高表达的Claudin18.2作为晚期胃印戒细胞癌（SRCC）的潜在治疗靶点。
Highly expressed Claudin18.2 as a potential therapeutic target in advanced gastric signet-ring cell carcinoma (SRCC).
作者信息
Xu Bo, Liu Fangcen, Liu Qin, Shi Tao, Wang Zhongda, Wu Nandie, Xu Xinyun, Li Lin, Fan Xiangshan, Yu Lixia, Liu Baorui, Wei Jia
机构信息
The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.
The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China.
出版信息
J Gastrointest Oncol. 2020 Dec;11(6):1431-1439. doi: 10.21037/jgo-20-344.
BACKGROUND
Advanced gastric signet-ring cell carcinoma (SRCC) is a specific type of malignant gastric cancer (GC) with distinct poorer survival. Claudin18.2 (CLDN18.2) is a promising neo-biomarker for the treatment of GC. Clinical trials of CLDN18.2-targeted antibody and T cell-based immunotherapy providing promising prospects for the treatment of GC. The effect of antibody therapy depended on the expression rate of CLDN18.2 has been found in clinical trials. This study aimed to determine the prevalence and the therapeutic value of CLDN18.2 in advanced gastric SRCC.
METHODS
Expression of CLDN18.2 in 105 formalin-fixed, paraffin-embedded (FFPE) tumor tissues was detected by immunohistochemistry (IHC) and evaluated according to FAST criteria. Next-generation sequencing (NGS) using 416 pan-cancer genes panel was performed to characterize the genomic landscape in 61 advanced gastric SRCC patients. Fisher's exact test was used to determine gene differences in different CLDN18.2 expression levels.
RESULTS
A total number of 105 advanced gastric SRCC samples were analyzed, of which 95.2% (100/105) were positive stained. Moderate-to-strong CLDN18.2 expression was observed in 64.8% (68/105) of all samples. In particularly, 21.0% (22/105) samples had positive staining in more than 90% tumor cells. No significance was found between CLDN18.2 expression and overall survival (OS). NGS results showed that single nucleotide variations (SNVs) could be frequently found in TP53 (26.2%), CDH1 (19.7%), MED12 (18.0%), PKHD1 (18.0%) and ARID1A (11.5%), besides, copy number variations (CNVs) were rich in NOTCH1 (18.0%) and FLT4 (9.8%) in SRCC samples. Moreover, SNVs in GRIN2A was found in 20% of the patients who had CLDN18.2 staining in <40% of tumor cells (P=0.043), indicating CLDN18.2 expression might be related to the aberration of GRIN2A in advanced gastric SRCC.
CONCLUSIONS
The highly expressed CLDN18.2 among advanced gastric SRCC patients that we found certified the value of CLDN18.2-targeted therapy in this specific type of GC. In addition, Analyses between CLDN18.2 expression and genetic abnormalities provided novel therapeutic options for advanced gastric SRCC.
背景
晚期胃印戒细胞癌（SRCC）是一种特殊类型的恶性胃癌（GC），其生存率明显更低。Claudin18.2（CLDN18.2）是一种有前景的用于GC治疗的新型生物标志物。针对CLDN18.2的抗体和基于T细胞的免疫疗法的临床试验为GC治疗提供了有前景的前景。在临床试验中已发现抗体疗法的效果取决于CLDN18.2的表达率。本研究旨在确定CLDN18.2在晚期胃SRCC中的患病率及其治疗价值。
方法
通过免疫组织化学（IHC）检测105例福尔马林固定、石蜡包埋（FFPE）肿瘤组织中CLDN18.2的表达，并根据FAST标准进行评估。使用416个泛癌基因面板进行下一代测序（NGS），以表征61例晚期胃SRCC患者的基因组图谱。采用Fisher精确检验确定不同CLDN18.2表达水平的基因差异。
结果
共分析了105例晚期胃SRCC样本，其中95.2%（100/105）呈阳性染色。在所有样本中，64.8%（68/105）观察到中度至强CLDN18.2表达。特别是，21.0%（22/105）的样本在超过90%的肿瘤细胞中呈阳性染色。CLDN18.2表达与总生存期（OS）之间未发现显著差异。NGS结果显示，除了SRCC样本中NOTCH1（18.0%）和FLT4（9.8%）存在丰富的拷贝数变异（CNV）外，单核苷酸变异（SNV）在TP53（26.2%）、CDH1（19.7%）、MED12（18.0%）、PKHD1（18.0%）和ARID1A（11.5%）中也经常出现。此外，在肿瘤细胞CLDN18.2染色<40%的患者中，20%发现GRIN2A存在SNV（P=0.043），表明CLDN18.2表达可能与晚期胃SRCC中GRIN2A的畸变有关。
结论
我们发现晚期胃SRCC患者中CLDN18.2高表达证实了CLDN18.2靶向治疗在这种特定类型GC中的价值。此外，CLDN18.2表达与基因异常之间的分析为晚期胃SRCC提供了新的治疗选择。
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