CpG island methylation is frequently present in tubulovillous and villous adenomas and correlates with size, site, and villous component

Kakar, Sanjay; Deng, Guoren; Cun, Lisa; Sahai, Vaibhav; Kim, Young S.

doi:10.1016/j.humpath.2007.06.002

Cited by 52 publications

(43 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Patients with ulcerative colitis have been reported to be at increased risk for developing colorectal cancer due to repetitive mucosal injury (25,26). However, OSMR methylation was not detected in any of 40 ulcerative colitis cases, indicating that its carcinogenesis pathway might be different from the polyps-carcinoma sequence pathway (23,24). This is consistent with the observations that ulcerative colitis-associated cancers showed less frequent CpG island methylator phenotype and higher p53 mutation rates than sporadic colorectal cancers (25,26).…”

Section: Discussionsupporting

confidence: 83%

Unique Methylation Pattern of Oncostatin M Receptor Gene in Cancers of Colorectum and Other Digestive Organs

Deng

Kakar²,

Okudiara³

et al. 2009

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Oncostatin M (OSM) is an interleukin-6 cytokine family member, which inhibits cell proliferation and induces cell differentiation and apoptosis in cancers. In melanoma cells, epigenetic silencing of OSM receptor (OSMR) by histone deacetylation contributes to escape of cell growth control by OSM. However, the silencing of OSMR by DNA methylation in any cancer has not been examined. Experimental Design: Methylation status of OSMR was determined by sequencing or methylation-specific PCR in primary tumors and cell lines. Cell lines were treated with DNA methyltransferase inhibitors 5-aza-2-deoxycytidine or DNA methyltransferase 1 small interfering RNA or a histone deacetylase inhibitor trichostatin A. OSMR mRNA level was determined by reverse transcription-PCR.The acetylation of histone H3 was analyzed by chromatin immunoprecipitation assay. Results: We observed methylation of OSMR in 88 of 98 (90%) colorectal cancers, 34 of 38 (89%) colorectal polyps, 17 of 31 (55%) normal-appearing mucosa adjacent to colorectal cancers, 13 of 40 (33%) gastric cancers, and 2 of 10 (20%) pancreatic cancers. OSMR methylation was absent or rarely detected in normal colonic mucosa from noncancer patients or in cancers of nondigestive organs, including breast, lung, liver, prostate, kidney, and melanoma. We observed a significant correlation between OSMR methylation and loss of mRNA expression in 39 cancer cell lines. Following the treatment of colorectal cancer cell lines with 5-aza-2-deoxycytidine, DNA methyltransferase 1small interfering RNA, or trichostatin A, the induction of OSMR mRNA and the enrichment in the level of histone acetylation were observed. Conclusions: The epigenetic silencing and DNA methylation of OSMR occur frequently in colorectal cancers and rarely in cancers of nondigestive organs. OSMR methylation is an early event in the colorectal carcinogenesis.

show abstract

Section: Discussionsupporting

confidence: 83%

Unique Methylation Pattern of Oncostatin M Receptor Gene in Cancers of Colorectum and Other Digestive Organs

Deng

Kakar²,

Okudiara³

et al. 2009

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Review of 9 previous studies demonstrate that BRAF mutations are extremely rare in Ads (conventional and atypical) occurring in only 7 of 609 adenomas tested. 5,8,[10][11][12][13][14][15][16] For this reason, BRAF mutation in a precursor lesion is sensitive and specific for SSAs. Of the 12 MSI-H Ad precursors associated with BRAF mutated CRC, 11 harboured a BRAF mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Approximately 60-80% of CIMP-H tumors also harbour mutations in BRAF, a serine threonine kinase in the RAS/RAF/MAPK pathway. [5][6][7][8][9] These particular CRCs are also often characterized by high levels of microsatellite instability (MSI-H) 5,8,[10][11][12][13][14][15][16] owing to the presence of a CpG island in the promoter region of the mismatch repair protein gene MLH1.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Proximal colon cancers and the serrated pathway: a systematic analysis of precursor histology and BRAF mutation status

et al. 2012

View full text Add to dashboard Cite

Although the serrated neoplasia pathway is thought to give rise to the majority of sporadic microsatellite instability-high (MSI-H) colon cancer, the exact proportion of these tumors that arise from serrated precursors has not been fully studied. Tubular and tubulovillous adenomas with features of the serrated neoplasia pathway have been described, and unlike sessile serrated adenomas, these lesions lack BRAF mutations. The contribution of these adenomas to sporadic MSI-H colon cancer is unclear. To this end, we conducted an analysis of right-sided sporadic MSI-H and microsatellite stable (MSS) colon cancer, with emphasis on precursor lesions. Overall 25% (19/75) of MSI-H colon cancer had a precursor, of which only 4 were recognized histologically as arising from a sessile serrated adenoma, and the remaining were best classified as adenomas. Of the 31 (of 89) MSS colon cancers with a precursor, only 1 was a sessile serrated adenoma (P ¼ 0.06). Histological analysis of the precursor adenomas to sporadic MSI-H colon cancer demonstrated a high frequency of crypt serrations compared with MSS colon cancer (93 vs 36%, Po0.001). BRAF mutations were found in 57/75 (76%) sporadic MSI-H and 10/89 (11%) MSS colon cancers (Po0.001). Molecular analysis demonstrated BRAF mutations in 11/12 adenoma and 3/3 sessile serrated adenoma precursors adjacent to BRAF-mutated MSI-H colon cancer. Similarly, all 4 precursors to BRAF-mutated MSS colon cancer were also BRAF mutated. The presence of BRAF mutations in these adenomatous precursors suggests that they represent sessile serrated adenomas with complete cytologic dysplasia. Finally, patients with sporadic MSI-H colon cancer were more likely to harbour synchronous sessile serrated adenomas (20 vs 8%; P ¼ 0.023). This is the largest study to rigorously evaluate the precursor and synchronous lesions in patients with right-sided colon cancer. Detailed molecular and histological analysis of these lesions confirms the importance of serrated precursors in the development of sporadic MSI-H colon cancer.

show abstract

“…29,30 It is seen frequently in serrated polyps and adenomas with a villous component, suggesting an involvement in the serrated neoplasia pathway. [23][24][25]31,32 Low levels of MGMT methylation have also been detected in the normal-appearing colonic mucosae of individuals with MGMT-methylated colorectal cancers as well as individuals without neoplasia. 12,30,33 This led to the suggestion that MGMT methylation may precede and predispose to malignant transformation through Slaughter's concept of 'field cancerisation', whereby the accrual of molecular alterations in patches of preneoplastic cells underlies the development of locally recurrent epithelial cancers.…”

mentioning

confidence: 99%

MGMT methylation is associated primarily with the germline C>T SNP (rs16906252) in colorectal cancer and normal colonic mucosa

Hawkins¹,

Lee²,

Wong³

et al. 2009

Modern Pathology

View full text Add to dashboard Cite

O6 -methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that restores mutagenic O 6 -methylguanine to guanine. MGMT methylation is frequently observed in sporadic colorectal cancer and was recently correlated with the C4T allele at SNP rs16906252, within the transcriptional enhancer element of the promoter. MGMT methylation has also been associated with KRAS mutations, particularly G4A transitions. We studied 1123 colorectal carcinoma to define the molecular and clinicopathological profiles associated with MGMT methylation. Furthermore, we assessed factors contributing to MGMT methylation in the development of colorectal cancer by studying the allelic pattern of MGMT methylation using SNP rs16906252, and the methylation status of neighbouring genes within 10q26 in selected tumours and matched normal colonic mucosa. MGMT methylation was detected by combined bisulphite restriction analysis in 28% of tumours and was associated with a number of characteristics, including CDKN2A methylation, absent lymphovascular space invasion and KRAS mutations (but not specifically with KRAS G4A transitions). In a multivariate analysis adjusted for age and sex, MGMT methylation was associated with the T allele of SNP rs16906252 (Po0.0001, OR 5.5, 95% CI 3.8-7.9). Low-level methylation was detected by quantitative methylation-specific PCR in the normal colonic mucosa of cases, particularly those with a correspondingly methylated tumour, as well as controls without neoplasia, and this was also associated with the C4T SNP. We show that the T allele at SNP rs16906252 is a key determinant in the onset of MGMT methylation in colorectal cancer, whereas the association of methylation at MGMT and CDKN2A suggests that these loci may be targets of a common mechanism of epigenetic dysregulation.

show abstract

CpG island methylation is frequently present in tubulovillous and villous adenomas and correlates with size, site, and villous component

Cited by 52 publications

References 28 publications

Unique Methylation Pattern of Oncostatin M Receptor Gene in Cancers of Colorectum and Other Digestive Organs

Unique Methylation Pattern of Oncostatin M Receptor Gene in Cancers of Colorectum and Other Digestive Organs

Proximal colon cancers and the serrated pathway: a systematic analysis of precursor histology and BRAF mutation status

MGMT methylation is associated primarily with the germline C>T SNP (rs16906252) in colorectal cancer and normal colonic mucosa

Contact Info

Product

Resources

About