Journal Article

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

Quintela-Fandino, Miguel, Manso, Luis, Ciruelos, Eva, Rodriguez-Peralto, Jose Luis, Tress, Michael, Gómez-López, Gonzalo, Mourón, Silvana, Rubio-Camarillo, Miriam, Pisano, David G., Morente, Manuel, Pujana, Miguel A.

2016

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alterations / Analysis / Antineoplastic Agents, Hormonal - therapeutic use / Aromatase / Aromatase Inhibitors - pharmacology / Bioinformatics / Biology and Life Sciences / Biomedical research / Breast - pathology / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Cancer metastasis / Cell cycle / Cloning / Comparative Genomic Hybridization / Deoxyribonucleic acid / Deprivation / Development and progression / DNA / DNA methylation / Drug Resistance, Neoplasm - genetics / Failure analysis / Female / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Genes / Genetic aspects / Genetic diversity / Genetic variance / Genetic Variation / Hormones / Hormones - metabolism / Humans / Hybridization / Medical research / Medical treatment / Medicine and Health Sciences / Metastases / Metastasis / Mutation / Myc protein / Neoplasm Recurrence, Local - genetics / Neoplasm Recurrence, Local - pathology / Oligonucleotide Array Sequence Analysis / Physiological aspects / Prognosis / Receptors, Estrogen - metabolism / Recurrence / Research and Analysis Methods / Retrospective Studies / Review boards / Risk / Sequence Analysis, DNA / Sequences / Studies / Tamoxifen - pharmacology / Treatment Outcome / Tumors