CGE22-102: Characterization of Genomic Alteration of FGFR-3 by Integrating Analysis The Cancer Genome Atlas

BACKGROUND: Mutations and fusions of the fibroblast growth factor receptor (FGFR) gene family occur in various cancer types. Currently, there are 4 FGFR inhibitors approved by the FDA for the treatment of solid tumor including Pazopanib, Lenvatinib, Erdafitinib, Sulfatinib. We performed an integrated analysis of the TCGA-pancancer atlas including 32 cancer types (n=10,953 patients) to illustrate the novel alterations of FGFR1-3. METHOD: To clarify FGFR alteration we performed an online analysis on the server https://www.cbioportal.org / . The FGFR alterations and clinicopathologic data were also downloaded for further investigation. We used the CellMiner web-server https://discover.nci.nih.gov/cellminercdb/ with the NC-60 and GDSC cancer cell line database to validate the cytotoxicity of FGFR inhibitor. RESULTS: FGFR1-3 alterations were found in 11% of queried patients of which 662 (∼6%), 360 (∼3%), 351 (∼3%) patients harbor FGFR1-3 alterations, respectively. Amplification was overwhelmed subtype (in 408 patients) of FGFR1 alteration (n=662), while in FGFR2 and FGFR3, these were mutations that correspond to appearance in 243/360 (67.5%) and 172/351 (49.0%) patients. Focus on FGFR2 mutant, the substitution of Serine by Tryptophan in codon 252 was a predominant mutation appearing in 26 patients. Similarly, it was S249C mutation in FGFR3 mutant with 41 patients. The most commonly affected cancers were Bladder Urothelial Carcinoma (31.87%); Endometrial Carcinoma (26.28%); Melanoma (19.59%), Non-Small Cell Lung Cancer (16.14%), and Invasive Breast Carcinoma 16.05%). Importantly, we performed the survival analysis of each FGFR alteration, FGFR1 alteration shows significant impact on PFS (p-value = 1.402e-3). Furthermore, Kaplan-Meier analysis pointed out that the alteration of FGFR3 indicated unfavorable PFS in non-small-cell lung carcinoma patients (p-value = 0.0109). The cytotoxicity of FGFRs inhibitors (ZD-4547) was found negatively correlated with FGFR1 and FGFR3 expression in endometrial carcinoma and ovary cancer (NC-60 database). Focus on the endometrial carcinoma cell lines of GDSC tested with PD173074 showed negative correlation between FGFR3 expression and response to PD173074. CONCLUSION: FGFR aberrations are common in a wide variety of cancers, with the majority being gene amplification or activating mutation. These data suggest that FGFR inhibition could be an important therapeutic option across multiple tumor types.