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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / therapeutic use
  • Aromatase Inhibitors / pharmacology
  • Breast / pathology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Comparative Genomic Hybridization
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genetic Variation
  • Hormones / metabolism*
  • Humans
  • Mutation
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Oligonucleotide Array Sequence Analysis
  • Prognosis
  • Receptors, Estrogen / metabolism
  • Recurrence
  • Retrospective Studies
  • Risk
  • Sequence Analysis, DNA
  • Tamoxifen / pharmacology
  • Treatment Outcome

Substances

  • Antineoplastic Agents, Hormonal
  • Aromatase Inhibitors
  • Hormones
  • Receptors, Estrogen
  • Tamoxifen

Grant support

This study was supported by the Fondo de Investigación Sanitaria (Ministry of Health, Spain) numbers FIS PI10/0288, FIS PI13/00430; Spanish Society of Medical Oncology (SEOM) research grant 2012; Mutua Madrileña grant AP103102012; MQF is a recipient of a 2010 Beca-Retorno from the AECC Scientific Foundation. Rosae Foundation and AVON España S.A.U. contributed to this work with philanthropic donations. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.