Oncogenic pathway of sporadic colorectal cancer with novel germline missense mutations in the hMSH2 gene

Yamada, Kazuo; Zhong, Xiaoling; Kanazawa, Shinsaku; Koike, Junki; Tsujita, Kazunori; Hemmi, Hiromichi

doi:10.3892/or.10.4.859

Cited by 8 publications

(11 citation statements)

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“…Of the 4 MSI-H cases, 3 showed altered hMSH2 or hMLH1 expression. One MSI-H tumor (CR079) was found to carry a germline mutation (G40S) in the hMSH2 gene and its tumor had additional somatic mutations, G203R and 697delA in the (A) 7 tract in the hMSH2 gene (20). A second (CR051) showed reduced hMSH2 protein expression (our unpublished results).…”

Section: Resultsmentioning

confidence: 99%

“…The two-fluorescein method was performed as described previously (20). Briefly, the PCR product derived from tumor DNA using the 6-FAM-labeled forward-primer was mixed with that derived from normal DNA using the HEX-or TAMURA-labeled forward-primer (typically 1:3, v/v).…”

Section: Msi Emast and Loh Analysesmentioning

confidence: 99%

“…Polymerase chain reaction (PCR) was performed as described previously for the TP53Alu marker (20) with the following modifications: 10 mM Tris-HCl (pH 8.3); 0.625 U Taq DNA polymerase; and 25 ng of genomic DNA in a total volume of 25 μl and 30 thermal cycles. For BAT25, D2S123 and D17S250, the N,N,N',N'-tetramethyl-6-carboxyrhodamine (TAMURA)-labeled forwardprimer was used instead of the HEX-labeled one.…”

Section: Msi Emast and Loh Analysesmentioning

confidence: 99%

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Microsatellite instability at tetranucleotide repeats in sporadic colorectal cancer in Japan

et al. 2009

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Abstract.Most tumors of patients with Lynch syndrome and a fraction of sporadic colorectal cancers (CRCs) exhibit high levels of microsatellite instability (MSI) at mono-and dinucleotide repeat loci. A different type of instability, elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has been found in non-colonic cancers. Our previous study demonstrated that EMAST is common in sporadic CRC. Here, we focused on the relationships between EMAST and other genomic instability parameters or clinicopathological features in an unselected series of 88 sporadic CRCs. Of the tumors in the sample, 4 (4.5%) were MSI-high (MSI-H), 9 (10.2%) were MSI-low (MSI-L) and 75 (85.2%) were microsatellite stable. EMAST status was determined using 7 EMAST markers. Fifty-three (60.2%) tumors without MSI-H showed instability at ≥1 EMAST loci. All 4 MSI-H tumors showed instability at several EMAST loci. Instability profiles of MSI-H tumors at EMAST loci were more complex than those of non-MSI-H tumors. A tendency of positive association was observed between MSI-L and EMAST (P=0.023). The frequency of loss of heterozygosity (LOH) for the 14 loci in EMAST-positive tumors was significantly higher than negative tumors (P=0.048). Among the clinicopathological parameters, only tumor location at the distal colon was associated with EMAST-negative tumors (P=0.0084, onetailed). A relatively higher frequency of well-differentiated adenocarcinomas was observed in EMAST tumors as opposed to non-EMAST tumors, though the survival rate was similar. These results suggest that overlapping mechanisms that cause MSI-L, EMAST and LOH in CRCs may exist.

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Section: Resultsmentioning

confidence: 99%

Section: Msi Emast and Loh Analysesmentioning

confidence: 99%

Section: Msi Emast and Loh Analysesmentioning

confidence: 99%

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Microsatellite instability at tetranucleotide repeats in sporadic colorectal cancer in Japan

et al. 2009

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“…The level of hMSH3 expression and the MSI status of these tissues have been previously described [13,14,22]. Paraffin-embedded tissues were deparaffinized and rehydrated, followed by antigen retrieval (121 °C for 15 min in 0.01 M citrate buffer, pH 6.0).…”

Section: Methodsmentioning

confidence: 99%

Down-regulation of MutS homolog 3 by hypoxia in human colorectal cancer

Li¹,

Koike²,

Kugoh³

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Down-regulation of hMSH3 is associated with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability in colorectal cancer (CRC). However, the mechanism that down-regulates hMSH3 in CRC is not known. In this study, a significant association between over-expression of glucose transporter 1, a marker for hypoxia, and down-regulation of hMSH3 in CRC tissues was observed. Therefore, we examined the effect of hypoxia on the expression of hMSH3 in human cell lines. When cells with wild type p53 (wt-p53) were exposed to hypoxia, rapid down-regulation of both hMSH2 and hMSH3 occurred. In contrast, when null or mutated p53 (null/mut-p53) cells were exposed to hypoxia, only hMSH3 was down-regulated, and at slower rate than wt-p53 cells. Using a reporter assay, we found that disruption of the two putative hypoxia response elements (HREs) located within the promoter region of the hMSH3 abrogated the suppressive effect of hypoxia on reporter activity regardless of p53 status. In an EMSA, two different forms of HIF-1α complexes that specifically bind to these HREs were detected. A larger complex containing HIF-1α predominantly bound to the HREs in hypoxic null/mut-p53 cells whereas a smaller complex predominated in wt-p53 cells. Finally, HIF-1α knockdown by siRNA significantly inhibited down-regulation of hMSH3 by hypoxia in both wt-p53 and mut-p53 cells. Taken together, our results suggest that the binding of HIF-1α complexes to HRE sites is necessary for down-regulation of hMSH3 in both wt-p53 and mut-p53 cells.

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“…MSI status was determined as described by Yamada et al (2003), using seven markers, five from the reference panel (BAT25, BAT26, D2S123, D5S346, and D17S250) and two from alternative markers (D18S64 and D18S69) in the International Guidelines (Boland et al 1998b). Clinicopathological properties were collected from medical records according to the Japanese classification of colorectal cancer (Japanese Society for Cancer of the Colon and Rectum 1997).…”

Section: Samplesmentioning

confidence: 99%

A Single Nucleotide Substitution (−107C → G) in the hMLH1 Promoter Found in Colorectal Cancer Population Reduces Transcriptional Activity

et al. 2007

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Inactivation of the DNA mismatch repair gene hMLH1 predisposes one to colorectal cancer. We have identified a C to G nucleotide substitution at position -107 relative to the hMLH1 gene translation initiation site in three of 163 colorectal cancer patients with an allele frequency of 0.0092 (3/326). One of the three -107G alleles occurred in one patient out of five with reduced hMLH1 expression in the tumor tissue. The -107G was not found in 63 healthy individuals. This substitution reduced transcriptional activity by 51% compared with -107C (P<0.01) and impeded the promoter-binding capacity of nuclear proteins. Although the small number of identified -107G alleles is insufficient to evaluate the contribution to the carcinogenesis and clinicopathological properties of the tumors, the effects of -107G on hMLH1 gene transcription and nuclear protein binding to the promoter sequence implicate the site, including -107C, as a crucial element interacting with the activator that maintains hMLH1 gene expression.

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Oncogenic pathway of sporadic colorectal cancer with novel germline missense mutations in the hMSH2 gene

Cited by 8 publications

References 0 publications

Microsatellite instability at tetranucleotide repeats in sporadic colorectal cancer in Japan

Microsatellite instability at tetranucleotide repeats in sporadic colorectal cancer in Japan

Down-regulation of MutS homolog 3 by hypoxia in human colorectal cancer

A Single Nucleotide Substitution (−107C → G) in the hMLH1 Promoter Found in Colorectal Cancer Population Reduces Transcriptional Activity

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