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Spatial analysis of hereditary diffuse gastric cancer reveals indolent phenotype of signet ring cell precursors

  1. Author:
    Gallanis, Amber F [ORCID]
    Gamble, Lauren A [ORCID]
    Oguz, Cihan [ORCID]
    Samaranayake, Sarah G [ORCID]
    Kedei, Noemi [ORCID]
    Hernandez, Maria O [ORCID]
    Wong, Madeline [ORCID]
    Tillo, Desiree [ORCID]
    Green, Benjamin L [ORCID]
    McClelland, Paul [ORCID]
    Bowden, Cassidy [ORCID]
    Gullo, Irene [ORCID]
    Raffeld, Mark [ORCID]
    Xi, Liqiang [ORCID]
    Kelly,Michael [ORCID]
    Miettinen, Markku [ORCID]
    Quezado, Martha [ORCID]
    Kim, Sun A [ORCID]
    Blakely, Andrew M [ORCID]
    Lack,Justin [ORCID]
    Heller, Theo [ORCID]
    Hernandez, Jonathan M [ORCID]
    Davis, Jeremy L [ORCID]

  2. Author Address

    National Institutes of Health Clinical Center, Bethesda, MD, United States., Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States., National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States., National Cancer Institute, Bethesda, MD, United States., National Cancer Institute, Bethesda, Maryland, United States., University of Porto, Portugal., NCI-Frederick, Bethesda, MD, United States., Frederick National Laboratory for Cancer Research, Frederick, MD, United States., National Institutes of Health, United States., University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States.,
    1. Year: 2025
    2. Date: Apr 07
    3. Epub Date: 2025 04 07
  2. Journal: Molecular Cancer Research : MCR
  4. Type of Article: Article
  1. Abstract:

    Germline CDH1 loss-of-function mutations are causally linked to an increased lifetime risk of diffuse gastric cancer (DGC). Early, multifocal signet ring cell (SRC) lesions are ubiquitous among CDH1 variant carriers, yet only a subset of patients will develop advanced DGC. A multi-omics analysis was performed to establish the molecular phenotype of early SRC lesions and how they differ from advanced DGC using 20 samples from human total gastrectomy specimens of germline CDH1 variant carriers. Spatial transcriptomic analysis demonstrated reduced CDH1 gene expression and increased expression of ECM remodeling in SRC lesions compared to unaffected adjacent gastric epithelium. Single cell RNA sequencing revealed an SRC-enriched signature with markers REG1A, VIM, AQP5, PRR4, MUC6, and AGR2. Importantly, SRC lesions lacked alterations in known drivers of gastric cancer (TP53, ARID1A, KRAS) and activation of associated signal transduction pathways. Advanced DGC demonstrated E-cadherin re-expression, somatic TP53 and ERBB3 mutations, and upregulated CTNNA1, MYC, and MET expression when compared to SRC lesions. Implications: The marked differences in genomic and transcriptomic profile of SRC lesions and advanced DGC support the consideration of SRC lesions as precancers in patients with germline CDH1 mutations.

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External Sources

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  2. DOI: 10.1158/1541-7786.MCR-24-1039
  3. PMID: 40192595
  4. PII : 755481

Library Notes

  1. Fiscal Year: FY2024-2025
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