title: Analysis of Paired Primary-Metastatic Hormone-Receptor Positive Breast Tumors (HRPBC) Uncovers Potential Novel Drivers of Hormonal Resistance.
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.
authors.affiliation: Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Manso
authors.affiliation: Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Silvana
authors.initials: S
authors.lastname: Mourón
authors.affiliation: Structural Computational Biology Group, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Michael
authors.initials: M
authors.lastname: Tress
authors.affiliation: Bioinformatics Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gómez-López
authors.affiliation: Biobank, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Morente
authors.affiliation: Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Ciruelos
authors.affiliation: Bioinformatics Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Rubio-Camarillo
authors.affiliation: Pathology Department, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Rodriguez-Peralto
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, Barcelona, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pujana
authors.affiliation: Bioinformatics Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: David G
authors.initials: DG
authors.lastname: Pisano
authors.affiliation: Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Quintela-Fandino
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D055028:Comparative Genomic Hybridization; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D012008:Recurrence; D012189:Retrospective Studies; D012306:Risk; D017422:Sequence Analysis, DNA; D013629:Tamoxifen / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D006728:Hormones; D011960:Receptors, Estrogen; D013629:Tamoxifen