An mRNA Gene Expression–Based Signature to Identify FGFR1-Amplified Estrogen Receptor–Positive Breast Tumors
2017
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.
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