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

Autor: Wang J; 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.; 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., Xiu J; Caris Life Sciences, Phoenix, AZ, USA., Battaglin F; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Arai H; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Soni S; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Zhang W; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Goldberg RM; West Virginia University Cancer Institute, Morgantown, WV, USA., Philip PA; Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA., Seeber A; Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria., Hwang JJ; Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA., Shields AF; Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA., Marshall JL; Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA., Astaturov I; Fox Chase Cancer Center, Philadelphia, PA, USA., Liu T; Department of Medical Oncology, Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China., Lockhart AC; University of Miami/Sylvester Comprehensive Cancer Center, Miami, FL, USA., Korn WM; Caris Life Sciences, Phoenix, AZ, USA., Shen L; Department of Medical Oncology, Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China., Lenz HJ; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Lenz@usc.edu.
Jazyk: angličtina
Zdroj: NPJ precision oncology [NPJ Precis Oncol] 2024 Sep 30; Vol. 8 (1), pp. 214. Date of Electronic Publication: 2024 Sep 30.
DOI: 10.1038/s41698-024-00694-8
Abstrakt: 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.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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