Prognostic implication of Fibroblast growth factor receptor 1 (FGFR1) gene copy number alteration in colorectal cancers using droplet digital polymerase chain reaction (ddPCR)

Abstract

Amplification of Fibroblast grow factor receptor 1 (FGFR1) is reported in several types of cancers. However, the clinicopathologic characteristics and prognostic implication of FGFR1 amplification in colorectal cancers (CRCs) are not well known. We measured copy number of FGFR1 gene using droplet digital polymerase chain reaction (ddPCR) and FGFR1 expression using immunohistochemistry in 789 surgically resected CRCs (384 CRCs for discovery set and 405 CRCs for validation set). CRCs with FGFR1 gene copy more than 3.15 were classified to FGFR1 amplification and CRCs with moderate and strong FGFR1 expression were classified to FGFR1 high-expression. FGFR1 amplification was found in 11 (2.9%) of 384 CRCs of discovery set and 32 (7.9%) of 405 CRCs of validation set. CRCs with FGFR1 amplification showed mutual exclusiveness with microsatellite instability and BRAF mutation. There was no predilection for sex, gross pattern, tumor location, stage and differentiation according to FGFR1 copy number status. FGFR1 high-expression was found in 50 (13.1%) of 382 CRCs of discovery set and 62 (16.5%) of 375 CRCs of validation set. FGFR1 amplification and FGFR1 high-expression did not show significant correlation. In the discovery set, CRCs with FGFR1 high-expression showed female preponderance, advanced N category and overall stage, frequent KRAS mutation and CIMP-high subtype. In survival analysis, CRCs with FGFR1 amplification showed significantly worse clinical outcome compared with CRCs with FGFR1 no-amplification in both discovery set and validation set. CRCs with FGFR1 high-expression showed worse progression-free survival compared with CRCs with FGFR1 low-expression only in the discovery set. FGFR inhibitor PD173074 repressed proliferation of CRC cell line with FGFR1 overexpression rather than CRC cell lines with FGFR1 amplification. In a conclusion, FGFR1 amplification measured by ddPCR can be a prognostic indicator of poor clinical outcome in CRCs.