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, 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.
Highlights
Gastric cancer (GC) is the fifth most common cancer in both sexes and the third cause of cancer-related death around the world [1]
Our findings suggest that IRF4, Engulfment and cell motility 1 (ELMO1), Containing Linker Protein Family Member 4 (CLIP4) and MSC promoter methylation coupled with a Global DNA Methylation Index (GDMI)>4 are useful molecular tools for gastric cancer risk stratification in endoscopic biopsies
We performed epigenome-wide DNA methylation analysis of 30 patients selected from the Discovery cohort and Validated the epigenome-wide DNA methylation results from Peru using data from 316 participants in the Cancer Genome Atlas project (Supplementary Figure 1B)
Summary
Gastric cancer (GC) is the fifth most common cancer in both sexes and the third cause of cancer-related death around the world [1]. Chronic infection of the stomach by the bacterium Helicobacter pylori leading to chronic inflammation is a major attributable risk factor [2], less than 2% of H. pylori carriers develop gastric cancer [3]. The prognosis of GC is closely related to the stage of disease at the time of diagnosis [4, 5]. GC is defined as cancer confined to the mucosa or submucosa regardless of the presence of lymph node metastasis [9], but due to the non specific symptomatology and to the difficulty in distinguishing early GC from benign peptic ulcer or gastritis in the ambulatory setting, less than 20% of GCs are diagnosed at an early stage worldwide [10]
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