Jaime Cok, Rafael Guerrero-Preston, Juan M. Combe, Andrea Mancinelli, Francesca Pirini, Masamichi Hayashi, Tikki Yudin, William Prado, David Sidransky, Martha H. Jahuira-Arias, Helen Unger, Sassan Noazin, Sebastian Rodriguez-Torres, Christina Michailidi, Gloria Vargas, Jimena Perez, Ethan Soudry, Douglas E. Berg, Robert H. Gilman, Priscilla Brebi-Mieville, Carmen Ili-Gangas, and Leah Friess
// Francesca Pirini 1, * , Sassan Noazin 2, * , Martha H. Jahuira-Arias 3, 4, * , Sebastian Rodriguez-Torres 3 , Leah Friess 3 , Christina Michailidi 3 , Jaime Cok 5 , Juan Combe 6 , Gloria Vargas 7 , William Prado 8 , Ethan Soudry 3 , Jimena Perez 3 , Tikki Yudin 3 , Andrea Mancinelli 3 , Helen Unger 3 , Carmen Ili-Gangas 9, 10 , Priscilla Brebi-Mieville 9, 10 , Douglas E. Berg 11, 12 , Masamichi Hayashi 3, 13 , David Sidransky 3 , Robert H. Gilman 2, 4 , Rafael Guerrero-Preston 3, 14 1 Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 2 The Johns Hopkins University, Bloomberg School of Public Health, Department of International Health, Baltimore, MD, USA 3 The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA 4 Universidad Peruana Cayetano Heredia, Lima, Peru 5 Hospital Nacional Cayetano Heredia, Pathology Department, Lima, Peru 6 Instituto Nacional de Enfermedades Neoplasicas, Gastroenterology Department, Lima, Peru 7 Hospital Nacional Arzobispo Loayza, Gastroenterology Department, Lima, Peru 8 Hospital Nacional Dos de Mayo, Gastroenterology Department, Lima, Peru 9 Laboratory of Molecular Pathology, Department of Pathological Anatomy, School of Medicine, Universidad de La Frontera, Temuco, Chile 10 Center of Excellence in Translational Medicine - Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Temuco, Chile 11 Washington University Medical School, Department of Molecular Microbiology, St Louis, MO, USA 12 University of California San Diego, Department of Medicine, La Jolla, CA, USA 13 Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan 14 University of Puerto Rico School of Medicine, Department of Obstetrics and Gynecology, San Juan, Puerto Rico * These authors equally contributed to this work Correspondence to: Rafael Guerrero-Preston, email: rafael.guerrero@upr.edu Robert H. Gilman, email: rgilman1@jhmi.edu Keywords: translational epigenomics, global DNA methylation index, epigenome-wide DNA methylation analysis, IRF4, ELMO1 Received: January 09, 2017 Accepted: February 24, 2017 Published: March 16, 2017 ABSTRACT Clinically useful molecular tools to triage gastric cancer patients are not currently available. We aimed to develop a molecular tool to predict gastric cancer risk in endoscopy-driven biopsies obtained from high-risk gastric cancer clinics in low resource settings. We discovered and validated a DNA methylation biomarker panel in endoscopic samples obtained from 362 patients seen between 2004 and 2009 in three high-risk gastric cancer clinics in Lima, Peru, and validated it in 306 samples from the Cancer Genome Atlas project (“TCGA”). Global, epigenome wide and gene-specific DNA methylation analyses were used in a Phase I Biomarker Development Trial to identify a continuous biomarker panel that combines a Global DNA Methylation Index (GDMI) and promoter DNA methylation levels of IRF4, ELMO1, CLIP4 and MSC . We observed an inverse association between the GDMI and histological progression to gastric cancer, when comparing gastritis patients without metaplasia (mean = 5.74, 95% CI, 4.97−6.50), gastritis patients with metaplasia (mean = 4.81, 95% CI, 3.77−5.84), and gastric cancer cases (mean = 3.38, 95% CI, 2.82−3.94), respectively ( p 4 are useful molecular tools for gastric cancer risk stratification in endoscopic biopsies.