Early Immune Changes Support Signet Ring Cell Dormancy in CDH1-Driven Hereditary Diffuse Gastric Carcinogenesis.

Autor:	Green BL; Surgical Oncology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Gamble LA; Surgical Oncology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Diggs LP; Surgical Oncology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Nousome D; Biomedical Informatics and Data Science, Frederick National Laboratory for Cancer Research, NCI, NIH, Frederick, Maryland., Patterson JC; Koch Institute for Integrative Cancer Research, MIT Center for Precision Cancer Medicine, Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, Maryland., Joughin BA; Koch Institute for Integrative Cancer Research, MIT Center for Precision Cancer Medicine, Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, Maryland., Gasmi B; Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Lux SC; Surgical Oncology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Samaranayake SG; Surgical Oncology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Miettinen M; Laboratory of Pathology, NCI, NIH, Bethesda, Maryland., Quezado M; Laboratory of Pathology, NCI, NIH, Bethesda, Maryland., Hernandez JM; Surgical Oncology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Yaffe MB; Surgical Oncology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.; Koch Institute for Integrative Cancer Research, MIT Center for Precision Cancer Medicine, Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, Maryland., Davis JL; Surgical Oncology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2023 Dec 01; Vol. 21 (12), pp. 1356-1365.
DOI:	10.1158/1541-7786.MCR-23-0122
Abstrakt:	Stage IA gastric adenocarcinoma, characterized by foci of intramucosal signet ring cells (SRC), is found in nearly all asymptomatic patients with germline pathogenic CDH1 variants and hereditary diffuse gastric cancer syndrome (HDGC). The molecular steps involved in initiating malignant transformation and promoting SRC dormancy in HDGC are unknown. Here, whole-exome bulk RNA sequencing (RNA-seq) of SRCs and adjacent non-SRC epithelium (NEP) was performed on laser-capture microdissected (LCM) regions of interest found in risk-reducing total gastrectomy specimens from patients with HDGC (Clinicaltrials.gov ID: NCT03030404). In total, 20 patients (6 male, 14 female) with confirmed HDGC were identified. Analysis of differentially expressed genes (DEG) demonstrated upregulation of certain individual EMT and proliferation genes. However, no oncogenic pathways were found to be upregulated in SRCs. Rather, SRC regions had significant enrichment in pathways involved in T-cell signaling. CIBERSORTx predicted significant increases in the presence of regulatory T cells (Treg) specific to SRC regions. IHC confirmed an increase in FOXP3+ cells in SRC foci, as well as elevations in CD4+ T cells and HLA-DR staining. In summary, the tumor immune microenvironment is microscopically inseparable from stage IA gastric SRCs using a granular isolation technique. An elevation in CD4+ T cells within SRC regions correlates with clinically observed SRC dormancy, while Treg upregulation represents a potential immune escape mechanism. Implications: Characterization of the tumor-immune microenvironment in HDGC underscores the potential for the immune system to shape the transcriptional profile of the earliest tumors, which suggests immune-directed therapy as a potential cancer interception strategy in diffuse-type gastric cancer. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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