Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer

Matthew D. Burstein, Anna Tsimelzon, Graham M. Poage, Kyle R. Covington, Alejandro Contreras, Suzanne A.W. Fuqua, Michelle I. Savage, C. Kent Osborne, Susan G. Hilsenbeck, Jenny C. Chang, Gordon Mills, Ching C. Lau, Powel H. Brown

Research output: Contribution to journalArticle

282 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1688-1698
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number7
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

Fingerprint

Triple Negative Breast Neoplasms
Androgen Receptors
Disease-Free Survival
Platelet-Derived Growth Factor Receptors
DNA Fingerprinting
Growth Factor Receptors
Gene Amplification
DNA
Mucins
Estrogen Receptors
Signal Transduction
Neoplasms
Research Design
Medicine
RNA
Breast Neoplasms
Cytokines
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Burstein, M. D., Tsimelzon, A., Poage, G. M., Covington, K. R., Contreras, A., Fuqua, S. A. W., ... Brown, P. H. (2015). Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clinical Cancer Research, 21(7), 1688-1698. https://doi.org/10.1158/1078-0432.CCR-14-0432

Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. / Burstein, Matthew D.; Tsimelzon, Anna; Poage, Graham M.; Covington, Kyle R.; Contreras, Alejandro; Fuqua, Suzanne A.W.; Savage, Michelle I.; Osborne, C. Kent; Hilsenbeck, Susan G.; Chang, Jenny C.; Mills, Gordon; Lau, Ching C.; Brown, Powel H.

In: Clinical Cancer Research, Vol. 21, No. 7, 01.04.2015, p. 1688-1698.

Research output: Contribution to journalArticle

Burstein, MD, Tsimelzon, A, Poage, GM, Covington, KR, Contreras, A, Fuqua, SAW, Savage, MI, Osborne, CK, Hilsenbeck, SG, Chang, JC, Mills, G, Lau, CC & Brown, PH 2015, 'Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer', Clinical Cancer Research, vol. 21, no. 7, pp. 1688-1698. https://doi.org/10.1158/1078-0432.CCR-14-0432
Burstein, Matthew D. ; Tsimelzon, Anna ; Poage, Graham M. ; Covington, Kyle R. ; Contreras, Alejandro ; Fuqua, Suzanne A.W. ; Savage, Michelle I. ; Osborne, C. Kent ; Hilsenbeck, Susan G. ; Chang, Jenny C. ; Mills, Gordon ; Lau, Ching C. ; Brown, Powel H. / Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 7. pp. 1688-1698.
@article{7a89d432d67f40cda26a46d558637d76,
title = "Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer",
abstract = "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.",
author = "Burstein, {Matthew D.} and Anna Tsimelzon and Poage, {Graham M.} and Covington, {Kyle R.} and Alejandro Contreras and Fuqua, {Suzanne A.W.} and Savage, {Michelle I.} and Osborne, {C. Kent} and Hilsenbeck, {Susan G.} and Chang, {Jenny C.} and Gordon Mills and Lau, {Ching C.} and Brown, {Powel H.}",
year = "2015",
month = "4",
day = "1",
doi = "10.1158/1078-0432.CCR-14-0432",
language = "English (US)",
volume = "21",
pages = "1688--1698",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer

AU - Burstein, Matthew D.

AU - Tsimelzon, Anna

AU - Poage, Graham M.

AU - Covington, Kyle R.

AU - Contreras, Alejandro

AU - Fuqua, Suzanne A.W.

AU - Savage, Michelle I.

AU - Osborne, C. Kent

AU - Hilsenbeck, Susan G.

AU - Chang, Jenny C.

AU - Mills, Gordon

AU - Lau, Ching C.

AU - Brown, Powel H.

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84927621560&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84927621560&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-14-0432

DO - 10.1158/1078-0432.CCR-14-0432

M3 - Article

C2 - 25208879

AN - SCOPUS:84927621560

VL - 21

SP - 1688

EP - 1698

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 7

ER -