title: An mRNA Gene Expression-Based Signature to Identify FGFR1-Amplified Estrogen Receptor-Positive Breast Tumors.
abstract: Fibroblast growth factor receptor 1 (FGFR1) amplification drives poor prognosis and is an emerging therapeutic target. We sought to construct a multigene mRNA expression signature to efficiently identify FGFR1-amplified estrogen receptor-positive (ER+) breast tumors. Five independent breast tumor series were analyzed. Genes discriminative for FGFR1 amplification were screened transcriptome-wide by receiver operating characteristic analyses. The METABRIC series was leveraged to construct/evaluate four approaches to signature composition. A locked-down signature was validated with 651 ER+formalin-fixed, paraffin-embedded tissues (the University of British Columbia-tamoxifen cohort). A NanoString nCounter assay was designed to profile selected genes. For a gold standard, FGFR1 amplification was determined by fluorescent in situ hybridization (FISH). Prognostic effects of FGFR1 amplification were assessed by survival analyses. Eight 8p11-12 genes (ASH2L, BAG4, BRF2, DDHD2, LSM1, PROSC, RAB11FIP1, and WHSC1L1) together with the a priori selected FGFR1 gene, highly discriminated FGFR1 amplification (area under the receiver operating characteristic curve ≥0.82, all genes and all cohorts). The nine-gene signature Call-FGFR1-amp accurately identified FGFR1 FISH-amplified ER+tumors in the University of British Columbia-tamoxifen cohort (specificity, 0.94; sensitivity, 0.96) and exhibited prognostic effects (disease-specific survival hazard ratio, 1.57; 95% CI, 1.14-2.16; P = 0.005). Call-FGFR1-amp includes several understudied 8p11-12 amplicon-driven oncogenes and accurately identifies FGFR1-amplified ER+breast tumors. Our study demonstrates an efficient approach to diagnosing rare amplified therapeutic targets with FISH as a confirmatory assay.
authors.affiliation: Division of Public Health Sciences, Washington University School of Medicine, St. Louis, Missouri; Department of Surgery, the Siteman Cancer Center Biostatistics Shared Resource, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jingqin
authors.initials: J
authors.lastname: Luo
authors.affiliation: Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Liu
authors.affiliation: Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Leung
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Gru
authors.affiliation: Division of Public Health Sciences, Washington University School of Medicine, St. Louis, Missouri; Department of Surgery, the Siteman Cancer Center Biostatistics Shared Resource, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hoog
authors.affiliation: Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Ho
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Sherri R
authors.initials: SR
authors.lastname: Davies
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: D Craig
authors.initials: DC
authors.lastname: Allred
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Salavaggione
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Snider
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
authors.affiliation: Lester and Sue Smith Breast Center, Baylor School of Medicine, Houston, Texas. Electronic address: matthew.ellis@bcm.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D015331:Cohort Studies; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D012372:ROC Curve; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D011960:Receptors, Estrogen / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1