Abstract
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.
Highlights
There have been extensive studies evaluating prognostic markers for early stage non-small cell lung cancer (NSCLC) patients
We examined whether the somatic variants within the 865 genes found in The Cancer Genome Atlas (TCGA) NSCLC patients could encode for tumor-specific antigens presented by MHC Class I molecules
number of altered genes (NAG) validated in three cohorts of early stage patients, we further showed that in three cohorts of early stage NSCLC
Summary
There have been extensive studies evaluating prognostic markers for early stage non-small cell lung cancer (NSCLC) patients. These studies included genes/proteins that are overexpressed in tumor compared to non-tumor lung tissue, mutations in specific “driver” oncogenes and tumor suppressor genes, and gene expression profiles [1,2,3]. No single gene/protein has been shown consistently to be prognostic especially in large multi-institutional patient cohorts [4,5,6,7]. Whole genome and targeted sequencing studies have observed a relationship between the mutational load of tumors and prognosis in NSCLC [10,11,12,13,14].
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