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.
Highlights
Gastric Cancer (GC) remains one of the most common and deadliest types of cancer in the world [1]. GC incidence and mortality has decreased throughout the years and novel therapies have been developed, less than one fifth of advanced GC patients survive 5 years post disease diagnosis [2,3].Late diagnosis and high intra/inter-tumor heterogeneity likely explain this dismal prognosis and therapeutic failure [4]
We explored whether the FGFR2 promoter methylation status could further explain its overexpression in GC: we observed that most tumors displaying low levels of FGFR2 promoter methylation showed increased RNA expression than those with higher methylation levels
Our study provides the first in-depth analysis of copy number and promoter methylation as the mechanisms dysregulating the expression of total FGFR2, its splicing regulator ESRP1 and the
Summary
Gastric Cancer (GC) remains one of the most common and deadliest types of cancer in the world [1]. GC incidence and mortality has decreased throughout the years and novel therapies have been developed, less than one fifth of advanced GC patients survive 5 years post disease diagnosis [2,3].Late diagnosis and high intra/inter-tumor heterogeneity likely explain this dismal prognosis and therapeutic failure [4]. GC incidence and mortality has decreased throughout the years and novel therapies have been developed, less than one fifth of advanced GC patients survive 5 years post disease diagnosis [2,3]. Trastuzumab combined with chemotherapy is given to patients harboring HER2 overexpressing tumors, used as a predictive marker of therapy response, and extends median overall survival in. Many other therapies have been tested targeting multiple cancer-associated receptors/ligands but failed to provide any survival benefit [8,9,10,11,12]. Most of these therapies were tested without resourcing to predictive markers of therapeutic response, and this may justify their inefficiency. Understanding the molecular complexity of GC to identify valuable predictors of therapy response is urgent to decrease/delay mortality in this disease
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