Inactivation of the hMSH3 mismatch repair gene in bladder cancer

Kawakami, Toshifumi; Shiina, Hìroaki; Igawa, Mikio; Deguchi, Masashi; Nakajima, Koichi; Ogishima, Tatsuya; Tokizane, Takashi; Urakami, Shinji; Enokida, Hideki; Miura, Kazukiyo; Ishii, Nobuhisa; Kane, Christopher J.; Carroll, Peter R.; Dahiya, Rajvir

doi:10.1016/j.bbrc.2004.10.114

Cited by 25 publications

(25 citation statements)

References 29 publications

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“…Moreover, for NSCLC, it has been shown that the shortest region of overlapping deletion does not extend to the more distally located tumor suppressor genes APC and MCC on chromosome 5q, basically excluding a simple bystander effect [45]. Genetic and epigenetic alterations in MSH3 have been associated with progression in bladder cancer [42], which is similar to the involvement in progression rather than initiation we have shown for MLH1-deficient CRCs [25]. Moreover, that MSH3 deficiency accelerates tumor progression can be inferred from the 10-year difference between the median age of tumor onset in Lynch syndrome associated with constitutional MSH2 and MSH6 mutations [19,47], whereby the apparent difference is the additional deficiency for the MutSβ (MSH2+MSH3) protein complex with MSH2 mutations compared with deficiency solely for MutSα (MSH2+MSH6) with MSH6 mutations.…”

Section: Discussionmentioning

confidence: 98%

“…For example, MLH1 silencing in sporadic tumors occurs almost exclusively by promoter hypermethylation despite the frequent occurrence of distinct mutations on the constitutional level in Lynch syndrome (reviewed in [2]). Hypermethylation of the MSH3 promoter might also underlie diminished expression and has indeed been reported to occur in bladder cancer [42]. Moreover, loss of MSH3 expression has been associated with aberrant MSH3 methylation in elderly patients with sporadic gastric carcinoma [43].…”

Section: Discussionmentioning

confidence: 98%

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Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability

Plaschke

Preußler

Ziegler

et al. 2012

Int J Colorectal Dis

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability

Plaschke

Preußler

Ziegler

et al. 2012

Int J Colorectal Dis

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“…1). Of other molecular events possibly underlying MSH3 loss in MLH1-deficient CRCs, loss of heterozygosity typically occurs only in MSS tumors (39,40) whereas gene promoter methylation has not been investigated. Having detected MSH3 biallelic frameshift mutations in about 80% of microdissected areas of MLH1-deficient cancers with MSH3 loss, we can assume Stepwise logistic regression; an OR < 1.00 represents a decreased likelihood of metastases whereas an OR > 1.00 represents an increased likelihood of metastases.…”

Section: Discussionmentioning

confidence: 99%

MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers

Laghi

Bianchi

Delconte

et al. 2012

Clinical Cancer Research

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Purpose: Patients with colorectal cancers (CRC) and high microsatellite instability (MSI) have a better outcome than their chromosome-unstable counterpart. Given the heterogeneity of microsatellite-unstable CRCs, we wanted to see whether any MSI-associated molecular features are specifically associated with prognosis.Experimental Design: One hundred and nine MSI-high CRCs were typed for primary mismatch repair (MMR) defect and for secondary loss of MMR proteins. Frameshifts at seven target genes, mutations in the RAS pathway, and methylation at MLH1/CDKN2A promoters were also searched. The interplay of molecular findings with clinicopathologic features and patient survival was analyzed.Results: Of 84 MLH1-deficient CRCs, 31 (36.9%) had MSH3 and 11 (13.1%) had MSH6 loss (P < 0.001), biallelic frameshift mutations at mononucleotide repeats accounting for most (78%) MSH3 losses. As compared with MSH3-retaining cancers, MLH1-deficient tumors with MSH3 loss showed a higher number of mutated target genes (3.94 AE 1.56 vs. 2.79 AE 1.75; P ¼ 0.001), absence of nodal involvement at pathology [N0; OR, 0.11; 95% confidence interval (CI), 0.04-0.43, P < 0.001], and better disease-free survival (P ¼ 0.06). No prognostic value was observed for KRAS status and for MLH1/CDKN2A promoter methylation. The association between MSH3 loss and N0 was confirmed in an independent cohort of 71 MLH1-deficient CRCs (OR, 0.23; 95% CI, 0.06-0.83, P ¼ 0.02).Conclusions: MLH1-deficient CRCs not expressing MSH3 have a more severe MSI, a lower rate of nodal involvement, and a better postsurgical outcome.

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“…There are CpG islands in hepaCAM exon 2. Bladder cancer is the most common malignancy of the urinary system, and many studies have manifested that the methylation of tu- mor suppressor genes is correlated with bladder cancer, such as RASSFIA [22,23] , DAPK [22] , APC [23] , P16 [24,25] , hMSH3 [26] and RUNX3 [27] and others. The relationship between the methylation of these tumor suppressor genes and the development of bladder cancer has been identified.…”

Section: Discussionmentioning

confidence: 99%

Exon 2 Methylation Inhibits hepaCAM Expression in Transitional Cell Carcinoma of the Bladder

Pan

Luo

et al. 2010

Urol Int

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Aim: We aimed to investigate the mechanisms of hepaCAM inactivation in transitional cell carcinoma of the bladder through the analysis of hepaCAM exon 2 methylation. Methods: The methylation of hepaCAM exon 2 and the expression of hepaCAM were determined by methylation-specific restriction PCR assay and RT-PCR in bladder cancer cells (T24, BIU-87) as well as in 55 paired bladder cancer specimens. The methylated bladder cancer cells were treated with 5-Aza- 2′-deoxycytidine (5-Aza-CdR), a demethylating agent. MTT was used to detect the proliferation of T24 and BIU-87 cells. Results: The proliferation of T24 and BIU-87 cells was suppressed by treatment with different concentrations of 5-Aza-CdR; the expression of hepaCAM was absent in T24 and BIU-87 cells, and we found that exon 2 of hepaCAM was methylated in the 2 cells. hepaCAM mRNA was re-expressed and the methylation status of hepaCAM exon 2 was reversed after treatment with 5-Aza-CdR. The expression of hepaCAM mRNA in bladder cancer tissues was significantly lower than that in adjacent tissues. The methylation rate of hepaCAM exon 2 was significantly higher in bladder cancer tissues than in adjacent tissues. The methylation of hepaCAM exon 2 was related to hepaCAM expression in bladder cancer tissues. Conclusions: Downregulation of hepaCAM expression plays an important role in the tumorigenesis and development of bladder cancer. DNA methylation may be important for downregulation of hepaCAM expression in bladder cancer.

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Inactivation of the hMSH3 mismatch repair gene in bladder cancer

Cited by 25 publications

References 29 publications

Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability

Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability

MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers

Exon 2 Methylation Inhibits hepaCAM Expression in Transitional Cell Carcinoma of the Bladder

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