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Mutations in DNA repair genes are associated with increased neoantigen burden and a distinct immunophenotype in lung squamous cell carcinoma.
- Source :
-
Scientific reports [Sci Rep] 2019 Mar 01; Vol. 9 (1), pp. 3235. Date of Electronic Publication: 2019 Mar 01. - Publication Year :
- 2019
-
Abstract
- Deficiencies in DNA repair pathways, including mismatch repair (MMR), have been linked to higher tumor mutation burden and improved response to immune checkpoint inhibitors. However, the significance of MMR mutations in lung cancer has not been well characterized, and the relevance of other processes, including homologous recombination (HR) and polymerase epsilon (POLE) activity, remains unclear. Here, we analyzed a dataset of lung squamous cell carcinoma samples from The Cancer Genome Atlas. Variants in DNA repair genes were associated with increased tumor mutation and neoantigen burden, which in turn were linked with greater tumor infiltration by activated T cells. The subset of tumors with DNA repair gene variants but without T cell infiltration exhibited upregulation of TGF-β and Wnt pathway genes, and a combined score incorporating these genes and DNA repair status accurately predicted immune cell infiltration. Finally, high neoantigen burden was positively associated with genes related to cytolytic activity and immune checkpoints. These findings provide evidence that DNA repair pathway defects and immunomodulatory genes together lead to specific immunophenotypes in lung squamous cell carcinoma and could potentially serve as biomarkers for immunotherapy.
- Subjects :
- Antigens, Neoplasm immunology
BRCA1 Protein genetics
BRCA2 Protein genetics
Biomarkers, Tumor immunology
Carcinoma, Squamous Cell immunology
Carcinoma, Squamous Cell therapy
Homologous Recombination genetics
Humans
Immunophenotyping
Immunotherapy methods
Kaplan-Meier Estimate
Lung Neoplasms immunology
Lung Neoplasms therapy
MutL Protein Homolog 1 genetics
MutS Homolog 2 Protein genetics
Transforming Growth Factor beta1 genetics
Wnt Signaling Pathway genetics
Antigens, Neoplasm genetics
Biomarkers, Tumor genetics
Carcinoma, Squamous Cell genetics
DNA Mismatch Repair genetics
Lung Neoplasms genetics
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 30824826
- Full Text :
- https://doi.org/10.1038/s41598-019-39594-4