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We conducted an RNA sequencing study to identify novel gene fusions in 80 discovery dataset tumors collected from young patients with diffuse gastric cancer (DGC). Twenty-five in-frame fusions are associated with DGC, three of which ( CLDN18-ARHGAP26, CTNND1-ARHGAP26 , and  ANXA2-MYO9A ) are recurrent in 384 DGCs based on RT-PCR. All three fusions contain a RhoGAP domain in their 3’ partner genes. Patients with one of these three fusions have a significantly worse prognosis than those without. Ectopic expression of  CLDN18-ARHGAP26  promotes the migration and invasion capacities of DGC cells. Parallel targeted RNA sequencing analysis additionally identifies  TACC2-PPAPDC1A  as a recurrent and poor prognostic in-frame fusion. Overall,  PPAPDC1A  fusions and in-frame fusions containing a RhoGAP domain clearly define the aggressive subset (7.5%) of DGCs, and their prognostic impact is greater than, and independent of, chromosomal instability and  CDH1  mutations. Our study may provide novel genomic insights guiding future strategies for managing DGCs.

RhoGAP domain-containing fusions and PPAPDC1A fusions are recurrent and prognostic in diffuse gastric cancer