Comprehensive Genomic Analysis Identifies Novel Subtypes and Targets of Triple-negative Breast Cancer
By M. Burstein, A. Tsimelzon, Graham Poage, K. Covington, A. Contreras, S. Fuqua, Michelle I Savage, K. Osborne, S. Hilsenbeck, Jenny C. Chang and 3 more. Clinical Cancer Research, 2014
1,111 citations recorded by the source corpus.
Purpose: Genomic profiling studies suggest that 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. Experimental Design: RNA and DNA profiling analyses were conducted on 198 TNBC tumors [estrogen receptor (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 (Houston, TX). An external dataset of seven 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: (i) luminal androgen receptor (AR; LAR), (ii) mesenchymal (MES), (iii) basal-like immunosuppressed (BLIS), and (iv) basal-like immune-activated (BLIA). Of these, prognosis is worst for BLIS tumors and best for BLIA tumors for both DFS (log-rank test: P = 0.042 and 0.041, respectively) and DSS (log-rank test: P = 0.039 and 0.029, respectively). DNA copy number analysis produced two major groups (LAR and MES/BLIS/BLIA) and suggested that gene amplification drives gene expression in some cases [FGFR2 (BLIS)]. Putative subtype-specific targets were identified: (i) LAR: androgen receptor and the cell surface mucin MUC1, (ii) MES: growth factor receptors [platelet-derived growth factor (PDGF) receptor A; c-Kit], (iii) BLIS: an immunosuppressing molecule (VTCN1), and (iv) 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 the effective treatment of TNBCs. Clin Cancer Res; 21(7); 1688–98. ©2014 AACR. See related commentary by Vidula and Rugo, p. 1511
Subfields: Cancer Research, Pathology and Forensic Medicine
View Paper: https://www.semanticscholar.org/paper/89488c476d2a353250e89ae8c9c3d7810d1f055d
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
Citations in the corpus
- Triple-negative breast cancer molecular subtyping and treatment progress (2020, background): “Although immunohistochemical analysis indicates that the LAR subtype is ER-negative, the signaling pathway expression profile shows the activation of the estrogen signaling pathway, suggesting that the LAR subtype may respond to antiandrogen and traditional antiestrogen therapy [19].”
- DeepST: identifying spatial domains in spatial transcriptomics by deep learning (2022, background): “In addition, we observed the upregulation of type I interferon signaling pathway ( ADAR , BST2 , IFI27 , IFITM3 and ISG15 ; Figure 4G and Supplementary Table 2), CGA and BAMBI , which exert antitumor and anti-metastatic effects (39–42), pointing towards reduced metastatic potential.”
- Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis (2018, background): “Nonetheless, a recent molecular profiling analysis of TNBCs also identified four stable subtypes, luminal androgen receptor, mesenchymal, basal-like immunosuppressed, and basal-like immune-activated.(296) While it is critical to identify molecular and genetic landscapes of TNBC at genomewide level, ”
- IDO in the Tumor Microenvironment: Inflammation, Counter-regulation and Tolerance (2016, positive): “, associated with increased T cell infiltration and inflammation [37, 54, 55].”
- Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer—How We Can Rise to the Challenge (2019, background): “TNBC Subtype and Its Characteristics [147,198] Promising Therapy Clinical Studies”
- A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging (2018, neutral): “Linking these micro-environmental immune features to existing molecular data on TNBC (Burstein et al., 2015; Lehmann et al., 2016) may provide future avenues for patient stratification and therapeutic design.”
- Recent advances in therapeutic strategies for triple-negative breast cancer (2022, background): “The BLIS cluster had the worst prognosis in terms of disease-free survival (DFS), suggesting the important role of the immune system in TNBC [8].”