Oncotarget

Research Papers:

Integrated analysis of somatic mutations and immune microenvironment of multiple regions in breast cancers

Taigo Kato, Jae-Hyun Park, Kazuma Kiyotani, Yuji Ikeda, Yasuo Miyoshi & Yusuke Nakamura _

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Oncotarget. 2017; 8:62029-62038. https://doi.org/10.18632/oncotarget.18790

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Abstract

Taigo Kato1, Jae-Hyun Park1, Kazuma Kiyotani1, Yuji Ikeda1, Yasuo Miyoshi2 and Yusuke Nakamura1,3

1Department of Medicine, The University of Chicago, Chicago, IL 60637, USA

2Divison of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Hyogo 663-8501, Japan

3Department of Surgery, The University of Chicago, Chicago, IL 60637, USA

Correspondence to:

Yusuke Nakamura, email: ynakamura@bsd.uchicago.edu

Keywords: breast cancer, heterogeneity, T cell receptor, non-synonymous mutation, neoantigen

Abbreviations: CDR3: complementary determining region 3; SI: similarity index; TCR: T cell receptor; TILs: tumor-infiltrating lymphocytes

Received: April 28, 2017     Accepted: May 20, 2017     Published: June 28, 2017

ABSTRACT

Next-generation sequencing technology enables us to analyze the complexity of intra- and inter-tumoral heterogeneity, which may influence to prognosis of cancer patients. In this study, we collected surgically-resected tumor tissues from five breast cancer patients and characterized three different portions of individual tumors through somatic mutation analysis by whole exome sequencing, T cell receptor beta (TCRB) repertoire analysis of tumor-infiltrating lymphocytes (TILs), and the expression analysis of immune-related genes at 15 different sites. This integrated analysis revealed distinguished patterns of somatic mutations and TIL clonotypes in the three portions of each tumor, implying that the tumor heterogeneity is comprised by spatially different somatic mutations as well as the presence of diverse T cell clones. Furthermore, higher numbers of the non-synonymous somatic mutations were significantly correlated with the higher ratio of GZMA/TCRB expression (P = 0.0004), implying that high somatic mutation load in tumor might be correlated to the number of immunogenic antigens and then functionally activate TILs with higher cytolytic activity. Our findings suggest that breast cancers comprise with very complex tumor heterogeneity by the spatially different mutational landscape and immune microenvironment, and that mutation/neoantigen load may be strongly correlated with induction of cancer-specific TILs and affect the immune microenvironment in breast tumors.


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