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

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  • 1 University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam

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.

Corresponding Author: Pham Quoc Thang, PhD, MD