Metabolomics reveals novel blood plasma biomarkers associated to the BRCA1-mutated phenotype of human breast cancer

Bàrbara Roig,Joan Borràs,Josep Gumà,Xavier Correig,Oscar Yanes,Eric W.-F Lam,Marta Rodríguez-Balada,Sara Samino,Ana R Gomes,Sandra Guaita-Esteruelas

doi:10.1038/s41598-017-17897-8

Abstract

Hereditary breast and ovarian cancer syndrome (HBOC) is partly due to the presence of mutations in the BRCA genes. Triple-negative (TN) breast cancer (BC) shares histological characteristics with germline BRCA1 mutation-associated tumours. We have investigated the metabolic profiles of human breast cancer (BC) cell lines carrying BRCA1 pathogenic mutations by non-targeted liquid chromatography coupled to mass spectrometry technology. Based on our in vitro results, we performed a targeted metabolomic analysis of plasma samples from TN HBOC patients taking into account their BRCA1 genotype. BRCA1 promoter hypermethylation and the BRCAness phenotype of BC cell lines were also studied. The purpose of this study was to determine the metabolic signature of HBOC syndrome and TNBC patients and to evaluate the potential contribution of the metabolites identified to the genetic diagnosis of breast cancer. The present results show the existence of a differential metabolic signature for BC cells based on the BRCA1 functionality. None of the studied BC cell lines presented hypermethylation of the BRCA1 promoter region. We provide evidence of the existence of free methylated nucleotides capable of distinguishing plasma samples from HBOC patients as BRCA1-mutated and BRCA1 non-mutated, suggesting that they might be considered as BRCA1-like biomarkers for TNBC and HBOC syndrome.

Highlights

Pathogenic germline mutations in the BRCA1 and BRCA2 genes predispose patients to hereditary breast and ovarian cancer syndrome (HBOC)[1]
Since cancer is a disease with metabolic alterations, there has been an increasing number of published studies related to breast cancer (BC) and metabolomics[20,35]
We presented the metabolomic based profile of BC cell lines for the characterization and identification of the breast cancer phenotype linked to the BRCA1 genotype

Summary

Introduction

Pathogenic germline mutations in the BRCA1 and BRCA2 genes predispose patients to hereditary breast and ovarian cancer syndrome (HBOC)[1]. TNBC is biologically and clinically more aggressive than receptor- or oncogene-expressing tumours These tumours frequently arise in younger patients, are generally larger in size at diagnosis, have a high histological grade and are responsible for many BC-related deaths[3,4,5,6]. TNBC specimens were found to frequently present a BRCA1-like profile based on comparative genomic hybridization-specific array analysis (aCGH), revealing phenotypic characteristics that are similar to those of hereditary breast tumours from carriers of germline BRCA1 mutations. This BRCA1-like profile is referred to as “BRCAness”[11]. Defects in other genes that modulate the HRR process may cause a BRCAness phenotype

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