Epigenetic changes in localized gastric cancer: the role of RUNX3 in tumor progression and the immune microenvironment
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Marta Jessica Llorca-Cardeñosa1,*, Tania Fleitas1,*, Maider Ibarrola-Villava1, María Peña-Chilet1, Cristina Mongort2, Carolina Martinez-Ciarpaglini2, Lara Navarro2, Valentina Gambardella1, Josefa Castillo1, Susana Roselló1, Samuel Navarro2, Gloria Ribas1, Andrés Cervantes1
1Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain
2Department of Pathology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain
*These authors contributed equally to this work
Gloria Ribas, email: [email protected]
Andrés Cervantes, email: [email protected]
Keywords: RUNX3, ARID1A, gastric cancer, gene methylation, immune microenvironment
Received: June 16, 2016 Accepted: August 15, 2016 Published: August 23, 2016
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.
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