Abstract
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.
Highlights
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)
To identify somatic alterations in transcriptomic profiles in earlyonset DGC, we performed RNA sequencing on DGCs collected from 80 young ( ≤ 45 years) Korean patients who had not been treated with chemotherapy or radiation[15]
Given that poorly cohesive cell growth is characteristic of DGC, these findings collectively suggest that relatively high prevalence of the CLDN18-ARHGAP26 fusion in young DGC patients underlies the strong enrichment of diffuse histology observed in early-onset gastric cancer
Summary
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). Palanisamy et al reported that a gastric cancer expresses the AGTRAP-BRAF fusion containing the C-terminal kinase domain of BRAF (7q34) fused to the N-terminal angiotensin II type 1 receptor-associated domain of AGTRAP (1p36)[6]. Except for the CLDN18-ARHGAP fusions[9], these in-frame gene fusions have not been validated by subsequent gastric cancer publications. Despite a trend for the prevalence of gene fusions in young cancer patients, no studies have systematically investigated novel fusions in young patients with DGCs due to the relative rarity of early-onset gastric cancer, which is notable for its strong enrichment of diffuse histology. CDH1 and RHOA mutations underlie unique phenotypes of DGC, such as poorly cohesive growth, but there is a subset of DGCs that are wild-type for CDH1 and RHOA15
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