Increased gene copy number and amplification of FGF2 and FGFR1 in metastatic colorectal cancer.

Abstract

402 Background: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play essential roles in tightly regulating cell proliferation, survival, migration, and angiogenesis in cancers. However, gene copy number and amplification of FGF2 and FGFR1 have not been extensively evaluated in patients with metastatic colorectal cancer (CRC). Methods: Two tissue microarrays (TMA) were constructed with resected CRC liver metastases from 120 patients. The TMAs included duplicated intratumoral regions and the invasive margin between tumor and normal hepatic parenchyma. Patients were either untreated, or previously treated with FOLFIRI or FOLFOX +/- bevacizumab. The TMA slides were subjected to a two-color FISH assay using a mixture of FGF2 and FGFR1 in-house developed probes. Results: Results were obtained from 118 patients. The analysis detected an average of 1.90 copies of FGF2 signal per cell (range, 1.10-3.46 copies) and an average of 2.27 copies of FGFR1 signal per cell (range, 1-12-7.14 copies). Three control specimens from each slide were also scored, with an average of 1.74 copies of FGF2 and 1.73 copies of FGFR1. High copy number per cell (mean > 2.5 copies) was detected in 9.3% of specimens for FGF2 and 27.9% for FGFR1, including 2 patients (1.7%) for FGF2 and 5 (4.2%) for FGFR1 with focal amplification, defined by ≥ 10% cells with > 4 copies. Additionally, duplications of gene signals in the same locus were detected in 10 samples (8.5%) for FGF2 and 19 (16.1%) for FGFR1. Intratumoral heterogeneity was rare (detected in 3 patients). There was no statistically significant correlation between FGF2 or FGFR1 gene copy number and prior treatment, pathologic response, relapse free survival, or overall survival, though there was a trend towards higher FGFR1 gene copy number in patients previously receiving bevacizumab (p=0.07). Conclusions: Both FGF2 and FGFR1 display variable copy number among resected CRC liver metastases, with larger variability detected for FGFR1. Gene amplification was rare but detected in several patients for both FGF2 and FGFR1. Follow up studies will investigate higher FGFR1 gene copy number in patients previously treated with bevacizumab, perhaps reflecting a potential escape or resistance mechanism.