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

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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Publication Details

Journal
npj Precision Oncology
Published
2024-09-30
DOI
https://doi.org/10.1038/s41698-024-00694-8
Citations
5
Primary Topic
Peptidase Inhibition and Analysis
Type
article
Field-Weighted Citation Impact
1.41

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article

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

Jingyuan Wang, Francesca Battaglin, W. Michael Korn, Shivani Soni et al.
5 citations
npj Precision Oncology
Peptidase Inhibition and Analysis
1.41
article

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

Jingyuan Wang, Francesca Battaglin, W. Michael Korn, Shivani Soni, Hiroyuki Arai, Heinz‐Josef Lenz, John L. Marshall, A. Craig Lockhart, Anthony F. Shields, Lin Shen, Joanne Xiu, Richard M. Goldberg, Andreas Seeber, Tianshu Liu, Wu Zhang, Jimmy J. Hwang, P. A. Philip, Igor Astaturov
article en
5 citations

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.

npj Precision OncologyVol. 8(1)
University of Southern California (US), West Virginia University (US), Fox Chase Cancer Center (US), Carolinas Healthcare System (US), Innsbruck Medical University (AT), University of Miami (US), Georgetown University (US), Wayne State University (US), Universität Innsbruck (AT), Peking University (CN), Fudan University (CN), Georgetown University Medical Center (US), The Barbara Ann Karmanos Cancer Institute (US), Peking University Cancer Hospital (CN), Levine Cancer Institute (US), USC Norris Comprehensive Cancer Center (US), Zhongshan Hospital (CN), Caris Life Sciences (United States) (US), Sylvester Comprehensive Cancer Center (US)
Dhont Family Foundation, National Natural Science Foundation of China, China Postdoctoral Science Foundation, National Institutes of Health, University of California, Los Angeles, National Postdoctoral Program for Innovative Talents, National Cancer Institute
No poverty
Openalex Percentile: Top 15%
Peptidase Inhibition and Analysis
1.41
DOIOpen Access PDFOpenAlex
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