underlying immunosuppressive mechanism. 57-MPS improved the predictive performance of PD-L1 for immunotherapy.