title: Epigenetic changes in localized gastric cancer: the role of RUNX3 in tumor progression and the immune microenvironment.
abstract: Gastric cancer (GC) pathogenesis involves genetic, epigenetic and environmental factors. Epigenetic alterations, such as DNA methylation are considered pivotal in the inactivation of tumor-related genes. We assessed a methylation panel of 5 genes to study their association to GC progression and microsatellite instability (MSI), and studied the role of RUNX3 in GC pathogenesis and the tumor immune microenvironment.The methylation status of 47 promoter-CpG islands was studied through MALDI-TOF mass spectrometry analysis in 35 Microsatellite stable (MSS) GC, 26 MSI, and 18 cancer-free samples (CFS), and 6 MSS GC and 4 MSI GC cell lines. We also studied RUNX3 expression by immunohistochemistry (IHC) in 40 samples, and validated differences in methylation levels between tumor, normal, and immune tissue in 14 additional samples.Unsupervised hierarchical clustering of methylation levels revealed no distinct subgroups between MSI and MSS samples or cell lines. CFSs clustered together showing higher levels of RUNX3 methylation compared to GC samples. RUNX3 showed protein silencing in cancer and normal mucosa, compared to inflammatory peritumoural infiltrate in almost all cases, showing a non-lymphocytic predominant pattern and being correlated with epigenetic silencing.Our results show aberrant promoter's methylation in APC, CDH1, CDKN2A, MLH1 and RUNX3 associated with GC, as well as a non-lymphocytic predominant infiltrate with high expression of RUNX3. Deep study of RUNX3 inflammation signaling could help in understanding inflammation and immune activation in the tumor microenvironment.
authors: Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors: Marta Jessica
authors: MJ
authors: Llorca-Cardeñosa
authors: Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors: Tania
authors: T
authors: Fleitas
authors: Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors: Maider
authors: M
authors: Ibarrola-Villava
authors: Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors: María
authors: M
authors: Peña-Chilet
authors: Department of Pathology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors: Cristina
authors: C
authors: Mongort
authors: Department of Pathology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors: Carolina
authors: C
authors: Martinez-Ciarpaglini
authors: Department of Pathology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors: Lara
authors: L
authors: Navarro
authors: Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors: Valentina
authors: V
authors: Gambardella
authors: Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors: Josefa
authors: J
authors: Castillo
authors: Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors: Susana
authors: S
authors: Roselló
authors: Department of Pathology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors: Samuel
authors: S
authors: Navarro
authors: Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors: Gloria
authors: G
authors: Ribas
authors: Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors: Andrés
authors: A
authors: Cervantes
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015996:Survival Rate; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D014408:Biomarkers, Tumor; D050677:Core Binding Factor Alpha 3 Subunit; C493729:Runx3 protein, human
keywords: ARID1A; RUNX3; gastric cancer; gene methylation; immune microenvironment