Comprehensive Genomic Analysis Identifies Novel Subtypes and Targets of Triple-Negative Breast Cancer

Abstract

Purpose Genomic profiling studies suggest triple-negative breast cancer (TNBC) is a heterogeneous disease. In this study we sought to define TNBC subtypes and identify subtype-specific markers and targets. Patients and Methods RNA and DNA profiling analyses were conducted on 198 TNBC tumors (ER-negativity defined as Allred Scale value ≤2) with >50% cellularity (discovery set: n=84; validation set: n=114) collected at Baylor College of Medicine. An external data set of 7 publically-accessible TNBC studies was used to confirm results. DNA copy number, disease-free survival (DFS) and disease-specific survival (DSS) were analyzed independently using these datasets. Results We identified and confirmed four distinct TNBC subtypes: (1) Luminal-AR (LAR); 2) Mesenchymal (MES); 3) Basal-Like Immune-Suppressed (BLIS), and 4) Basal-Like Immune-Activated (BLIA). Of these, prognosis is worst for BLIS tumors and best for BLIA tumors for both DFS (logrank test p=0.042 and 0.041, respectively) and DSS (logrank test p=0.039 and 0.029, respectively). DNA copy number analysis produced two major groups (LAR and MES/BLIS/BLIA), and suggested gene amplification drives gene expression in some cases (FGFR2 (BLIS)). Putative subtype-specific targets were identified: 1) LAR: androgen receptor and the cell surface mucin MUC1; 2) MES: growth factor receptors (PDGF receptor A; c-Kit); 3) BLIS: an immune suppressing molecule (VTCN1); and 4) BLIA: Stat signal transduction molecules and cytokines. Conclusion There are four stable TNBC subtypes characterized by the expression of distinct molecular profiles that have distinct prognoses. These studies identify novel subtype-specific targets that can be targeted in the future for effective treatment of TNBCs.

Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis

“…Burstein et al 25 identified four different TNBC subtypes (LAR, MES, BLIS, BLIA) with the identification of similar pathways and a prognostic value for the BLIA subgroup similar to that for the signature identified in our study. This subgroup displays an upregulation of B-cell, T-cell, and natural killer cell immune-regulating pathways and an activation of STAT transcription factor-mediated pathways.…”

“…The two immune modules identified in this study had many biological connections with other eight immune prognosis signatures published for TNBC. [18][19][20][21][22][23][24][25] Neoadjuvant chemotherapy is increasingly being used for TNBC, because these tumors have a poor prognosis, are assumed to be chemosensitive and no alternative specific systemic treatment is available. Patients with a complete pathologic response (pCR) after neoadjuvant chemotherapy have a better outcome than those with residual disease, and pCR is a good surrogate for long-term survival and cure in this specific subgroup.…”

“…String database connections between the Immunity1 or Immunity2 genes and the genes of the eight published prognostic immune signatures [18][19][20][21][22][23][24][25] are provided in Fig. 4.…”

TRPC1 is a differential regulator of hypoxia-mediated events and Akt signalling in PTEN-deficient breast cancer cells

“…The UNC dataset classified its 855 tumours into the five intrinsic PAM50 molecular subtypes and further sub-divided the basal-like and normal-like subtypes into claudin-low tumours, basal-like (basal, 140), claudin-low (C-Low, 90), HER2-enriched (HER2, 144), luminal A (LumA, 243), luminal B (LumB, 162) and normal-like (N-Like, 76). Triple-negative breast cancers (TNBCs) from the UNC cohort [based on immunohistochemistry (IHC) of the oestrogen (ER) and progesterone receptors (PR) and HER2] were assigned a TNBC subtype based on the expression of subtype-specific gene signatures (Burstein et al, 2015). This analysis classified the 200 TNBCs into 83 basal-like immune-activated (BLIA), 95 basal-like immune-suppressed (BLIS), 6 luminal androgen receptor (LAR) and 16 mesenchymal (MES).…”

Risk Factors contributing to Methylation Shifts in BRCA1 and associated genes in African Americans with Triple Negative Breast Cancer

“…Subtype 3 is Basal-like immune suppressed (BLIS) which involves down regulation of pathways relating to the function of immune cell regulatory pathways. Lastly, subtype 4 Basal-like immune activated (BLIA) shows the up regulation of pathways relating to immune cell function [34]. The (LAR) and (MES) subtypes overlap with Lehmann and colleagues while the (BLIS) and (BLIA) take from the other four types.…”