CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability

Hawkins, Nicholas J.; Norrie, Mark; Cheong, Kay; Mokany, Elisa; Ku, Su–Lyn; Meagher, Alan P.; O'Connor, Terence W.; Ward, Robyn L.

doi:10.1053/gast.2002.32997

Cited by 322 publications

(350 citation statements)

References 18 publications

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“…[20][21][22][23] It has been argued that CpG island methylation phenotype-positive tumors constitute a distinct subtype of colorectal cancer, and have been variously associated with different features such as BRAF mutation, KRAS mutation, favorable prognosis and adverse outcome. [24][25][26][27][28][29][30]42 These differences are likely related to different criteria used for defining CpG island methylation phenotype-positive status, as well as the number and type of markers used.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19] The role of transcriptional silencing of tumorsuppressor genes by aberrant methylation of promoter region has been widely studied in colorectal cancer. [20][21][22][23][24][25] The term CpG island methylator phenotype has been used for classifying colorectal cancers based on promoter methylation of multiple genes, although there is no universally accepted definition of CpG island methylation phenotype-positive tumors. Some, but not all, studies have shown that CpG island methylation phenotype-positive phenotype is associated with aggressive behavior.…”

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confidence: 99%

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Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

et al. 2012

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The relationship of molecular abnormalities with clinicopathologic features and survival in colorectal signet ring cell carcinoma, and its comparison with mucinous and conventional adenocarcinomas, has not been well studied. High-level microsatellite instability, loss of heterozygosity (LOH) at four loci, CpG island methylation phenotype based on seven loci, BRAF V600E mutation and KRAS mutation in signet ring cell carcinoma were compared with mucinous and conventional adenocarcinomas. The relationship of these molecular features in signet ring cell carcinoma with clinicopathologic features and survival was examined. LOH was observed in 93% of signet ring cell carcinomas compared with 62 and 70% of mucinous and conventional adenocarcinomas. Also, 80% of signet ring cell carcinomas with high-level microsatellite instability showed LOH compared with 14% each of mucinous and conventional adenocarcinomas. High-level microsatellite instability, CpG island methylation phenotype-positive status and BRAF V600E mutation were more often seen in signet ring cell carcinoma and mucinous adenocarcinoma compared with conventional adenocarcinoma. BRAF V600E mutation was significantly associated with CpG island methylation phenotype-positive status. Stage and BRAF V600E mutation in microsatellite-stable cases were the only variables with an affect on survival. In conclusion, chromosomal instability manifested by LOH is nearly a universal finding in signet ring cell carcinoma, including cases with highlevel microsatellite instability. This may explain the aggressive behavior of signet ring cell carcinoma irrespective of high-level microsatellite-instability status. BRAF V600E mutation and CpG island methylation phenotypepositive status are similar in signet ring cell carcinoma and mucinous adenocarcinoma but more frequent when compared with conventional adenocarcinoma. In signet ring cell carcinoma, BRAF V600E mutation adversely affects survival in microsatellite-stable tumors, but not in high-level microsatellite-unstable tumors. The high frequency of methylation and BRAF V600E mutation suggests that many signet ring cell carcinomas may be related to the serrated pathway of carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

et al. 2012

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“…15 The frequency of methylation in those tumors was significantly correlated with aging. 21,25 Methylation has been observed not only in the hMLH1 promoter but also in other gene promoters, such as the estrogen receptor (ER), N33, MyoD, etc. 26,27 Furthermore, our previous study showed that age-related methylation was found in gastric cancer as well as colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly

Arai

Esaki²,

Sawabe

et al. 2004

Modern Pathology

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To clarify the significance of hMLH1 promoter hypermethylation in the development of medullary-type poorly differentiated colorectal adenocarcinoma, we studied the status of promoter methylation and hMLH1 expression in 23 medullary-type and 12 pleomorphic-type carcinomas, as well as the pathology and microsatellite status. In medullary-type carcinomas, the percentages of cases with promoter methylation (83%) and an absence of hMLH1 expression (91%) were significantly higher than in pleomorphic-type carcinomas (14 and 17%), respectively. The rate of microsatellite instability in the medullary type was significantly higher than that of the pleomorphic type (87 vs 40%, Po0.01). Compared with pleomorphic-type carcinomas, medullary-type carcinomas were significantly associated with hMLH1 promoter methylation, absent expression of hMLH1 protein, microsatellite instability, as well as a proximal location, a Crohn's-like lymphoid reaction, a low incidence of lymph node metastasis, and a favorable outcome. Medullary-type carcinomas accumulated with advancing age, especially in the female. These results indicated that hMLH1 hypermethylation, concurrent with a lack of its protein expression, may play an important role in the development of medullary-type poorly differentiated colorectal adenocarcinomas in the elderly.

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“…To compare the frequencies of methylation index 4-10 (or [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] in CACNA1G, for example, we limited the denominator to tumors with CACNA1G methylation index 44 (methylation positive) ( Table 1). This was because, compared to CIMP-high tumors, CIMP-low tumors had a higher proportion of tumors negative for CACNA1G methylation (methylation index o4), which, if included in the denominator, would have by itself decreased Table 1).…”

Section: Low-level Methylation At An Individual Promoter Was Common Imentioning

confidence: 99%

“…1,2 A subset of colorectal cancers have been shown to exhibit widespread promoter methylation, which is referred to as the CpG island methylator phenotype (CIMP). 1,3 CIMPhigh colorectal tumors have a distinct clinical, pathologic and molecular profile, such as associations with proximal tumor location, female sex, poor tumor differentiation, inactive WNT/b-catenin (CTNNB1) and high BRAF and low TP53 mutation rates, [4][5][6] independent of microsatellite instability status. [7][8][9][10] Although controversial, CIMP may have prognostic implications in colorectal cancer.…”

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confidence: 99%

CpG island methylator phenotype-low (CIMP-low) colorectal cancer shows not only few methylated CIMP-high-specific CpG islands, but also low-level methylation at individual loci

et al. 2008

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The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct phenotype in colorectal cancer. However, the concept of CIMP-low with less extensive CpG island methylation is still evolving. Our aim is to examine whether density of methylation in individual CpG islands was different between CIMP-low and CIMP-high tumors. Utilizing MethyLight technology and 889 population-based colorectal cancers, we quantified DNA methylation (methylation index, percentage of methylated reference) at 14 CpG islands, including 8 CIMP-high-specific loci (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1). Methylation positivity in each locus was defined as methylation index44. Low-level methylation (methylation index40, o20) in each CIMP-high-specific locus was significantly more common in 340 CIMP-low tumors (1/8-5/8 methylation-positive loci) than 133 CIMP-high tumors (Z6/8 methylation-positive loci) and 416 CIMP-0 tumors (0/8 methylation-positive loci) (Pr0.002). In the other six loci (CHFR, HIC1, IGFBP3, MGMT, MINT31 and WRN), which were not highly specific for CIMP-high, low-level methylation, was not persistently more prevalent in CIMP-low tumors. In conclusion, compared to CIMP-high and CIMP-0 tumors, CIMP-low colorectal cancers show not only few methylated CIMP-high-specific CpG islands, but also more frequent low-level methylation at individual loci. Our data may provide supporting evidence for a difference in pathogenesis of DNA methylation between CIMP-low and CIMP-high tumors. Modern Pathology (2008) 21, 245-255; doi:10.1038/modpathol.3800982; published online 18 January 2008 Keywords: colon cancer; CpG island methylator phenotype; DNA methylation; promoter; MethyLight; CIMP-low Epigenetic aberrations are important mechanisms in human carcinogenesis. 1 A number of tumor suppressor genes are silenced by promoter methylation in colorectal cancers. 1,2 A subset of colorectal cancers have been shown to exhibit widespread promoter methylation, which is referred to as the CpG island methylator phenotype (CIMP). 1,3 CIMPhigh colorectal tumors have a distinct clinical, pathologic and molecular profile, such as associations with proximal tumor location, female sex, poor tumor differentiation, inactive WNT/b-catenin (CTNNB1) and high BRAF and low TP53 mutation rates, 4-6 independent of microsatellite instability status. 7-10 Although controversial, CIMP may have prognostic implications in colorectal cancer. [11][12][13][14] In contrast to CIMP-high in colorectal cancer, the concept of CIMP-low (with less widespread CIMPspecific promoter methylation) is still emerging. 15,16 While CIMP-high colorectal cancer is associated with female sex and BRAF mutation, CIMP-low is associated with KRAS mutation. 17 Thus, CIMP-low cannot be explained by a simple mixture of CIMPhigh and CIMP-0 (CIMP-negative). 17 We have also demonstrated a possible link between CIMP-low, microsatellite instability-low, MGMT methylation and KRAS mutation in colorectal cancer. 18 18q loss of heterozy...

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CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability

Cited by 322 publications

References 18 publications

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly

CpG island methylator phenotype-low (CIMP-low) colorectal cancer shows not only few methylated CIMP-high-specific CpG islands, but also low-level methylation at individual loci

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