Abstract
Background: Fibroblast growth factor receptor 2 (FGFR2) is frequently altered in tumors and one of the top therapeutic targets in cholangiocarcinoma (CHOL) with FGFR2 fusions. Although there have been several studies on individual tumors, a comprehensive analysis of FGFR2 genetic aberrations and their simultaneous clinical implications across different tumors have not been reported.Methods: In this study, we used the large comprehensive datasets available, covering over 10,000 tumor samples across more than 30 cancer types, to analyze FGFR2 abnormal expression, methylation, alteration (mutations/fusions and amplification/deletion), and their clinical associations.Results: Alteration frequency, mutation location distribution, oncogenic effects, and therapeutic implications varied among different cancers. The overall mutation rate of FGFR2 is low in pancancer. CHOL had the highest mutation frequency, and fusion accounted for the major proportion. All these fusion aberrations in CHOL were targetable, and an FDA-approved drug was approved recently. Uterine corpus endometrial carcinoma (UCEC) had the highest number of FGFR2 mutations, and the most frequently mutated positions were S252W and N549K, where the functional impact was oncogenic, but targeted therapy was less effective. Additionally, DNA methylation was associated with FGFR2 expression in several cancers. Moreover, FGFG2 expression and genetic aberrations showed clinical associations with patient survival in several cancers, indicating their potential for application as new tumor markers and therapeutic targets.Conclusions: This study showed the full FGFR2 alteration spectrum and provided a broad molecular perspective of FGFR2 in a comprehensive manner, suggesting some new directions for clinical targeted therapy of cancers.
Highlights
The fibroblast growth factor receptor 2 (FGFR2) gene is located at chromosome 10q26 and encodes two major isoforms, FGFR2b and FGFR2c, which act as FGF receptors with different functional domains and ligand specificities [1,2,3,4]
Compared with the corresponding normal tissue, significantly differential expression was found in 13 cancer types, with four cancer types upregulated (lung squamous cell carcinoma (LUSC), stomach adenocarcinoma (STAD), testicular germ cell tumors (TGCT), and thymoma (THYM)) and nine cancer types downregulated (adrenocortical carcinoma (ACC), colon adenocarcinoma (COAD), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), skin cutaneous melanoma (SKCM), and uterine carcinosarcoma (UCS)) (Figure 1A)
We found that decreased FGFR2 expression was associated with short patient overall survival (OS) in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), EAC, head and neck squamous cell carcinoma (HNSC), KIRC, lung adenocarcinoma (LUAD), and LUSC, while increased FGFR2 expression was associated with short patient OS in KIRP (Figure 8A)
Summary
The fibroblast growth factor receptor 2 (FGFR2) gene is located at chromosome 10q26 and encodes two major isoforms, FGFR2b and FGFR2c, which act as FGF receptors with different functional domains and ligand specificities [1,2,3,4]. The FGFR2 protein belongs to a superfamily of four membrane-bound receptor tyrosine kinases (RTKs) [5,6,7,8], which includes FGFR1, FGFR2, FGFR3, and FGFR4 and exhibits biological activity by interacting with fibroblast growth factor (FGF) ligands [9]. Enhanced FGFR2 signaling, mediated by FGFR2 alterations containing genetic amplification, mutation, and fusion, has been observed in several cancers and is associated with tumorigenesis [6]. Frequent activating mutations of FGFR2 are discovered in 10% of bladder urothelial carcinomas (BLCAs) and UCECs. FGFR2 fusion aberrations are commonly observed in CHOL [15,16,17]. Fibroblast growth factor receptor 2 (FGFR2) is frequently altered in tumors and one of the top therapeutic targets in cholangiocarcinoma (CHOL) with FGFR2 fusions. There have been several studies on individual tumors, a comprehensive analysis of FGFR2 genetic aberrations and their simultaneous clinical implications across different tumors have not been reported
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