Poorly cohesive (PC) is a unique histologic subtype of gastric cancer (GC), with an increasing incidence in recent years. However, the molecular characteristics and therapeutic targets of PC GC are not yet well studied and there are no effective therapies for these patients. Formalin fixed paraffin embedded (FFPE) samples of 556 GC patients, including 64 PC GC, were collected for next-generation sequencing (NGS). Clinical characteristics and genomic profiling were analyzed. FGFR2 expression was detected by quantitative real time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). FGFR2 inhibitors response was studied in vitro. Among 556 GC patients, PC GC patients were younger (P = 0.004), had lower tumor mutation burden (TMB-L) (P = 0.001) than non-PC GC. The top 10 most frequently mutated genes in PC GC were TP53 (48%), CDH1 (31%), ARID1A (14%), FGFR2 (14%), ERBB2 (9%), CDKN2A (9%), FGF3 (8%), LRP1B (9%), FGF19 (8%) and FGF4 (8%). Noticeably, FGFR2 is more frequently mutated than non-PC GC (14% vs. 6%, P = 0.037), including copy number variants (CNVs, 12.5%) and gene rearrangements (3.1%, FGFR2/VTI1A and FGFR2/TACC2). Former studies have confirmed that gain of copy number could increase FGFR2 expression and sensitivity to FGFR2 inhibitors in GC. However, no research has verified the function of FGFR2 rearrangements in GC. Our results showed that cell lines of GC transfected with TACC2-FGFR2 fusion had increased mRNA and protein expression of FGFR2, and were more sensitive to FGFR2 inhibitors. FGFR2 inhibitors might be a new therapeutic target for PC GC. In addition, we found patients of PC GC harboring gene rearrangements (n = 9) had poorer overall survival (OS) in comparison with patients without any gene rearrangement (n = 19) (16.0 months vs 21.0 months, P = 0.043). Gene rearrangement might be an adverse prognostic factor for PC GC patients. FGFR2 alterations were recurrent in PC GC and FGFR2 inhibitors might be a new therapeutic target for PC GC.

中文翻译：

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FGFR2 改变作为低黏附性胃癌的潜在治疗靶点

内聚性差（PC）是胃癌（GC）的一种独特的组织学亚型，近年来发病率呈上升趋势。然而，PC GC 的分子特征和治疗靶点尚未得到很好的研究，也没有针对这些患者的有效治疗方法。收集了 556 名 GC 患者（包括 64 名 PC GC）的福尔马林固定石蜡包埋 (FFPE) 样本用于下一代测序 (NGS)。分析了临床特征和基因组谱。通过定量实时聚合酶链反应 (qRT-PCR) 和免疫组织化学 (IHC) 检测 FGFR2 表达。在体外研究了FGFR2抑制剂的反应。在 556 名 GC 患者中，PC GC 患者比非 PC GC 患者更年轻 (P = 0.004)，肿瘤突变负荷 (TMB-L) (P = 0.001) 较低。PC GC 中突变频率最高的 10 个基因是 TP53（48%），CDH1 (31%)、ARID1A (14%)、FGFR2 (14%)、ERBB2 (9%)、CDKN2A (9%)、FGF3 (8%)、LRP1B (9%)、FGF19 (8%) 和 FGF4 ( 8%）。值得注意的是，FGFR2 比非 PC GC 更频繁地发生突变（14% 对 6%，P = 0.037），包括拷贝数变异（CNV，12.5%）和基因重排（3.1%，FGFR2/VTI1A 和 FGFR2/TACC2） . 以前的研究已经证实，拷贝数的增加可以增加 GC 中 FGFR2 的表达和对 FGFR2 抑制剂的敏感性。然而，没有研究证实 FGFR2 重排在 GC 中的作用。我们的研究结果表明，转染 TACC2-FGFR2 融合物的 GC 细胞系增加了 FGFR2 的 mRNA 和蛋白表达，并且对 FGFR2 抑制剂更敏感。FGFR2 抑制剂可能是 PC GC 的新治疗靶点。此外，我们发现与没有任何基因重排的患者（n = 19）相比，携带基因重排的 PC GC 患者（n = 9）的总生存期（OS）较差（16.0 个月对 21.0 个月，P = 0.043）。基因重排可能是 PC GC 患者的不良预后因素。FGFR2 改变在 PC GC 中反复出现，FGFR2 抑制剂可能是 PC GC 的新治疗靶点。