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

Hanna Yang, Dongwan Hong, Soo Young Cho, Young Soo Park, Woo Ri Ko, Ju Hee Kim, Hoon Hur, Jongkeun Lee, Su-Jin Kim, Sun Young Kwon, Jae-Hyuk Lee, Do Youn Park, Kyu Sang Song, Heekyung Chang, Min-Hee Ryu, Kye Soo Cho, Jeong Won Kang, Myeong-Cherl Kook, Nina Thiessen, An He, Andy Mungall, Sang-Uk Han () and Hark Kyun Kim ()
Additional contact information
Hanna Yang: National Cancer Center
Dongwan Hong: National Cancer Center
Soo Young Cho: National Cancer Center
Young Soo Park: University of Ulsan College of Medicine
Woo Ri Ko: National Cancer Center
Ju Hee Kim: National Cancer Center
Hoon Hur: Ajou University School of Medicine
Jongkeun Lee: National Cancer Center
Su-Jin Kim: Dong-A University College of Medicine
Sun Young Kwon: Keimyung University School of Medicine
Jae-Hyuk Lee: Chonnam National University Medical School
Do Youn Park: Pusan National University Hospital and Pusan National University School of Medicine
Kyu Sang Song: Chungnam National University
Heekyung Chang: Kosin University College of Medicine
Min-Hee Ryu: University of Ulsan College of Medicine
Kye Soo Cho: National Cancer Center
Jeong Won Kang: National Cancer Center
Myeong-Cherl Kook: National Cancer Center
Nina Thiessen: British Columbia Cancer Agency
An He: British Columbia Cancer Agency
Andy Mungall: British Columbia Cancer Agency
Sang-Uk Han: Ajou University School of Medicine
Hark Kyun Kim: National Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06747-4

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