Molecular Dissection of Premalignant Colorectal Lesions Reveals Early Onset of the CpG Island Methylator Phenotype

Yamamoto, Eiko; Suzuki, Hiromu; Yamano, Hiro‐o; Maruyama, Reo; Nojima, Masanori; Kamimae, Seiko; Sawada, Takeshi; Ashida, Masami; Yoshikawa, Kenjiro; Kimura, Tomoaki; Takagi, Ryo; Harada, Taku; Suzuki, Ryo; Satô, Akiko; Kai, Masahiro; Sasaki, Yasushi; Tokino, Takashi; Sugai, Tamotsu; Imai, Kohzoh; Shinomura, Yasuhisa; Toyota, Minoru

doi:10.1016/j.ajpath.2012.08.007

Cited by 73 publications

(122 citation statements)

References 47 publications

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“…found that methylation was sufficiently accumulated at the adenoma stage to develop an epigenotype, suggesting that accumulation of aberrant promoter methylation was mostly complete at the adenoma stage 18, 19. This finding suggests that MSS‐type CRC has an epigenotype similar to that of early precursor lesions, irrespective of tumor location 6, 18, 19…”

Section: Discussionmentioning

confidence: 90%

“…Therefore, mutation of KRAS is thought to be a critical genetic event in colorectal carcinogenesis 4, 6, 7, 2326.…”

Section: Discussionmentioning

confidence: 99%

“…Based on different forms of genomic instability, sporadic CRC can broadly be divided into two groups: the microsatellite instability (MIN; MSI) type, caused by MLH1 methylation of the promoter region, and the chromosome instability (CIN) type, characterized by genomic instability at the gross chromosomal level 3, 4, 5. The majority of sporadic CRCs (∼90%) are classified into the CIN type, whereas only approximately 10% of sporadic CRCs are classified into the MIN type 3, 4, 5, 6, 7. In addition, the microsatellite stable (MSS) type, which is similar to CIN, is also important in colorectal carcinogenesis.…”

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confidence: 99%

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Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

Takahashi

Sugai

Habano

et al. 2016

Intl Journal of Cancer

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Differences in the pathogenesis of microsatellite stable (MSS) sporadic colorectal cancers (CRCs) between left‐sided CRC (LC) and right‐sided CRC (RC) have not been clarified. To identify pathogenesis‐related genomic differences between MSS CRCs within the two locations, we performed a comprehensive molecular analysis using crypt isolation with samples from 92 sporadic CRCs. Microsatellite instability (MSI; high and low/negative) and DNA methylation status (low methylation epigenome; intermediate methylation epigenome [IME] or high methylation epigenome [HME]) were determined using polymerase chain reaction (PCR) microsatellite analysis and PCR‐bisulfite pyrosequencing, respectively. Additionally, mutations in the TP53, KRAS, BRAF and PIK3CA genes were examined using PCR‐bisulfite pyrosequencing (for KRAS and BRAF mutations) or PCR‐single conformation polymorphism (for TP53 and PIK3CA mutations), followed by sequencing of aberrant bands. Finally, a genome‐wide study using a copy number alteration (CNA)‐targeted single nucleotide polymorphism array was performed. Ninety‐two CRCs were classified into 71 MSS and 21 MSI phenotypes. We examined 71 CRCs with the MSS phenotype (LC, 56; RC, 15). Mutations in KRAS were associated with RC with the MSS phenotype, whereas mutations in TP53 were more frequently found in LC with the MSS phenotype. There were significant differences in the frequencies of KRAS and TP53 mutations in the IME between LC and RC with the MSS phenotype. Although CNA gains were associated with LC with the MSS phenotype, CNA losses were not major alterations associated with the MSS phenotype. These findings suggested that the molecular pathogenesis of the MSS phenotype in LC was different from that in RC.

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Section: Discussionmentioning

confidence: 90%

“…Therefore, mutation of KRAS is thought to be a critical genetic event in colorectal carcinogenesis 4, 6, 7, 2326.…”

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

Takahashi

Sugai

Habano

et al. 2016

Intl Journal of Cancer

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“…Therefore, molecular dissection of precancerous (adenoma) and cancerous (adenocarcinoma) components within the same tumor may help to understand the onset timing of CIMP during tumorigenesis (25). We analyzed mixed lesions containing both precancerous and cancerous components in CIMP-P tumors and found that CIMP status and/or BRAF mutation were frequently observed (10/12, 83% and 9/12, 75%, respectively) in precancerous components, whereas TET1 methylation was much less common (2/12, 17%, P ¼ 0.002; Fig.…”

Section: Analysis Of Tet1 Methylation In Colon Polyps and Cancersmentioning

confidence: 99%

Aberrant TET1 Methylation Closely Associated with CpG Island Methylator Phenotype in Colorectal Cancer

Ichimura

Shinjo

An³

et al. 2015

Cancer Prevention Research

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Inactivation of methylcytosine dioxygenase, ten-eleven translocation (TET) is known to be associated with aberrant DNA methylation in cancers. Tumors with a CpG island methylator phenotype (CIMP), a distinct subgroup with extensive DNA methylation, show characteristic features in the case of colorectal cancer. The relationship between TET inactivation and CIMP in colorectal cancers is not well understood. The expression level of TET family genes was compared between CIMP-positive (CIMP-P) and CIMP-negative (CIMP-N) colorectal cancers. Furthermore, DNA methylation profiling, including assessment of the TET1 gene, was assessed in colorectal cancers, as well as colon polyps. The TET1 was silenced by DNA methylation in a subset of colorectal cancers as well as cell lines, expression of which was reactivated by demethylating agent. TET1 methylation was more frequent in CIMP-P (23/55, 42%) than CIMP-N (2/113, 2%, P < 0.0001) colorectal cancers. This trend was also observed in colon polyps (CIMP-P, 16/40, 40%; CIMP-N, 2/24, 8%; P ¼ 0.002), suggesting that TET1 methylation is an early event in CIMP tumorigenesis. TET1 methylation was significantly associated with BRAF mutation but not with hMLH1 methylation in the CIMP-P colorectal cancers. Colorectal cancers with TET1 methylation have a significantly greater number of DNA methylated genes and less pathological metastasis compared to those without TET1 methylation (P ¼ 0.007 and 0.045, respectively). Our data suggest that TET1 methylation may contribute to the establishment of a unique pathway in respect to CIMP-mediated tumorigenesis, which may be incidental to hMLH1 methylation. In addition, our findings provide evidence that TET1 methylation may be a good biomarker for the prediction of metastasis in colorectal cancer. Cancer Prev Res; 8(8); 702-11. Ó2015 AACR.

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“…For example, DNA methylation is different between esophageal cancer exposed to cigarette smoking and gastric cancer induced by H. pylori infection. In colorectal cancers, the cancer phenotype with augmentation of enhanced DNA methylation in CpG islands in numerous genes is termed the CpG island methylator phenotype (CIMP), and gene instability due to inactivated BRAF and MLH1 genes in CIMP-high colon cancers, KRAS gene abnormality in CIMP-low colon cancers, and the TP53 gene abnormality in CIMP-negative colon cancers have been reported (5).…”

Section: Discussionmentioning

confidence: 99%

RhoA activity increases due to hypermethylation of ARHGAP28 in a highly liver-metastatic colon cancer cell line

et al. 2016

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Abstract. Certain cell lines exhibit metastatic ability (highly metastatic cell lines) while their parent cell lines have no metastatic ability. Differences in methylation, which are not derived from differences in the gene sequence between cell lines, were extensively analyzed. Using an established highly metastatic cell line, KM12SM, and its parent cell line, KM12C, differences in the frequency of methylation were analyzed in the promoter regions of ~480,000 gene sites using Infinium HumanMethylation450. The promoter region of the Rho GTPase-activating protein 28 (ARHGAP28) gene was the most markedly methylated region in KM12SM compared with KM12C. ARHGAP28 is a GTPase-activating protein (GAP), and it converts activated RhoA to inactivated RhoA via GTPase. RhoA activity was compared between these two cell lines. The activated RhoA level was compared using western blot analysis and G-LISA. The activated RhoA level was higher in KM12SM compared to KM12C for western blot analysis and G-LISA analysis. RhoA is a protein involved in cytoskeleton formation and cell motility. RhoA, for which ARHGAP28 acts as a GAP, is possibly a factor involved in the metastatic ability of cancer. IntroductionClinical cancer lesions are masses of heterologous cancer cells. The mainstream hypothesis of cancer metastasis is that 'a population of highly malignant cells acquires metastatic ability due to the accumulation of gene mutations forming metastatic lesions' (1), i.e., it is hypothesized that highly malignant cancer cells with metastatic ability and low-malignant cancer cells with no metastatic ability are present in the same cancer lesion, and metastatic lesions are mainly formed by the former. Certain established cancer cell lines have a high metastatic ability (highly metastatic cell lines) that is similar to clinical cancers. To establish a highly metastatic cell line, an animal model of metastasis is prepared and cells collected from metastatic lesions are transplanted into another animal, and this procedure is repeated. A highly metastatic cell line is established by passaging only a cell population that has metastasized in the metastasis model, however, why such a highly malignant cell line is established from a genetically cloned cell line through this passaging method is questionable. It is unlikely that a new change in a gene sequence, such as gene mutation, occurs through only several passages even in a metastasis model. Cancer cell lines are manufactured on the assumption that cells will be passaged a specific number of times. When a gene mutation occurs within a small number of passages, this contradicts the stability of the cancer cell line. Therefore, the difference between a highly metastatic cell line and its parent cell line with no metastatic ability is of interest and we hypothesize that the difference is not a genetic mutation.Recent studies identified the presence of the alternation of cell phenotypes, termed epigenetic abnormality, in cancers, in addition to genetic mutation. The representative epigenetic ch...

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Molecular Dissection of Premalignant Colorectal Lesions Reveals Early Onset of the CpG Island Methylator Phenotype

Cited by 73 publications

References 47 publications

Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

Aberrant TET1 Methylation Closely Associated with CpG Island Methylator Phenotype in Colorectal Cancer

RhoA activity increases due to hypermethylation of ARHGAP28 in a highly liver-metastatic colon cancer cell line

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