Uncovering the Subtype-Specific Molecular Characteristics of Breast Cancer by Multiomics Analysis of Prognosis-Associated Genes, Driver Genes, Signaling Pathways, and Immune Activity.

Xinhui Li,Shuoshuo Wang,Yuan Zhuang,Yan Zhao,Xiaobo Li,Mingming Xiao,Lingyu Zhao,Jian Zhou,Minghui Zhang,Yi Niu,Shuangshu Gao,Jing Tang,Yuanyuan Zhu,Shijun Li

doi:10.3389/fcell.2021.689028

Abstract

Breast cancer is a heterogeneous malignant disease with different prognoses and has been divided into four molecular subtypes. It is believed that molecular events occurring in breast stem/progenitor cells contribute to the carcinogenesis and development of different breast cancer subtypes. However, these subtype-specific molecular characteristics are largely unknown. In this study, we employed 1217 breast cancer samples from The Cancer Genome Atlas (TCGA) database for a multiomics analysis of the molecular characteristics of different breast cancer subtypes based on PAM50 algorithms. We detected the expression changes of subtype-specific genes and revealed that the expression of particular subtype-specific genes significantly affected prognosis. We also investigated the mutations and copy number variations (CNVs) of breast cancer driver genes and the representative genes of ten signaling pathways in different subtypes and revealed several subtype-specifically altered genes. Moreover, we detected the infiltration of various immune cells in different subtypes of breast cancer and showed that the infiltration levels of major immune cell types are different among these subtypes. Additionally, we investigated the factors affecting the immune infiltration level and the immune cytolytic activity in different breast cancer subtypes, namely, the mutation burden, genome instability and cancer-associated fibroblast (CAF) infiltration. This study may shed light on the molecular events contributing to carcinogenesis and development and provide potential markers and targets for the clinical diagnosis and treatment of different breast cancer subtypes.

Highlights

IntroductionMATERIALS AND METHODSBreast cancer is a heterogeneous disease. In 2000, Perou first reported the molecular characteristics-based classification of breast cancer, namely, the luminal subtype (lumA and lumB), basal-like subtype, HER2-overexpression subtype and normal breast-like subtype (Perou et al, 2000). Sorlie et al (2003) divided the luminal subtype into A type and B/C type
MATERIALS AND METHODSBreast cancer is a heterogeneous disease
Breast cancer is a heterogeneous disease with different molecular characteristics and various clinical treatment responses and prognoses

Summary

Introduction

MATERIALS AND METHODSBreast cancer is a heterogeneous disease. In 2000, Perou first reported the molecular characteristics-based classification of breast cancer, namely, the luminal subtype (lumA and lumB), basal-like subtype, HER2-overexpression subtype and normal breast-like subtype (Perou et al, 2000). Sorlie et al (2003) divided the luminal subtype into A type and B/C type. In 2000, Perou first reported the molecular characteristics-based classification of breast cancer, namely, the luminal subtype (lumA and lumB), basal-like subtype, HER2-overexpression subtype and normal breast-like subtype (Perou et al, 2000). The prognosis of patients with the lumA and lumB subtypes is relatively good, and the primary treatments are surgery, chemotherapy and endocrine therapy (Harbeck et al, 2019). The 5-year survival rate of patients with the basal-like subtype is low, and there is a lack of effective treatments. Studies have shown that the clinically identified HER2 and basal-like subtypes are complex, explaining why the clinical effects of drugs such as Herceptin on patients with the HER2 subtype are general, and why triple-negative breast cancer is largely difficult to treat (Kumar and Aggarwal, 2016)

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