Integrated Analysis of Structural Variation and RNA Expression of FGFR2 and Its Splicing Modulator ESRP1 Highlight the ESRP1amp-FGFR2norm-FGFR2-IIIchigh Axis in Diffuse Gastric Cancer

Abstract

Gastric Cancer (GC) is one of the most common and deadliest types of cancer in the world. To improve GC prognosis, increasing efforts are being made to develop new targeted therapies. Although FGFR2 genetic amplification and protein overexpression in GC have been targeted in clinical trials, so far no improvement in patient overall survival has been found. To address this issue, we studied genetic and epigenetic events affecting FGFR2 and its splicing regulator ESRP1 in GC that could be used as new therapeutic targets or predictive biomarkers. We performed copy number variation (CNV), DNA methylation, and RNA expression analyses of FGFR2/ESRP1 across several cohorts. We discovered that both genes were frequently amplified and demethylated in GC, resulting in increased ESRP1 expression and of a specific FGFR2 isoform: FGFR2-IIIb. We also showed that ESRP1 amplification in GC correlated with a significant decreased expression of FGFR2-IIIc, an alternative FGFR2 splicing isoform. Furthermore, when we performed a survival analysis, we observed that patients harboring diffuse-type tumors with low FGFR2-IIIc expression revealed a better overall survival than patients with FGFR2-IIIc high-expressing diffuse tumors. Our results encourage further studies on the role of ESRP1 in GC and support FGFR2-IIIc as a relevant biomarker in GC.

Clinical difference between fibroblast growth factor receptor 2 subclass, type IIIb and type IIIc, in gastric cancer

“…Since FGFR2 has two isoforms, IIIb type and IIIc type, it is important to examine the frequency of FGFR2-IIIc expression among FGFR2 overexpressing gastric cancers. However few reports of FGFR2 subclass of IIIb and IIIc expression are available in gastric cancer 36 . In this study, the overexpression of FGFR2IIIb was 4.9% and that of FGFR2IIIc was 0.7% in 562 gastric cancers.…”

“…There are a few reports of FGFR2IIIb and FGFR2IIIc expression in some other types of solid cancers including gastric carcinomas [36][37][38] . In this study, we conducted to examine the clinicopathologic significance of the expression of FGFR2IIIb and that of FGFR2IIIc using a large sample of gastric cancer.…”

Alternative Splicing, Epigenetic Modifications and Cancer: A Dangerous Triangle, or a Hopeful One?

“…In gastric cancer, an imbalance of the ratio of FGFR2-IIIb to FGFR2-IIIc of the gene encoding the fibroblast growth factor receptor 2 has been recently reported. This alteration in AS is concomitant to the promoter demethylation of FGFR2 and of ESRP1 [58]. The latter gene codes for the epithelial splicing regulatory protein 1, an RNA-binding protein that regulates AS related to epithelial phenotype.…”

Promises of Fibroblast Growth Factor Receptor–Directed Therapy in Tailored Cancer Treatment

“…For instance, epithelial splicing regulatory factor-1 ( ESRP1 ) was shown to promote the expression of the epithelial isoform of FGFR2, FGFR-2-IIIb (which binds specific ligands of the paracrine FGF family such as FGF-7 ), at the expense of the mesenchymal isoform FGFR-2-IIIc [ 3 , 15 ]. Both FGFR2 and ESRP1 are frequently amplified and demethylated in gastric cancer, hence leading to increased expression of ESRP1 and the FGFR isoform IIIb [ 16 ]. A class switch from FGFR-2-IIIb to FGFR-2-IIIc has been observed during the progression of prostate and bladder cancer, with FGFR-2-IIIc being associated with a more malignant phenotype [ 17 ].…”

“…A class switch from FGFR-2-IIIb to FGFR-2-IIIc has been observed during the progression of prostate and bladder cancer, with FGFR-2-IIIc being associated with a more malignant phenotype [ 17 ]. Interestingly, restoration of FGFR-2-IIIb in prostate cancer cells enhanced their sensitivity to radiation and chemotherapy, indicating that modulating alternative splicing may be a possible alternative to selectively target the FGFR–FGF pathway [ 16 ].…”