Aberrant Methylation of the Eyes Absent 4 Gene in Ulcerative Colitis–Associated Dysplasia

Osborn, Neal; Zou, Hongzhi; Molina, Julian R.; Lesche, Ralf; Lewin, Joern; Lofton-Day, Cathy; Klatt, Kristie K.; Harrington, John P.; Burgart, Lawrence J.; Ahlquist, David A.

doi:10.1016/j.cgh.2005.11.009

Cited by 40 publications

(27 citation statements)

References 16 publications

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“…16,[34][35][36][37][38][39] The non-thiol protein tyrosine phosphatase EYA4 has recently been identified as a potential tumor suppressor gene in CRC using multiple detection techniques. 21,40,41,42 Furthermore, it was reported that promoter of ECM pathway gene, Laminin α 1 (LAMA1), is methylated in nearly 67% of CRC patients tested. 43,44 One of the 20 top ranking hypermethylated genes in CRC is Potassium voltage-gated channel, KQT-like subfamily, member 5 (KCNQ5).…”

Section: Resultsmentioning

confidence: 99%

Toward a comprehensive and systematic methylome signature in colorectal cancers

et al. 2013

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CpG Island Methylator Phenotype (CIMP) is one of the underlying mechanisms in colorectal cancer (CRC). This study aimed to define a methylome signature in CRC through a methylation microarray analysis and a compilation of promising CIMP markers from the literature. Illumina HumanMethylation27 (IHM27) array data was generated and analyzed based on statistical differences in methylation data (1st approach) or based on overall differences in methylation percentages using lower 95% CI (2nd approach). Pyrosequencing was performed for the validation of nine genes. A meta-analysis was used to identify CIMP and non-CIMP markers that were hypermethylated in CRC but did not yet make it to the CIMP genes' list. Our 1st approach for array data analysis demonstrated the limitations in selecting genes for further validation, highlighting the need for the 2nd bioinformatics approach to adequately select genes with differential aberrant methylation. A more comprehensive list, which included non-CIMP genes, such as APC, EVL, CD109, PTEN, TWIST1, DCC, PTPRD, SFRP1, ICAM5, RASSF1A, EYA4, 30ST2, LAMA1, KCNQ5, ADHEF1, and TFPI2, was established. Array data are useful to categorize and cluster colonic lesions based on their global methylation profiles; however, its usefulness in identifying robust methylation markers is limited and rely on the data analysis method. We have identified 16 non-CIMP-panel genes for which we provide rationale for inclusion in a more comprehensive characterization of CIMP+ CRCs. The identification of a definitive list for methylome specific genes in CRC will contribute to better clinical management of CRC patients.

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Section: Resultsmentioning

confidence: 99%

Toward a comprehensive and systematic methylome signature in colorectal cancers

et al. 2013

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“…Based on our earlier observations, 16 mEYA4 is typically present in colorectal neoplasia tissue from patients with UC but absent in mucosa from UC controls without neoplasia. More recently, our preliminary data suggested feasibility of mEYA4 assay in stool for the detection of both CRC and precancers in patients with UC or Crohn’s disease.…”

Section: Discussionmentioning

confidence: 78%

“…14 Methylation of some markers, such as RUNX3 and MINT1 , are found in both CRC and nonadjacent non-neoplastic mucosa (NNM) of patients with UC. 15 We have previously shown that aberrant methylation of the Eyes Absent 4 gene ( mEYA4 ) highly discriminates UC cases with colorectal neoplasia from UC controls without neoplasia in both tissue 16 and stool. 17 It is not yet known if mEYA4 is confined to neoplastic tissue or if it is also found in NNM of UC patients with CRC.…”

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confidence: 99%

Methylated Eyes Absent 4 (EYA4) Gene Promotor in Non-neoplastic Mucosa of Ulcerative Colitis Patients with Colorectal Cancer

Kisiel¹,

Garrity‐Park²,

Taylor³

et al. 2013

Inflammatory Bowel Diseases

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Background Aberrant methylation of the EYA4 gene (mEYA4) highly discriminates ulcerative colitis (UC) cases with colorectal neoplasia from UC controls in both tissue and stool. It is not known if mEYA4 is also present in nonadjacent non-neoplastic mucosa (NNM) of UC patients with colorectal neoplasia. Methods Formalin-fixed tissues from 25 UC cases with colorectal cancer (CRC) and 25 UC controls with neither CRC nor dysplasia were matched on gender, age, disease duration, disease extent, and coexistence of primary sclerosing cholangitis. DNA was extracted from sections of CRC and NNM from cases and UC control mucosae. Bisulfite-treated DNA was amplified using real-time methylation-specific PCR. The Wilcoxon rank-sum test assessed differences in mEYA4 levels from CRC, NNM, and control samples. Logistic regression was used to estimate sensitivity and specificity. Results Sufficient DNA was available for 20 cases and 20 controls. The median mEYA4 level (with interquartile range) was 2 (0–5.7) in control mucosae but 93 (38.5–306) in CRC (P < 0.0001) and 27.4 (3–140) in NNM (P = 0.0009). At 95% specificity, mEYA4 was present in 80% of CRC and 50% of NNM tissue samples. The odds ratio of mEYA4 in NNM as an indicator of synchronous CRC was 19 (95% confidence interval, 2–170). Conclusions The authors demonstrate significantly higher mEYA4 levels in NNM and synchronous CRC from UC cases than in colorectal mucosae of UC controls without neoplasia. The finding of this CRC-associated field change has important implications to the use of mEYA4 as a potential UC surveillance marker in tissue or stool.

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“…Matsumura et al reported that methylation of a DNA repair gene O 6 -methylguanine-DNA methyltransferase (MGMT) is rare in UC-associated colorectal cancer, but in sporadic cancer, in contrast, it is rather common (Matsumura et al, 2003). On the other hand, Osborn et al reported that the eyes absent 4 gene (EYE4) is hypermethylated both in sporadic and in UC-associated colorectal cancer (Osborn et al, 2006).…”

Section: Resultsmentioning

confidence: 97%

DNA hypermethylation in colorectal neoplasms and inflammatory bowel disease: a mini review

et al. 2006

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DNA hypermethylation is one of major epigenetic changes. Hypermethylation of many genes has been reported to be related with carcinogenesis and tumor progression of colorectal cancer. Some genes including estrogen receptor is associated with ageing, and changes related with ageing may be accelerated in inflammatory bowel disease. Furthermore, fecal DNA methylation will be able to be used as a marker of colorectal cancer and inflammatory bowel disease. Evaluation of hypermethylation potentially contributes diagnosis of colorectal diseases.

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Aberrant Methylation of the Eyes Absent 4 Gene in Ulcerative Colitis–Associated Dysplasia

Cited by 40 publications

References 16 publications

Toward a comprehensive and systematic methylome signature in colorectal cancers

Toward a comprehensive and systematic methylome signature in colorectal cancers

Methylated Eyes Absent 4 (EYA4) Gene Promotor in Non-neoplastic Mucosa of Ulcerative Colitis Patients with Colorectal Cancer

DNA hypermethylation in colorectal neoplasms and inflammatory bowel disease: a mini review

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