Somatic alteration burden involving non-cancer genes predicts prognosis in early-stage non-small cell lung cancer

The burden of somatic mutations and neoantigens has been associated with improved survival in cancer treated with immunotherapies, especially non-small cell lung cancer (NSCLC). However, there is uncertainty about their effect on outcome in early-stage untreated cases. We posited that the burden of mutations in a specific set of genes may also contribute to the prognosis of early NSCLC patients. From a small cohort of 36 NSCLC cases, we were able to identify somatic mutations and copy number alterations in 865 genes that contributed to patient overall survival. Simply, the number of altered genes (NAG) among these 865 genes was associated with longer disease-free survival (hazard ratio (HR) = 0.153, p = 1.48 × 10−4). The gene expression signature distinguishing patients with high/low NAG was also prognostic in three independent datasets. Patients with a high NAG could be further stratified based on the presence of immunogenic mutations, revealing a further subgroup of stage I NSCLC with even better prognosis (85% with >5 years survival), and associated with cytotoxic T-cell expression. Importantly, 95% of the highly-altered genes lacked direct relation to cancer, but were implicated in pathways regulating cell proliferation, motility and immune response.