Two Distinct Subtypes Revealed in Blood Transcriptome of Breast Cancer Patients With an Unsupervised Analysis

Wenlong Ming; Hui Xie; Zixi Hu; Yuanyuan Chen; Yanhui Zhu; Yunfei Bai; Hongde Liu; Xiao Sun; Yun Liu; Wanjun Gu

doi:10.3389/fonc.2019.00985

Two Distinct Subtypes Revealed in Blood Transcriptome of Breast Cancer Patients With an Unsupervised Analysis

Front Oncol. 2019 Oct 1:9:985. doi: 10.3389/fonc.2019.00985. eCollection 2019.

Authors

Wenlong Ming¹, Hui Xie², Zixi Hu¹, Yuanyuan Chen¹, Yanhui Zhu², Yunfei Bai¹, Hongde Liu¹, Xiao Sun¹, Yun Liu², Wanjun Gu¹

Affiliations

¹ State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
² The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Abstract

Background: Breast cancer (BC) is a highly heterogeneous cancer. The interaction between immune system and BC is complex, widespread yet unclear. In this study, we aimed to reveal the heterogeneity of host systemic immune response to BC and understand the possible mechanisms that may drive the heterogeneity using transcriptomic data from peripheral blood mononuclear cells (PBMCs). Methods: Transcriptome-wide gene expressions of PBMCs in 33 BC patients were generated by RNA sequencing. An unsupervised clustering algorithm was employed to discover PBMC transcriptome subtypes among BC patients. Association analysis between PBMC subtypes and age, clinical stage, abundance of immune cells, and other clinical factors was performed to understand the underlying biological processes that may drive this heterogeneity. Immune gene signature identification and in silico survival analysis were performed to investigate the potential clinical implications of these PBMC subtypes. The findings were validated using the whole blood transcriptomes of an independent cohort. Results: We observed that established BC subtypes were not associated with PBMC gene expression profiles. Instead, we discovered and validated two new BC subtypes using PBMC transcriptome, which have distinct immune cell proportions, especially for lymphocytes (P = 5.22 × 10^-12) and neutrophils (P = 1.13 × 10^-14). Enrichment analysis of differentially expressed genes revealed that these two subtypes had distinct patterns of immune responses, including osteoclast differentiation and interleukin-10 signaling pathway. We developed two immune gene signatures that can differentiate these two BC PBMC subtypes. Further analysis suggested they had the ability to predict the clinical outcome of BC patients. Conclusions: PBMC transcriptome profiles can classify BC patients into two distinct subtypes. These two subtypes are mainly shaped by different immune cell abundance, which may have implications on clinical outcomes.

Keywords: breast cancer subtype; breast cancer survival; immune gene signature; peripheral blood mononuclear cells; unsupervised analysis.