Dataset Information

Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma.

ABSTRACT: Mutations in DNA repair genes lead to increased genomic instability and mutation frequency. These mutations represent potential biomarkers for cancer immunotherapy efficacy, as high tumor mutational burden has been associated with increased neo-antigens and tumor infiltrating lymphocytes. While mismatch repair mutations have successfully predicted response to anti-PD-1 therapy in colorectal and other cancers, they have not yet been tested for lung cancer, and few have investigated genes from other DNA repair pathways. We utilized TCGA samples to comprehensively immunophenotype lung tumors and analyze the links between DNA repair mutations, neo-antigen and total mutational burden, and tumor immune infiltration. Overall, 73% of lung tumors contained infiltration by at least one T cell subset, with high mutational burden tumors containing significantly increased infiltration by activated CD4 and CD8 T cells. Further, mutations in mismatch repair genes, homologous recombination genes, or POLE accurately predicted increased tumor mutational burden, neo-antigen load, and T cell infiltration. Finally, neo-antigen load correlated with expression of M1-polarized macrophage genes, PD-1, PD-L1, IFN?, GZMB, and FASLG, among other immune-related genes. Overall, after defining the immune infiltrate in lung tumors, we demonstrate the potential value of utilizing gene mutations from multiple DNA repair pathways as biomarkers for lung cancer immunotherapy.

SUBMITTER: Chae YK

PROVIDER: S-EPMC5814272 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma.

Chae Young Kwang YK Anker Jonathan F JF Bais Preeti P Namburi Sandeep S Giles Francis J FJ Chuang Jeffrey H JH

Oncotarget 20171215 8

Mutations in DNA repair genes lead to increased genomic instability and mutation frequency. These mutations represent potential biomarkers for cancer immunotherapy efficacy, as high tumor mutational burden has been associated with increased neo-antigens and tumor infiltrating lymphocytes. While mismatch repair mutations have successfully predicted response to anti-PD-1 therapy in colorectal and other cancers, they have not yet been tested for lung cancer, and few have investigated genes from oth ...[more]

PMID: 29487705

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Project description:Background: aldolase A (ALDOA) has been reported to be involved in kinds of cancers. However, the role of ALDOA in lung adenocarcinoma has not been fully elucidated. In this study, we explored the prognostic value and correlation with immune infiltration of ALDOA in lung adenocarcinoma. Methods: The expression of ALDOA was analyzed with the Oncomine database, the Cancer Genome Atlas (TCGA), and the Human Protein Atlas (HPA). Mann-Whitney U test was performed to examine the relationship between clinicopathological characteristics and ALDOA expression. The receiver operating characteristic (ROC) curve and Kaplan-Meier method were conducted to describe the diagnostic and prognostic importance of ALDOA. The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape were used to construct PPI networks and identify hub genes. Functional annotations and immune infiltration were conducted. Results: The mRNA and protein expression of ALDOA were higher in lung adenocarcinoma than those in normal tissues. The overexpression of ALDOA was significantly correlated with the high T stage, N stage, M stage, and TNM stage. Kaplan-Meier showed that high expression of ALDOA was correlated with short overall survival (38.9 vs 72.5 months, p < 0.001). Multivariate analysis revealed that ALDOA (HR 1.435, 95%CI, 1.013-2.032, p = 0.042) was an independent poor prognostic factor for overall survival. Functional enrichment analysis showed that positively co-expressed genes of ALDOA were involved in the biological progress of mitochondrial translation, mitochondrial translational elongation, and negative regulation of cell cycle progression. KEGG pathway analysis showed enrichment function in carbon metabolism, the HIF-1 signaling pathway, and glycolysis/gluconeogenesis. The "SCNA" module analysis indicated that the copy number alterations of ALDOA were correlated with three immune cell infiltration levels, including B cells, CD8+ T cells, and CD4+ T cells. The "Gene" module analysis indicated that ALDOA gene expression was negatively correlated with infiltrating levels of B cells, CD8+ T cells, CD4+ T cells, and macrophages. Conclusion: Our study suggested that upregulated ALDOA was significantly correlated with tumor progression, poor survival, and immune infiltrations in lung adenocarcinoma. These results suggest that ALDOA is a potential prognostic biomarker and therapeutic target in lung adenocarcinoma.

Dataset Information

Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma.

Publications

Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma.

Similar Datasets

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