Genetic and epigenetic landscape of leukocyte infiltration identifies an immune prognosticator in lung adenocarcinoma

BACKGROUND: Leukocyte infiltration plays an critical role in outcome of various diseases including Lung adenocarcinoma (LUAD). OBJECTIVES: To understand the genetic and epigenetic factors affecting leukocyte infiltration and identification and validation of immune based biomarkers. METHOD: Correlation analysis was done to get the associations of the factors. CIBERSORT analysis was done for immune cell infiltration. Genetic and epigenetic analysis were performed. Cox regression was carried out for survival. RESULTS: We categorized the TCGA-LUAD patients based on Leukocyte fraction (LF) and performed extensive immunogenomic analysis. Interestingly, we showed that LF has a negative correlation with copy number variation (CNV) but not with mutational load. However, several individual genetic mutations, including KRAS and KEAP1, were significantly linked with LF. Also, as expected, patients with high LF showed significantly increased expression of genes involved in leukocyte migration and activation. DNA methylation changes also showed a strong association with LF and regulated a significant proportion of genes associated with LF. We also developed and validated an independent prognostic immune signature using the top six prognostic genes associated with LF. CONCLUSION: Together, we have identified clinical, genetic, and epigenetic variations associated with LUAD LF and developed an immune gene-based signature for disease prognostication.