Format

Send to

Choose Destination
PLoS One. 2016 May 19;11(5):e0155840. doi: 10.1371/journal.pone.0155840. eCollection 2016.

Analysis of Paired Primary-Metastatic Hormone-Receptor Positive Breast Tumors (HRPBC) Uncovers Potential Novel Drivers of Hormonal Resistance.

Author information

1
Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain.
2
Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
3
Structural Computational Biology Group, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
4
Bioinformatics Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
5
Biobank, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
6
Pathology Department, Hospital 12 de Octubre, Madrid, Spain.
7
Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, Barcelona, Spain.

Abstract

We sought to identify genetic variants associated with disease relapse and failure to hormonal treatment in hormone-receptor positive breast cancer (HRPBC). We analyzed a series of HRPBC with distant relapse, by sequencing pairs (n = 11) of tumors (primary and metastases) at >800X. Comparative genomic hybridization was performed as well. Top hits, based on the frequency of alteration and severity of the changes, were tested in the TCGA series. Genes determining the most parsimonious prognostic signature were studied for their functional role in vitro, by performing cell growth assays in hormonal-deprivation conditions, a setting that mimics treatment with aromatase inhibitors. Severe alterations were recurrently found in 18 genes in the pairs. However, only MYC, DNAH5, CSFR1, EPHA7, ARID1B, and KMT2C preserved an independent prognosis impact and/or showed a significantly different incidence of alterations between relapsed and non-relapsed cases in the TCGA series. The signature composed of MYC, KMT2C, and EPHA7 best discriminated the clinical course, (overall survival 90,7 vs. 144,5 months; p = 0.0001). Having an alteration in any of the genes of the signature implied a hazard ratio of death of 3.25 (p<0.0001), and early relapse during the adjuvant hormonal treatment. The presence of the D348N mutation in KMT2C and/or the T666I mutation in the kinase domain of EPHA7 conferred hormonal resistance in vitro. Novel inactivating mutations in KMT2C and EPHA7, which confer hormonal resistance, are linked to adverse clinical course in HRPBC.

PMID:
27195705
PMCID:
PMC4873174
DOI:
10.1371/journal.pone.0155840
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center