National Cancer Center, Goyang, Gyeonggi, 10408, Republic of Korea.
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Nat Commun. 2018 Oct 25;9(1):4439. doi: 10.1038/s41467-018-06747-4.
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.
我们进行了一项 RNA 测序研究，以鉴定 80 个来自年轻弥漫性胃癌 (DGC) 患者的发现数据集肿瘤中的新基因融合。25 个框内融合与 DGC 相关，其中 3 个（CLDN18-ARHGAP26、CTNND1-ARHGAP26 和 ANXA2-MYO9A）基于 RT-PCR 在 384 个 DGC 中反复出现。所有三个融合在其 3' 伙伴基因中都含有 RhoGAP 结构域。这些融合之一的患者预后明显比没有融合的患者差。CLDN18-ARHGAP26 的异位表达促进了 DGC 细胞的迁移和侵袭能力。平行靶向 RNA 测序分析还鉴定出 TACC2-PPAPDC1A 是一种反复出现的不良预后框内融合。总体而言，PPAPDC1A 融合和含有 RhoGAP 结构域的框内融合清楚地定义了 DGC 的侵袭性亚组（7.5%），其预后影响大于且独立于染色体不稳定性和 CDH1 突变。我们的研究可能为指导未来 DGC 管理策略提供新的基因组见解。
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