Stratification of Estrogen Receptor-Negative Breast Cancer Patients by Integrating the Somatic Mutations and Transcriptomic Data

Abstract

Patients with estrogen receptor-negative breast cancer generally have a worse prognosis than estrogen receptor-positive patients. Nevertheless, a significant proportion of the estrogen receptor-negative cases have favorable outcomes. Identifying patients with a good prognosis, however, remains difficult, as recent studies are quite limited. The identification of molecular biomarkers is needed to better stratify patients. The significantly mutated genes may be potentially used as biomarkers to identify the subtype and to predict outcomes. To identify the biomarkers of receptor-negative breast cancer among the significantly mutated genes, we developed a workflow to screen significantly mutated genes associated with the estrogen receptor in breast cancer by a gene coexpression module. The similarity matrix was calculated with distance correlation to obtain gene modules through a weighted gene coexpression network analysis. The modules highly associated with the estrogen receptor, called important modules, were enriched for breast cancer-related pathways or disease. To screen significantly mutated genes, a new gene list was obtained through the overlap of the important module genes and the significantly mutated genes. The genes on this list can be used as biomarkers to predict survival of estrogen receptor-negative breast cancer patients. Furthermore, we selected six hub significantly mutated genes in the gene list which were also able to separate these patients. Our method provides a new and alternative method for integrating somatic gene mutations and expression data for patient stratification of estrogen receptor-negative breast cancers.

Elucidating the Role of MicroRNA-18a in Propelling a Hybrid Epithelial–Mesenchymal Phenotype and Driving Malignant Progression in ER-Negative Breast Cancer

“…Genome sequencing and mutational profiling conducted by the TCGA network and multiple other groups have led to the identification of mutational signatures that not only affect genomic signatures but also bring about epigenetic changes [5,7]. This may be causal for tumour heterogeneity leading to differential activation of signalling pathways that eventually lead to divergent molecular signatures.…”

“…The ER-negative subtype is also heterogeneous at the pathological, clinical and at the molecular level with a mutational profile vastly distinct from other subtypes [5,6]. Epigenetic alterations resulting in deviant gene expression profiles are also key contributors to the process of tumour progression in ER-negative breast cancer [7].…”

Acquisition of hybrid E/M phenotype associated with increased migration, drug resistance and stemness is mediated by reduced miR-18a levels in ER-negative breast cancer

“…The molecular subtyping studies especially the PAM50 classification has unravelled the existence of a basal-like and Her2-enriched subclasses within the ER-negative subtype. Genome sequencing and mutational profiling done by the TCGA network and multiple other groups have led to identification of mutational signatures that not only affect genomic signatures but also bring about epigenetic changes (1)(2)(3). This may be causal for tumour heterogeneity leading to differential activation of signalling pathways that eventually leads to divergent molecular signatures.…”

“…The mutational profile of ER-negative breast cancer is vastly distinct from other subtypes. In addition to mutations, epigenetic alterations resulting in deviant gene expression profile are also key contributors to the process of tumour progression in ER-negative breast cancer (3). Deregulated expression of microRNAs (miRNAs) has been attributed to bring about such epigenetic alterations that can affect the process of tumour progression.…”

A review of deubiquitinases and thier roles in tumorigenesis and development

“…Androgen receptor (AR) can suppress tumor cell proliferation through suppressing ERα signaling of ER-positive BC, thereby promoting ER-negative BC cell growth (Peters et al, 2009;Cochrane et al, 2014;Mina et al, 2017;Hou et al, 2021). USP14 can inhibit AR degradation by deubiquitination.…”