An mRNA Gene Expression-Based Signature to Identify FGFR1-Amplified Estrogen Receptor-Positive Breast Tumors

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• 作者：Jingqin Luo^&lowast ; ; ^&dagger ; ; Shuzhen Liu^&Dagger ; ; Samuel Leung^&Dagger ; ; Alejandro A. Gru^§ ; ; Yu Tao^&lowast ; ; ^&dagger ; ; Jeremy Hoog^¶ ; ; Julie Ho^&Dagger ; ; Sherri R. Davies^¶ ; ; D. Craig Allred^§ ; ; Andrea L. Salavaggione^§ ; ; Jacqueline Snider^§ ; ; Elaine R. Mardis^‖ ; Torsten O. Nielsen^&Dagger ; ; Matthew J. Ellis^&lowast ; &lowast ; ; ^{matthew.ellis@bcm.edu}
• 刊名：The Journal of Molecular Diagnostics
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：19
• 期：1
• 页码：147-161
• 全文大小：2356 K
• 卷排序：19

文摘

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.