Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up
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Oxford University Press
Abstract
Background: Lung adenocarcinomas (LUADs) lead to the majority of deaths attributable to lung cancer. We performed whole-exome sequencing (WES) and immune profiling analyses of a unique set of clinically annotated early-stage LUADs to better understand the pathogenesis of this disease and identify clinically relevant molecular markers. Methods: We performed WES of 108 paired stage I-III LUADs and normal lung tissues using the Illumina HiSeq 2000 platform. Ten immune markers (PD-L1, PD-1, CD3, CD4, CD8, CD45ro, CD57, CD68, FOXP3 and Granzyme B) were profiled by imagingbased immunohistochemistry (IHC) in a subset of LUADs (n=92). Associations among mutations, immune markers and clinicopathological variables were analyzed using ANOVA and Fisher's exact test. Cox proportional hazards regression models were used for multivariate analysis of clinical outcome. Results: LUADs in this cohort exhibited an average of 243 coding mutations. We identified 28 genes with significant enrichment for mutation. SETD2-mutated LUADs exhibited relatively poor recurrence- free survival (RFS) and mutations in STK11 and ATM were associated with poor RFS among KRAS-mutant tumors. EGFR, KEAP1 and PIK3CA mutations were predictive of poor response to adjuvant therapy. Immune marker analysis revealed that LUADs in smokers and with relatively high mutation burdens exhibited increased levels of immune markers. Analysis of immunophenotypes revealed that LUADs with STK11 mutations exhibited relatively low levels of infiltrating CD4+/CD8+T-cells indicative of a muted immune response. Tumoral PD-L1 was significantly elevated in TP53 mutant LUADs whereas PIK3CA mutant LUADs exhibited markedly downregulated PD-L1 expression. LUADs with TP53 or KEAP1 mutations displayed relatively increased CD57 and Granzyme B levels indicative of augmented natural killer (NK) cell infiltration. Conclusion(s): Our study highlights molecular and immune phenotypes that warrant further analysis for their roles in clinical outcomes and personalized immune-based therapy of LUAD. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
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Immune profiles, Lung adenocarcinoma, Whole-exome sequencing, Adenocarcinoma, Biomarkers, tumor, Disease-free survival, Dna mutational analysis, Exome, Female, Follow-up studies, Genome-wide association study, Humans, Immunohistochemistry, Kaplan-meier estimate, Lung neoplasms, Male, Mutation, Neoplasm staging, Prognosis, Proportional hazards models, Atm protein, Cd3 antigen, Cd4 antigen, Cd45ro antigen, Cd57 antigen, Cd68 antigen, Cd8 antigen, Epidermal growth factor receptor, Granzyme b, Kelch like ech associated protein 1, Programmed death 1 ligand 1, Programmed death 1 receptor, Protein kinase lkb1, Transcription factor foxp3, Tumor marker, Article, Atm gene, Cancer staging, Cd4+ t lymphocyte, Cd8+ t lymphocyte, Cell infiltration, Cohort analysis, Controlled study, Egfr gene, Follow up, Gene, Gene sequence, Genetic variability, Human, Immunophenotyping, Keap1 gene, Major clinical study, Natural killer cell, Pathogenesis, Pik3ca gene, Point mutation, Recurrence free survival, Setd2 gene, Single nucleotide polymorphism, Somatic mutation, Stk11 gene, Tumor suppressor gene, Disease free survival, Genetics, Immunology, Kaplan meier method, Lung tumor, Mortality, Proportional hazards model