Wang Jingyuan, Xiu Joanne, Battaglin Francesca, Arai Hiroyuki, Soni Shivani, Zhang Wu, Goldberg Richard M, Philip Philip A, Seeber Andreas, Hwang Jimmy J, Shields Anthony F, Marshall John L, Astaturov Igor, Liu Tianshu, Lockhart A Craig, Korn W Michael, Shen Lin, Lenz Heinz-Josef
Department of Medical Oncology, Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
NPJ Precis Oncol. 2024 Sep 30;8(1):214. doi: 10.1038/s41698-024-00694-8.
Although histological and molecular classifications have been extensively studied for gastric cancer (GC), targeted therapies for GC remain limited. CDH1 mutations (MT) are characteristic of genomically stable GC and are associated with poor prognosis, but lack effective or targeted therapies. Here, we showed the overall mutation frequency of CDH1 was 9.7% (155 of 1596). CDH1-MT GC showed significantly lower rates of PD-L1 positivity (CPS score ≥1) than CDH1-wildtype (WT) GC (56.7% vs. 73.3%, p < 0.05). Compared to CDH1-WT GC, mutations of ARID1A, WRN, POT1, CDK12, and FANCC were significantly higher, while TP53 and APC were significantly lower in CDH1-MT GC (p < 0.05); The rates of KRAS and HER2 amplifications were significantly lower, while CRKL and IGF1R amplifications were significantly higher in CDH1-MT GC, compared to CDH1-WT GC (p < 0.05). Frequently altered genes in CDH1-MT GC were especially enriched in DNA damage repair and cell cycle checkpoint pathways. Inhibition of E-cadherin sensitized GC cell lines to PARP and Wee1 inhibitors by disrupting DNA damage repair pathway and cell cycle checkpoint. This is the largest study to investigate the distinct genomic landscape of CDH1-MT GC. Our data indicated GC patients with CDH1 mutations could potentially benefit from agents targeting PARP and Wee1.
尽管针对胃癌（GC）的组织学和分子分类已得到广泛研究，但GC的靶向治疗仍然有限。CDH1突变（MT）是基因组稳定型GC的特征，与预后不良相关，但缺乏有效的或靶向治疗方法。在此，我们发现CDH1的总体突变频率为9.7%（1596例中的155例）。与CDH1野生型（WT）GC相比，CDH1-MT GC的PD-L1阳性率（CPS评分≥1）显著更低（56.7%对73.3%，p<0.05）。与CDH1-WT GC相比，CDH1-MT GC中ARID1A、WRN、POT1、CDK12和FANCC的突变显著更高，而TP53和APC的突变显著更低（p<0.05）；与CDH1-WT GC相比，CDH1-MT GC中KRAS和HER2扩增率显著更低，而CRKL和IGF1R扩增率显著更高（p<0.05）。CDH1-MT GC中频繁改变的基因尤其富集于DNA损伤修复和细胞周期检查点通路。抑制E-钙黏蛋白通过破坏DNA损伤修复通路和细胞周期检查点使GC细胞系对PARP和Wee1抑制剂敏感。这是研究CDH1-MT GC独特基因组格局的最大规模研究。我们的数据表明，携带CDH1突变的GC患者可能从靶向PARP和Wee1的药物中获益。
