Department of Gastrointestinal Surgery, Institute of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041, Chengdu, Sichuan, China.
Precision Medicine Center, State Key Laboratory of Biotherapy and Precision Medicine, Key Laboratory of Sichuan Province, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041, Chengdu, Sichuan, China.
Nat Commun. 2018 Jun 30;9(1):2447. doi: 10.1038/s41467-018-04907-0.
Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer, however, with no systematical investigation for prognostic genomic features. Here we report a systematic investigation conducted in 1868 Chinese gastric cancer patients indicating that signet-ring cells content was related to multiple clinical characteristics and treatment outcomes. We thus perform whole-genome sequencing on 32 pairs of SRC samples, and identify frequent CLDN18-ARHGAP26/6 fusion (25%). With 797 additional patients for validation, prevalence of CLDN18-ARHGAP26/6 fusion is noticed to be associated with signet-ring cell content, age at diagnosis, female/male ratio, and TNM stage. Importantly, patients with CLDN18-ARHGAP26/6 fusion have worse survival outcomes, and get no benefit from oxaliplatin/fluoropyrimidines-based chemotherapy, which is consistent with the fact of chemo-drug resistance acquired in CLDN18-ARHGAP26 introduced cell lines. Overall, this study provides insights into the clinical and genomic features of SRCC, and highlights the importance of frequent CLDN18-ARHGAP26/6 fusions in chemotherapy response for SRCC.
印戒细胞癌 (SRCC) 在胃癌中有其特定的流行病学和发生机制，但目前尚缺乏对其预后相关基因组特征的系统研究。本研究报告了对 1868 例中国胃癌患者进行的一项系统研究，结果表明印戒细胞含量与多种临床特征和治疗结果相关。因此，我们对 32 对 SR 样本进行了全基因组测序，发现了高频的 CLDN18-ARHGAP26/6 融合（25%）。在另外 797 例患者中进行验证，发现 CLDN18-ARHGAP26/6 融合的发生率与印戒细胞含量、诊断时的年龄、男女比例和 TNM 分期有关。重要的是，CLDN18-ARHGAP26/6 融合的患者生存预后较差，且不能从奥沙利铂/氟嘧啶类为基础的化疗中获益，这与 CLDN18-ARHGAP26 导入的细胞系中获得的化疗耐药事实一致。总之，本研究深入了解了 SRCC 的临床和基因组特征，并强调了 CLDN18-ARHGAP26/6 融合的高频发生在 SRCC 化疗反应中的重要性。
