Abstract
BackgroundFibroblast (FGFs) and insulin (IGF) growth factor pathways are among 10 most recurrently altered genomic pathways in pancreatic ductal adenocarcinoma (PDAC). However, the prognostic and therapeutic relevance of FGF and IGF pathways in PDAC is largely unknown.MethodsWe investigated the relationship between fibroblast and insulin pathway gene expression and clinicopathological features in three independent transcriptomic cohorts of 532 PDAC patients. Furthermore, we have examined the coexpressed genes specific to the prognostic marker identified from these cohorts. Statistical tests including Fisher-exact\\Chi-square, Kaplan–Meier, Pearson Correlation and cox regression analyses were performed. Additionally, pathway analysis of gene-specific co-expressed genes was also performed.ResultsThe dysregulation of six genes including FGF9, FGF14, FGFR1, FGFR4, IGF2BP2 and IGF2BP3 were significantly associated with different clinical characteristics (including grade, stage, recurrence and nodes) in PDAC cohorts. 11 genes (including FGF9, FGF13, FGF14, FGF17, FGFR1, FGFRL1, FGFBP3, IGFBP3, IGF2BP2, IGF2BP3 and IGFBPL1) showed association with overall survival in different PDAC cohorts. Interestingly, overexpression of FGF14 was found associated with better overall survival (OS) in all three cohorts. Of note, multivariate analysis also revealed FGF14 as an independent prognostic marker for better OS in all three cohorts. Furthermore, FMN2 and PGR were among the top genes that correlated with FGF14 in all 3 cohorts. Of note, overexpression of FMN2 and PGR was found significantly associated with good overall survival in PDAC patients, suggesting FMN2 and PGR can also act as potential markers for the prediction of prognosis in PDAC patients.ConclusionFGF14 may define a distinct subset of PDAC patients with better prognosis. Moreover, FGF14-based sub-classification of PDAC suggests that FMN2 and PGR can be employed as good prognostic markers in PDAC and this classification may lead to new therapeutic approaches.
Highlights
Pancreatic adenocarcinoma (PDAC) is the fourth most fatal cancer with increasing mortality rate [1]
The dysregulation of six genes including FGF9, FGF14, FGFR1, FGFR4, IGF2BP2 and IGF2BP3 were significantly associated with different clinical characteristics in pancreatic ductal adenocarcinoma (PDAC) cohorts. 11 genes showed association with overall survival in different PDAC cohorts
FMN2 and PGR were among the top genes that correlated with FGF14 in all 3 cohorts
Summary
Pancreatic adenocarcinoma (PDAC) is the fourth most fatal cancer with increasing mortality rate [1]. PDAC imposes great mortality risk due to its rapid spread, poor prognosis, scarcity of available treatment options, late detection, invulnerability towards chemotherapy and lower overall survival rate [3]. The major non-genetic risk factors of PDAC are chronic pancreatitis, diabetes, and obesity [7]. Among all these risk factors, diabetes is the most prominent factor, as pancreatic cancer and diabetes both affect the same organ [8]. Fibroblast (FGFs) and insulin (IGF) growth factor pathways are among 10 most recurrently altered genomic pathways in pancreatic ductal adenocarcinoma (PDAC). The prognostic and therapeutic relevance of FGF and IGF pathways in PDAC is largely unknown
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