Microsatellite instability and protein expression of the DNA mismatch repair gene,hMLH1, of lung cancer in chromate-exposed workers

Takahashi, Yûji; Kondo, Kazuya; Hirose, Toshiyuki; Nakagawa, Hidewaki; Tsuyuguchi, Masaru; Hashimoto, Masato; Sendo, Toshiaki; Ochiai, Atsushi; Monden, Yasumasa

doi:10.1002/mc.20073

Cited by 110 publications

(95 citation statements)

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“…In fact exposure to environmental toxicants/ carcinogens, particularly heavy metals, is correlated with microsatellite instability in adult cancers due to occupational exposure. 33,34 In our hepatoblastoma series the high-and low-level microsatellite instability phenotypes did not appear to be specifically associated with b-catenin alterations, p53 mutations, and epithelial vs epithelial/mesenchymal histology. A role of preoperative chemotherapy in determining the observed genetic alterations is unlikely, as mutations and microsatellite instability were found in both preoperatively-treated and -untreated hepatoblastoma cases.…”

Section: Discussionmentioning

confidence: 70%

Sporadic childhood hepatoblastomas show activation of β-catenin, mismatch repair defects and p53 mutations

et al. 2008

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Hepatoblastoma, a rare embryonic tumor that may arise sporadically or in the context of hereditary syndromes (familial adenomatous polyposis and Beckwith-Wiedemann's) is the most frequent liver cancer of childhood. Deregulation of the APC/b-catenin pathway occurs in a consistent fraction of hepatoblastomas, with mutations in the APC and b-catenin genes implicated in familial adenomatous polyposis-associated and sporadic hepatoblastomas, respectively. Alterations in other cancer-related molecular pathways have not been reported. We investigated a series of 21 sporadic paraffin-embedded hepatoblastoma cases for mutations in the p53 (exons 5-8) and b-catenin (exon 3) genes, loss of heterozygosity at APC, microsatellite instability and immunohistochemical expression of b-catenin and of the two main mismatch repair proteins, MLH1 and MSH2. No loss of heterozygosity at APC was detected. We found mutations in b-catenin and p53 in 4/21 (19%) and 5/21 (24%) cases respectively, b-catenin protein accumulation in 14/21 cases (67%), microsatellite instability in 17/21 cases (81%), of which eight resulted positive for high-level of microsatellite instability (in four cases associated with loss of MLH1/MSH2 immunostaining). No correlations between involved molecular pathway(s) and hepatoblastoma histotype(s) emerged. This study confirms that b-catenin deregulation is involved in sporadic hepatoblastoma and also suggests that mismatch repair defects and p53 mutations contribute to this rare liver cancer. Sporadic hepatoblastoma appears to be molecularly and phenotypically heterogeneous and may reflect different pathways of liver carcinogenesis.

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Section: Discussionmentioning

confidence: 70%

Sporadic childhood hepatoblastomas show activation of β-catenin, mismatch repair defects and p53 mutations

et al. 2008

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“…In a previous study from Korea, the variation À93 G>A within MLH1 was found associated with increased risk of squamous cell lung carcinoma (42). Moreover, the exposure to chromate seems to promote lung cancer also through the inhibition of hMLH1 (43). Finally, engineered mice deficient in the MMR gene Mutyh are prone to develop lung cancer (44).…”

Section: Discussionmentioning

confidence: 92%

DNA Repair and Cell Cycle Control Genes and the Risk of Young-Onset Lung Cancer

et al. 2006

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Exposure to tobacco smoke and to mutagenic xenobiotics can cause various types of DNA damage in lung cells, which, if not corrected by DNA repair systems, may lead to deregulation of the cell cycle and, ultimately, to cancer. Genetic variation could thus be an important factor in determining susceptibility to tobacco-induced lung cancer with genetic susceptibility playing a larger role in young-onset cases compared with that in the general population. We have therefore studied 102 single-nucleotide polymorphisms (SNP) in 34 key DNA repair and cell cycle control genes in 299 lung cancer cases diagnosed before the age of 50 years and 317 controls from six countries of Central and Eastern Europe. We have found no association of lung cancer risk with polymorphisms in genes related to cell cycle control, single-strand/double-strand break repair, or base excision repair. Significant associations (P < 0.05) were found with polymorphisms in genes involved in DNA damage sensing (ATM) and, interestingly, in four genes encoding proteins involved in mismatch repair (LIG1, LIG3, MLH1, and MSH6). The strongest associations were observed with heterozygote carriers of LIG1 À7C>T [odds ratio (OR), 1.73; 95% confidence interval (95% CI), 1.13-2.64] and homozygote carriers of LIG3 rs1052536 (OR, 2.05; 95% CI, 1.25-3.38). Consideration of the relatively large number of markers assessed diminishes the significance of these findings; thus, these SNPs should be considered promising candidates for further investigation in other independent populations.

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“…Prenatal methylmercury exposure increases the level of H3K27me3 and decreases the level of H3Ac their promoters. 18,82 Furthermore, DNA hypermethylation in the promoter regions of the Adenomatous Polyposis Coli (APC) tumor suppressor and MGMT is detected in these samples, although a correlation with their gene expression levels is not established. 16 Chromium has also been found to induce DNA hypermethylation of the gpt promoter and subsequent silencing of its expression in cells.…”

Section: Mercurymentioning

confidence: 99%