Candidate Luminal B Breast Cancer Genes Identified by Genome, Gene Expression and DNA Methylation Profiling

Stéphanie Cornen,Patrice Viens,Anne Letessier,Salvatore Spicuglia,Hugues De The,François Bertucci,Max Chaffanet,Pascal Finetti,Ismahane Bekhouche,Arnaud Guille,Lynda Addou-Klouche,José Adélaïde,Nadine Carbuccia,Stéphane Raynaud,Marie-Rose Saade,Emmanuelle Charafe-Jauffret,Daniel Birnbaum,Marwa Manai,Jocelyne Jacquemier

doi:10.1371/journal.pone.0081843

Abstract

Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15) and UTRN (6q24), were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype.

Highlights

Breast cancer (BC) is a complex and heterogeneous disease whose therapeutic approach must be refined in view of recent studies allowing better classification and/or prognosis assessment [1]
To further define molecular alterations associated with the luminal B subtype we studied DNA copy number aberrations (CNAs), DNA promoter methylation alterations (DPMAs), gene expression deregulation (EXP), and selected gene mutations in 188 primary BC samples
The highest proportion of simplex patterns was observed in luminal A tumors (58%) whereas the highest proportion of complex patterns was found in ERBB2 (100%), luminal B and basal (91% for both) cases (Fig. S4)

Summary

Introduction

Breast cancer (BC) is a complex and heterogeneous disease whose therapeutic approach must be refined in view of recent studies allowing better classification and/or prognosis assessment [1]. Combining expression and genomic data allowed the identification of candidate BC genes [6,9,10,11,12,13,14,15,16,17,18,19]. The identification of new fusion genes by RNA-seq approaches [25,26] and of driver mutations in cancer genes in various molecular and clinical BC entities [27,28,29,30,31] will help design targeted treatments

Methods

Results

Conclusion