Methylated <i>B3GAT2</i> and <i>ZNF793</i> Are Potential Detection Biomarkers for Barrett's Esophagus

Yu, Ming; O'Leary, Rachele M.; Kaz, Andrew M.; Morris, Shelli M.; Carter, Kelly; Chak, Amitabh; Chandar, Apoorva K.; Willis, Joseph E.; Moinova, Helen; Markowitz, Sanford D.; Brenner, Dean E.; Anandabapasathy, Sharmila; Westerhoff, Maria; Wong, Chao Jen; Shaheen, Nicholas J.; Chen, Yanwen; Barnholtz‐Sloan, Jill S.; Grady, William M.

doi:10.1158/1055-9965.epi-15-0370

Cited by 14 publications

(10 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is ample evidence regarding cancer-specific DNA methylation patterns [20][21][22][23]. Moreover, several reports [24][25][26] have revealed that significant DNA methylation alterations occur in precancerous lesions. These facts support the notion that changes in DNA methylation could be promising biomarkers for early disease detection.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation profiling identifies epigenetic signatures of gastric cardiac intestinal metaplasia

Lin

Liu

et al. 2020

J Transl Med

View full text Add to dashboard Cite

Background: Measuring the DNA methylome may offer the opportunity to identify novel disease biomarkers and insights into disease mechanisms. Although aberrant DNA methylation has been investigated in many human cancers and precancerous lesions, the DNA methylation landscape of gastric cardiac intestinal metaplasia (IM) remains unknown. Therefore, we aimed to investigate the genome-wide DNA methylation landscape and to search for potential epigenetic biomarkers of gastric cardiac IM. Methods: Histopathologic profiling was performed on a total of 118 gastric cardiac biopsies from cancer-free individuals. Genome-wide DNA methylation analysis was performed on 11 gastric cardiac mucosal biopsies (IM = 7; normal = 4) using Illumina 850K microarrays. Transcriptional relevance of any candidate epigenetic biomarker was validated by qRT-PCR. Results: The detection rate of gastric cardiac IM was 23% (27/118) in cancer-free individuals. Genome-wide DNA methylation profiling showed a global decrease in methylation in IM compared with normal tissues (median methylation = 0.64 and 0.70 for gastric cardiac IM and normal tissues, respectively). Differential methylation analysis between gastric cardiac IM and normal tissues identified 38,237 differentially methylated probes (DMPs) with a majority of sites showing hypermethylation in IM compared with normal tissues (56.3% vs. 43.7%). Subsequent analysis revealed a significant enrichment of hypermethylated DMPs in promoter and CpG islands (p < 0.001 for both, Pearson χ 2 test). For DMPs located in promoter CpG islands showing extreme hypermethylation, the candidate gene with the largest number of DMPs (n = 7) was mapped to HOXA5. Accordingly, mRNA expression of HOXA5 was significantly reduced in IM compared to normal tissue. Conclusions: Our results suggest the implication of alterations in DNA methylation in gastric cardiac IM and highlight that HOXA5 hypermethylation may be a promising epigenetic biomarker, emphasizing the role of aberrant HOXA5 expression in the pathogenesis of gastric cardiac IM.

show abstract

Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation profiling identifies epigenetic signatures of gastric cardiac intestinal metaplasia

Lin

Liu

et al. 2020

J Transl Med

View full text Add to dashboard Cite

show abstract

“…Clinical validation studies confirmed B3GAT2 and ZNF793 methylation levels were significantly higher in BE samples (median 32.5% and 33.1%, respectively) than in control tissues (median 2.29% and 2.52%, respectively; P < .0001 for both genes) and that gene-specific MethyLight assays could accurately detect BE (P < .0001 for both) in endoscopic brushing samples, with mZNF793 having a sensitivity of 70% and specificity of 100% for BE. 203 These markers show promise to further improve the performance of a methylated gene panel for BE screening.…”

Section: Barrett's Esophagus Screening Markersmentioning

confidence: 99%

Epigenetic Alterations in the Gastrointestinal Tract: Current and Emerging Use for Biomarkers of Cancer

2021

Self Cite

View full text Add to dashboard Cite

Colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, and esophageal cancer are leading causes of cancer-related deaths worldwide. A fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological processes of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the clinical behavior of the precancers and cancers and can be used as biomarkers for cancer risk determination, early detection of cancer and precancer, determination of the prognosis of cancer and prediction of the response to therapy. Epigenetic alterations have emerged as one of most robust classes of biomarkers and are the basis for a growing number of clinical tests for cancer screening and surveillance.

show abstract

“…We focused on hypermethylation events because it is well known that epigenetic silencing of relevant genes by a gain of CpG methylation in regulatory regions is a hallmark of cancer [8], and in addition, we ascertained that a gain of methylation in the intestinal type of gastric cancer was most frequent in regulatory sequences (Figure 1B). We found that only 13 CpG sequences were commonly hypermethylated (≥0.25 delta β-values between disease and normal mucosa) in the IM and intestinal types of gastric cancer, but the list includes probes in the regulatory regions of well-known epigenetically deregulated genes in cancer (Figure 2F), such as: ubiquitin-specific peptidase 44 (USP44), a gene frequently hypermethylated in patients with inflammatory bowel disease, who are at high risk of progression to colorectal cancer [18]; ST8 Alpha-N-Acetyl-Neuraminide Alpha-2,8-Sialyltransferase 1 (ST8SIA1), a candidate proposed as a biomarker for colorectal screening programs in non-invasive samples [19]; REPRIMO (RPRM, TP53-dependent G2 arrest mediator homolog gene), a tumor suppressor gene commonly hypermethylated in gastric cancer both in tumor biopsy and blood [20], and zinc finger protein 793 (ZNF793), a gene methylated in the preneoplastic Barret's esophagus disease [21].…”

Section: Identification Of Aberrant Promoter Methylation At Rprm and Znf793 Genes In The Intestinal Type Of Gastric Cancer Previously Estmentioning

confidence: 99%

“…Taking this list into consideration, we selected two candidate genes based on the following criteria: first, high methylation similarities in the IM and intestinal types of gastric cancer; second, the previously described roles in gastric tumorigenesis; and third, previous evidence of gene regulation by CpG methylation [20,21]. We selected three CG probes from Illumina methylation arrays upstream of the TSS of ZNF793 (cg02717801, cg23296010, cg14732998) and three CG probes upstream of the TSS of RPRM (cg00341742, cg15400238, cg00143045) (Figure 3A), to further validate the methylation of their regulatory regions.…”

Section: Identification Of Aberrant Promoter Methylation At Rprm and Znf793 Genes In The Intestinal Type Of Gastric Cancer Previously Estmentioning

confidence: 99%

Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions

Gómez

Pato

Bujanda

et al. 2021

Cancers

View full text Add to dashboard Cite

To adopt prevention strategies in gastric cancer, it is imperative to develop robust biomarkers with acceptable costs and feasibility in clinical practice to stratified populations according to risk scores. With this aim, we applied an unbiased genome-wide CpG methylation approach to a discovery cohort composed of gastric cancer (n = 24), and non-malignant precursor lesions (n = 64). Then, candidate-methylation approaches were performed in a validation cohort of precursor lesions obtained from an observational longitudinal study (n = 264), with a 12-year follow-up to identify repression or progression cases. H. pylori stratification and histology were considered to determine their influence on the methylation dynamics. As a result, we ascertained that intestinal metaplasia partially recapitulates patterns of aberrant methylation of intestinal type of gastric cancer, independently of the H. pylori status. Two epigenetically regulated genes in cancer, RPRM and ZNF793, consistently showed increased methylation in intestinal metaplasia with respect to earlier precursor lesions. In summary, our result supports the need to investigate the practical utilities of the quantification of DNA methylation in candidate genes as a marker for disease progression. In addition, the H. pylori-dependent methylation in intestinal metaplasia suggests that pharmacological treatments aimed at H. pylori eradication in the late stages of precursor lesions do not prevent epigenome reprogramming toward a cancer signature.

show abstract

Methylated B3GAT2 and ZNF793 Are Potential Detection Biomarkers for Barrett's Esophagus

Cited by 14 publications

References 31 publications

Genome-wide DNA methylation profiling identifies epigenetic signatures of gastric cardiac intestinal metaplasia

Genome-wide DNA methylation profiling identifies epigenetic signatures of gastric cardiac intestinal metaplasia

Epigenetic Alterations in the Gastrointestinal Tract: Current and Emerging Use for Biomarkers of Cancer

Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions

Contact Info

Product

Resources

About