Pan-cancer analysis of FGFR1-3 genomic alterations to reveal a complex molecular landscape.

Abstract

3620 Background: Activating genomic alterations (GAs) in the fibroblast growth factor receptor (FGFR) gene family occur in many tumor types. FGFR1-3 mutations and rearrangements are of particular interest given evidence of clinical activity of selective FGFR inhibitors in patients (pts) with susceptible alterations. We queried FGFR1-3 GAs in patient tumor samples analyzed using comprehensive genomic profiling (CGP) and performed in vitro characterization of select novel alterations. Methods: Tumor samples were assayed by hybrid capture based CGP on 0.8-1.2 Mb of the genome to identify GAs in exons and select introns in up to 404 genes (Foundation Medicine, Inc, Cambridge MA). Cell lines were stably transduced with alterations of interest and transformation assays and drug sensitivity assays were performed to determine oncogenic potential and sensitivity to FGFR inhibition by pemigatinib. Results: GAs in FGFR1-3 were present in 6314 of 274,694 pt specimens (2.3%), of which 4091 (64.8%) were short variants and 2269 (35.9%) were rearrangements. Tumor types with the highest frequency of FGFR1-3 alterations were bladder cancer (17.9%), cholangiocarcinoma (11.1%), endometrial cancer (7.9%), and glioma (5.5%) (Table). We identified 270 unique FGFR1-3 short-variants, including 144 missense mutations and 94 truncating alterations. Of short variants, the most frequent were FGFR3 p.S249C (18.3%), FGFR2 p.S252W (9.9%) and FGFR1 p.N546K (6.9%). Truncating alterations were largely identified in exon 18, downstream of the kinase domain. We identified 476 unique FGFR1-3 rearrangement pairs ( FGFR1; n=77, FGFR2; n=338, FGFR3; n=61). FGFR3-TACC3 was the most prevalent FGFR rearrangement (29.0%), followed by FGFR2-BICC1 and FGFR2-N/A (both 9.7%). In vitro analysis of the transforming potential and drug sensitivity for select alterations will be reported. Conclusions: FGFR1-3 mutations and rearrangements are highly diverse and present at low to moderate frequencies across many cancers. Therefore, cataloging and characterizing these diverse alterations has the potential to facilitate precision medicine. Tumor-specific and -agnostic trials of selective FGFR inhibitors in pts with susceptible alterations are ongoing. [Table: see text]