Hypermethylation of the TPEF/HPP1 Gene in Primary, Metastatic Colorectal Cancers

Ebert, Matthias; Mooney, Suzanne; Tonnes-Priddy, Lori; Lograsso, Joe; Hoffmann, Juliane; Chen, Jie; Röcken, Christoph; Schulz, Hans–Ulrich; Malfertheiner, Peter; Lofton–Day, Catherine

doi:10.1593/neo.05235

Cited by 63 publications

(38 citation statements)

References 25 publications

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“…Thus, quantitative assessment of DNA methylation is very important. 24,25,27,39,40 Our findings provide additional supporting evidence for molecular features of CIMP-low tumors different from CIMP-high and CIMP-0 tumors. CIMP-low tumors generally appear to methylate at multiple CIMP-specific CpG islands at low levels, whereas CIMP-0 tumors tend to show more loci with no evidence of methylation and CIMP-high tumors tend to show more loci with high-level methylation.…”

Section: Discussionsupporting

confidence: 67%

“…MethyLight assays (quantitative methylation-specific PCR) are robust and reproducible in quantifying methylation in DNA from paraffinembedded tumor tissue. [21][22][23][24][25][26][27] Low index of methylation in MethyLight analysis is not associated with gene silencing, 24 indicating that low methylation index in MethyLight indeed reflects low-level DNA methylation.…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 67%

mentioning

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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“…HPP1 has been previously reported to be methylated in adenocarcinomas from the esophagus, stomach, small bowel and colorectum. [26][27][28][29][30][31] A previous study found HPP1 to be downregulated in fibrolamellar carcinomas at the mRNA level 10 and the current results demonstrate that the downregulation of HPP1 expression is associated with promoter methylation. The function of this gene is unknown; however, it codes for a transmembrane protein that contains both epidermal growth factor and follistatin-like domains and may play a role in inhibiting serine proteases.…”

Section: Figuresupporting

confidence: 58%

Epigenetic instability is rare in fibrolamellar carcinomas but common in viral-associated hepatocellular carcinomas

Vivekanandan

Torbenson

2008

Modern Pathology

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Fibrolamellar carcinomas have a unique predilection for younger individuals and arise in livers without recognizable liver disease. In contrast to typical hepatocellular carcinomas, fibrolamellar carcinomas show few chromosomal changes and lack mutation in key genes such as TP53 and CTNNB1. Epigenetic instability, manifesting as methylation of important tumor suppressor gene promoters, has not been investigated in fibrolamellar carcinomas. Thus, the methylation status of 11 tumor suppressor gene promoters was investigated using methylation-specific PCR: RASSF1, CDH1, CDKN2B, HPP1, CDKN2A, GSTP1, P16, RARA, FLJ13081, SOCS1, and TP53. Nine fibrolamellar carcinomas were studied including primary tumors (N ¼ 5) and metastatic deposits (N ¼ 4) along with control groups of typical hepatocellular carcinoma arising in livers with (N ¼ 21) and without cirrhosis (N ¼ 10). In fibrolamellar carcinomas, RASSF1A and CDH1 (e-cadherin) were the most commonly methylated genes with 80-100% of tumors methylated. However, overall fibrolamellar carcinomas showed low levels of methylation with no differences between fibrolamellar carcinomas and their paired normal livers. However, fibrolamellar carcinomas showed significantly less methylation than hepatocellular carcinomas that arose in the background of viral cirrhosis. Overall, methylation was most strongly linked to viral cirrhosis. In conclusion, fibrolamellar carcinoma shows low levels of methylation. In contrast, higher levels of promoter methylation are associated with hepatocellular carcinomas that arise in the setting of viral induced cirrhosis.

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“…It has been shown that these three genes can be methylated in patients with CRC and precancerous lesions [6][7][8][12][13][14][15][16] . Of the genes chosen for this study, SFRP2 gene belongs to a new class of tumor suppressor genes (SFRPs), which are secreted glycoproteins working as inhibitory modulators of a putative tumorigenic pathway (the Wnt signaling pathway).…”

Section: Discussionmentioning

confidence: 99%

Detection of aberrant methylation in fecal DNA as a molecular screening tool for colorectal cancer and precancerous lesions

Huang

Li²,

Yang³

et al. 2007

WJG

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AIM: To i nve s t i g a t e t h e fe a s i b i l i ty o f d e t e c t i n gmethylated fecal DNA as a screening tool for colorectal carcinoma (CRC) and precancerous lesions. METHODS:Methylated secreted frizzled-related protein gene 2 (SFRP2 ), hyperplastic polyposis protein gene (HPP1 ) and O 6 -methylguanine-DNA methyltransferase gene (MGMT ) in stools from 52 patients with CRC, 35 patients with benign colorectal diseases and 24 normal individuals were analyzed using methylation-specific PCR.RESULTS: Methylated SFRP2 , HPP1 and MGMT were detected in 94.2%, 71.2%, 48.1% of CRC patients and 52.4%, 57.1%, 28.6% of adenoma patients, respectively. The overall prevalence of fecal DNA with at least one methylated gene was 96.2% and 81.8% in patients with CRC and precancerous lesions, respectively. In contrast, only one of the 24 normal individuals revealed methylated DNA. These results indicated a 93.7% sensitivity and a 77.1% specificity of the assay for detecting CRC and precancerous lesions. CONCLUSION:Methylation testing of fecal DNA using a panel of epigenetic markers may be a simple and promising non-invasive screening method for CRC and precancerous lesions.

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Hypermethylation of the TPEF/HPP1 Gene in Primary, Metastatic Colorectal Cancers

Cited by 63 publications

References 25 publications

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

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

Epigenetic instability is rare in fibrolamellar carcinomas but common in viral-associated hepatocellular carcinomas

Detection of aberrant methylation in fecal DNA as a molecular screening tool for colorectal cancer and precancerous lesions

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