Early detection of gastric cancer using global, genome-wide and IRF4, ELMO1, CLIP4 and MSC DNA methylation in endoscopic biopsies

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.

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease

“…ELMO1 encodes a member of the engulfment and cell motility protein family and has been previously linked to T2DM (98-100), hepatocellular carcinoma (101) and inflammatory arthritis (102). Previous methylation analyses of this gene have shown associations with gastric cancer (103) and CKD (20). The eight top-ranked dmCpGs within ELMO1 were present within various regions of the gene and each dmCpG site reported an increase in the FC in individuals with T1DM-ESKD.…”

<p>Allylated Curcumin Analog CA6 Inhibits TrxR1 and Leads to ROS-Dependent Apoptotic Cell Death in Gastric Cancer Through Akt-FoxO3a</p>

“…BGC-823 cells were injected subcutaneously into the right flank of each mouse at 1×10 6 cells in 0.1 mL PBS. Once the tumors reached a volume of 100-160 mm 3 , mice were randomly distributed into 4 groups (n=6) as follows: 1) control mice treated with vehicle only; 2) mice treated with 10 mg/kg CA6; 3) mice treated with 20 mg/kg CA6; 4) mice treated with 50 mg/kg curcumin. All treatments were carried out with intraperitoneal injections every day.…”

“…1,2 Many patients have inoperable disease at diagnosis. 3 Typically, locally advanced disease is treated with adjuvant or neoadjuvant therapy, in possible combination with surgery. However, the metastatic disease outcome is extremely poor.…”

DNA Methylation Levels of the ELMO Gene Promoter CpG Islands in Human Glioblastomas

“…CpG islands are genomic regions with a high frequency of CpG sites, which are often located near the transcription start site of genes. DNA methylation changes in gene promoter CpG islands are responsible for altering the expression of many different tumor suppressor genes and oncogenes in cancer [ 22 , 23 , 24 ], including ELMO1 in gastric cancer [ 25 ] and ELMO3 in lung adenocarcinoma, and associated brain metastases [ 8 ]. The detection of specific DNA methylation changes in clinical samples are promising as diagnostic and prognostic biomarkers and for assisting therapeutic decision-making [ 26 , 27 ].…”