The Relationship between Global Methylation Level, Loss of Heterozygosity, and Microsatellite Instability in Sporadic Colorectal Cancer

Matsuzaki, Koji; Deng, Guoren; Tanaka, Hirofumi; Kakar, Sanjay; Miura, Soichiro; Kim, Young S.

doi:10.1158/1078-0432.ccr-05-0859

Cited by 107 publications

(96 citation statements)

References 31 publications

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“…High-level microsatellite-unstable tumors tend to be diploid 38 and chromosomal instability is a relatively infrequent phenomenon; LOH is observed in 16-21% of cancers with high-level microsatellite instability, compared with 56-83% of microsatellite-stable tumors. [38][39][40] Hence, it has been argued that chromosomal instability is not a major mechanism for carcinogenesis in high-level microsatellite-unstable tumors. 41 Several studies have shown that chromosomal instability is an adverse prognostic factor in colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

“…19 Hence, the infrequent occurrence of chromosomal instability may be related to the better outcome observed in tumors with high-level microsatellite instability. However, signet ring cancers were either not included in these studies 40 or the histologic details were not provided. 39 Our study shows that chromosomal instability, as manifested by LOH at one or more of the four loci studied, is present in nearly all signet ring cell carcinomas, including those with high-level microsatellite instability.…”

Section: Discussionmentioning

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%

Section: Discussionmentioning

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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“…For example, in prostatic adenocarcinomas, genome-wide DNA hypomethylation by LINE-1 was associated with alterations (either loss or gain) of chromosome 8, 33 and global hypomethylation in colorectal cancers was more common in microsatellite stable tumors than in microsatellite instability-high tumors. 34 However, at least in some tumor sites, methylation of CpG islands in the promoter regions of the genes were unassociated with global hypomethylation, including colorectal neoplasms 35 and stomach cancers. 36 We did not have any survival difference with methylation levels of LINE-1 and Alu in these indolent tumors, but in a previous study of patients with acute lymphoblastic leukemia, LINE-1 hypomethylation and methylation of multiple CpG islands were independent prognostic factors for prognosis.…”

Section: Discussionmentioning

confidence: 99%

Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors)

et al. 2007

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Neuroendocrine tumors including carcinoid tumors and pancreatic endocrine tumors are uncommon, and the genetic alterations in these indolent tumors are not well characterized. We studied global hypomethylation by analyzing long interspersed nucleotide elements (LINE)-1 and Alu methylation using pyrosequencing in 35 neuroendocrine tumors and corresponding normal tissue. The tumor samples were less methylated than normal tissue at LINE-1 (P ¼ 0.04) and Alu (P ¼ 0.001). The mean relative tumor hypomethylation (difference in methylation between normal tissue and in tumor) was 11.5710.0 for LINE-1 and 5.876.4 for Alu, and were correlated with each other (correlation coefficient 0.6, P ¼ 0.001). Relative tumor hypomethylation of LINE-1 was higher in ileal carcinoid tumors than in non-ileal carcinoid tumors and pancreatic endocrine tumors (P ¼ 0.047), and tumors with lymph node metastasis (P ¼ 0.02), chromosome 18 loss (P ¼ 0.001) and RAS-association domain family 1, isoform A gene methylation (P ¼ 0.02). Alu methylation in tumors was inversely correlated with methylation of O 6 -methyl-guanine methyltransferase gene (P ¼ 0.02). Our study shows that hypomethylation is more common in carcinoid tumors than in pancreatic endocrine tumors and is associated with clinicopathologic features, and genetic and epigenetic alterations in these tumors, including lymph node metastasis.

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“…5 Global hypomethylation plays a causal role in tumor formation by promoting chromosomal instability, activation of proto-oncogenes, and loss of heterozygosity, all of which are highly correlated with tumorigenesis. [6][7][8] Genetic and epigenetic alterations following global DNA hypomethylation in noncoding regions have been shown to play a significant role in animal models and human hepatocarcinogenesis. DNA hypomethylation is one of the key events in the initiation of the carcinogenic process in animal models.…”

Section: Introductionmentioning

confidence: 99%

Global DNA Hypomethylation in Liver Cancer Cases and Controls: A Phase I Preclinical Biomarker Development Study

Guerrero-Preston

Santella²,

Blanco³

et al. 2007

Epigenetics

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Key woRDSglobal genomic hypomethylation, epigenetics of hepatocarcinogenesis, epigenetic biomarkers for early detection, molecular cancer screening technology, epigenetic approaches to cancer epidemiology ABStRActBackground: Global genomic DNA hypomethylation is a feature of genomic DNA derived from solid and hematologic tumors in animal models and human carcinogenesis. Global genomic DNA hypomethylation may be the earliest epigenetic change from a normal to a pre-malignant cell.Objectives: To test if global hypomethylation is a good marker for early detection of cancer we used a novel quantification method of 2'-deoxynucleosides to evaluate DNA methylation in liver cancer cases and controls.Methods: Frozen tissue from liver cancer patients and controls were obtained from the Cooperative Human Tissue Network. DNA was extracted using standard methods. Genomic DNA samples were boiled and treated with nuclease P1 and alkaline phosphatase. Global genomic DNA methylation patterns were obtained using HPLC for fraction separation and mass spectrometry for quantification. A two-sample t-test was performed using Welch's approximation for samples with unequal variances. A Wilcoxon rank sum test was also performed.Results: A global genomic DNA methylation index measuring methylated cytidine relative to global cytidine in the genome was significantly lower (p value = 0.001) for all cases, mean = 2.43 (95% CI, 2.08, 2.78), when compared to controls, mean = 3.55 (95% CI, 3.16, 3.93).Discussion: A correlation between global genomic DNA methylation patterns and type of liver tissue was observed. These results add to the accumulating body of evidence suggesting that global DNA hypomethylation may be a useful biomarker to distinguish between liver cancer cases and controls.

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The Relationship between Global Methylation Level, Loss of Heterozygosity, and Microsatellite Instability in Sporadic Colorectal Cancer

Cited by 107 publications

References 31 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

Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors)

Global DNA Hypomethylation in Liver Cancer Cases and Controls: A Phase I Preclinical Biomarker Development Study

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