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  3. Large-scale analysis of CDH1 mutations defines a distinctive molecular subset with treatment implications in gastric cancer

Large-scale analysis of CDH1 mutations defines a distinctive molecular subset with treatment implications in gastric cancer

  • NPJ Precis Oncol. 2024 Sep 30;8(1):214. doi: 10.1038/s41698-024-00694-8.
Jingyuan Wang 1 2 3,  Joanne Xiu 4,  Francesca Battaglin 2,  Hiroyuki Arai 2,  Shivani Soni 2,  Wu Zhang 2,  Richard M Goldberg 5,  Philip A Philip 6,  Andreas Seeber 7,  Jimmy J Hwang 8,  Anthony F Shields 6,  John L Marshall 9,  Igor Astaturov 10,  Tianshu Liu 1,  A Craig Lockhart 11,  W Michael Korn 4,  Lin Shen 1,  Heinz-Josef Lenz 12
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2 Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 3 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
  • 4 Caris Life Sciences, Phoenix, AZ, USA.
  • 5 West Virginia University Cancer Institute, Morgantown, WV, USA.
  • 6 Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
  • 7 Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
  • 8 Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA.
  • 9 Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
  • 10 Fox Chase Cancer Center, Philadelphia, PA, USA.
  • 11 University of Miami/Sylvester Comprehensive Cancer Center, Miami, FL, USA.
  • 12 Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Lenz@usc.edu.
PMID: 39349771 DOI: 10.1038/s41698-024-00694-8
Abstract

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.

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