Early detection of gastric cancer using global, genome-wide and IRF4, ELMO1, CLIP4 and MSC DNA methylation in endoscopic biopsies
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Francesca Pirini1,*, Sassan Noazin2,*, Martha H. Jahuira-Arias3,4,*, Sebastian Rodriguez-Torres3, Leah Friess3, Christina Michailidi3, Jaime Cok5, Juan Combe6, Gloria Vargas7, William Prado8, Ethan Soudry3, Jimena Pérez3, Tikki Yudin3, Andrea Mancinelli3, Helen Unger3, Carmen Ili-Gangas9,10, Priscilla Brebi-Mieville9,10, Douglas E. Berg11,12, Masamichi Hayashi3,13, David Sidransky3, Robert H. Gilman2,4, Rafael Guerrero-Preston3,14
1Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
2The Johns Hopkins University, Bloomberg School of Public Health, Department of International Health, Baltimore, MD, USA
3The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA
4Universidad Peruana Cayetano Heredia, Lima, Perú
5Hospital Nacional Cayetano Heredia, Pathology Department, Lima, Perú
6Instituto Nacional de Enfermedades Neoplásicas, Gastroenterology Department, Lima, Perú
7Hospital Nacional Arzobispo Loayza, Gastroenterology Department, Lima, Perú
8Hospital Nacional Dos de Mayo, Gastroenterology Department, Lima, Perú
9Laboratory of Molecular Pathology, Department of Pathological Anatomy, School of Medicine, Universidad de La Frontera, Temuco, Chile
10Center of Excellence in Translational Medicine - Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Temuco, Chile
11Washington University Medical School, Department of Molecular Microbiology, St Louis, MO, USA
12University of California San Diego, Department of Medicine, La Jolla, CA, USA
13Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
14University of Puerto Rico School of Medicine, Department of Obstetrics and Gynecology, San Juan, Puerto Rico
*These authors equally contributed to this work
Rafael Guerrero-Preston, email: firstname.lastname@example.org
Robert H. Gilman, email: email@example.com
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
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, Perú, 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 < 0.0001). Promoter methylation of IRF4 (p < 0.0001), ELMO1 (p < 0.0001), CLIP4 (p < 0.0001), and MSC (p < 0.0001), is also associated with increasing severity from gastritis with no metaplasia to gastritis with metaplasia and gastric cancer.
Our findings suggest that IRF4, ELMO1, CLIP4 and MSC promoter methylation coupled with a GDMI>4 are useful molecular tools for gastric cancer risk stratification in endoscopic biopsies.
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