TY - JOUR
T1 - Early detection of gastric cancer using global, genome-wide and IRF4, ELMO1, CLIP4 and MSC DNA methylation in endoscopic biopsies
AU - Pirini, Francesca
AU - Noazin, Sassan
AU - Jahuira-Arias, Martha H.
AU - Rodriguez-Torres, Sebastian
AU - Friess, Leah
AU - Michailidi, Christina
AU - Cok, Jaime
AU - Combe, Juan
AU - Vargas, Gloria
AU - Prado, William
AU - Soudry, Ethan
AU - Pérez, Jimena
AU - Yudin, Tikki
AU - Mancinelli, Andrea
AU - Unger, Helen
AU - Ili-Gangas, Carmen
AU - Brebi-Mieville, Priscilla
AU - Berg, Douglas E.
AU - Hayashi, Masamichi
AU - Sidransky, David
AU - Gilman, Robert H.
AU - Guerrero-Preston, Rafael
N1 - Funding Information:
This research was supported in part by National Cancer Institute grants K01-CA164092 and U01-CA84986; Proyecto de Atracción de Capital Humano-Modalidad de Estadía Corta-Comisión Nacional de Ciencia y Tecnología (CONICYT), Chile (RGP); FONDECYT No 11150802 and FONDECYT No 11150622; E. Soudry is recipient of a fellowship grant from the American Physicians Fellowship for Medicine in Israel. Dr. Berg is supported by grants R21 AI078237 and R21 AI088337 from the US National Institute of Health.
Publisher Copyright:
© Pirini et al.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - ELMO1
KW - Epigenome-wide DNA methylation analysis
KW - Global DNA methylation index
KW - IRF4
KW - Translational epigenomics
UR - http://www.scopus.com/inward/record.url?scp=85020693441&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85020693441&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.16258
DO - 10.18632/oncotarget.16258
M3 - Article
C2 - 28418867
AN - SCOPUS:85020693441
SN - 1949-2553
VL - 8
SP - 38501
EP - 38516
JO - Oncotarget
JF - Oncotarget
IS - 24
ER -