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Sci Rep. 2019 Mar 1;9(1):3235. doi: 10.1038/s41598-019-39594-4.

Mutations in DNA repair genes are associated with increased neoantigen burden and a distinct immunophenotype in lung squamous cell carcinoma.

Author information

1
Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. young.chae@northwestern.edu.
2
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, 60611, USA. young.chae@northwestern.edu.
3
Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
4
The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06030, USA.
5
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, 60611, USA.
6
Department of Genetics and Genome Sciences, University of Connecticut Health, Farmington, CT, 06032, USA.

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.

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