Abstract 4057: Identification of DNA repair genes that affect clonal heterogeneity and the immune microenvironment in breast cancers
Authors: Kawaguchi Tstutomu , Peng Xuan , Qi Qianya , McDonald Kerry-Ann , Young Jessica , Liu Song , Otsuji Eigo , Yan Li , Takabe Kazuaki 
Published: August 2018

Abstract
Background: While genetic aberrations of DNA repair genes are known to increase immunogenicity in breast cancer, the clinical significance of the tumor microenvironment including tumor-infiltrating immune cells in regard to DNA repair genes has not yet been elucidated in breast cancer patients. We sought to determine the significance of DNA repair genes and their impact on the immune microenvironment, which could provide insight for the development of immunotherapy in breast cancer. We aimed to correlate DNA repair gene deficiency with tumor-infiltrating immune cells and tumor immune microenvironment, and assess its clinical relevance.
Materials and Methods: Integrated and unbiased transcriptomics approach was conducted on genomic and clinical information of 3,614 breast cancer patients of The cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) to assess the association between the aberration of DNA repair genes and the tumor immune microenvironment in breast cancer, as well as the clinical significance utilizing an integrated immunogenomic pipeline. Tumor-infiltrating immune cells (TICs) composition was calculated using the CIBERSORT system that estimates the fraction of 22 immune cell types in each tumor. Intratumor clonal heterogeneity and T-cell receptor diversity was evaluated utilizing mutant allele tumor heterogeneity (MATH) index and TCR repertoire analysis.
Results: We found that low expression of DNA repair genes, especially low BRCA1 expression, was significantly associated with improved survival and higher CD8+ cell composition. Tumors with low expression of BRCA1 enriched immune-response related gene sets, using gene set enrichment analysis, significantly associated to higher expression of the immune gene signature, such as HLA-A, PRF1, GZMA, and GZMB, as well as local immune cytolytic activity (CYT). Intratumor clonal heterogeneity was associated with low expression of BRCA1 with high composition of CD8+ T-cells. T-cell receptor (TCR) repertoire analysis elucidated that lower TCR diversity correlated to low BRCA1 expression in hormone-negative or triple-negative breast cancer patients. Utilizing the GEO database with clinical information of response to neoadjuvant chemotherapy (NAC) in breast cancer, patients with low BRCA1 expression showed significantly better response to NAC.
Conclusions: We conclude that the comprehensive and unbiased immunogenomic analysis clearly elucidated that low expression of BRCA1, was associated with higher intratumor immune response including immune gene signature, TICs, intratumor clonal heterogeneity, and TCR diversity, all of which have a significant impact on the clinical outcome in breast cancer.
Citation Format: Tstutomu Kawaguchi, Xuan Peng, Qianya Qi, Kerry-Ann McDonald, Jessica Young, Song Liu, Eigo Otsuji, Li Yan, Kazuaki Takabe. Identification of DNA repair genes that affect clonal heterogeneity and the immune microenvironment in breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4057.