The Genomic Microenvironment of Gastric Cancers with Over-Expression of FGFR2 Reveals Pathogenic Diversity and Suggests Therapeutic Avenues

Abstract Background Gastric cancer is an aggressive malignancy and invariably fatal when advanced. Few options are available for metastatic gastric cancer patients and survival benefits are usually small. Targeted therapies offer hope for improved outcomes. FGFR2b, a cell surface receptor of the receptor tyrosine kinase super-family is often expressed in gastric cancers and has been targeted with a newly introduced monoclonal antibody drug. Methods Gastric cancers with over-expression of FGFR2 mRNA were identified in the cohort of gastric cancers from The Cancer Genome Atlas (TCGA). Over-expression was defined as an mRNA expression z score above 1 compared with all samples. The two groups with and without over-expression of FGFR2 were compared for clinical, pathologic and genomic differences. Results The two groups of gastric cancers with and without over-expression of FGFR2 displayed no significant clinical and pathologic differences but showed noteworthy differences in the prevalence of mutations in frequently mutated and copy number altered genes in gastric cancer including ARID1A , and CDH1 mutations, which were more prevalent in FGFR2 over-expressing gastric cancers and KRAS mutations and ERBB2 amplifications, which were more prevalent in FGFR2 not over-expressing cancers. Moreover, FGFR2 over-expressing cancers maintained expression of SOX2 and showed no up-regulation of the gastric intestinal metaplasia network transcription factors. Conclusion Discovered differences in critical gastric cancer networks between FGFR2 over-expressing and not over-expressing gastric cancers suggest diverse pathogenic pathways and differences in the gastric intestinal metaplasia process. These differences may guide personalized therapeutic approaches.