Mismatch repair deficiency leads to a unique mode of colorectal tumorigenesis characterized by intratumoral heterogeneity

Habano, Wataru; Sugai, Tamotsu; Nakamura, Shinichi

doi:10.1038/sj.onc.1201651

Cited by 21 publications

(19 citation statements)

References 29 publications

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“…Intratumoral heterogeneity was observed in the majority of samples. Intratumoral heterogeneity in MLH1 and MSH2 gene alterations has previously been reported by Habano et al (1998) in sporadic colorectal cancer using a sensitive technique for allelic loss detection in different crypts within the same tumour after microdissection. This is therefore in agreement with our findings using immunohistochemistry, which has the benefits of being simpler and more convenient.…”

Section: Discussionmentioning

confidence: 79%

Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

et al. 2001

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Mutation of human homologues of DNA mismatch repair (MMR) genes in tumours has been shown to be associated with the phenomenon of microsatellite instability (MSI). Several studies have reported the occurrence of MSI in bladder cancer, but evidence of involvement of MMR genes in the pathogenesis of this cancer is still unclear. We therefore utilized quantitative immunohistochemical (IHC) image analysis and PCR-based allelotype analysis to determine hMLH1 and hMSH2 genes alteration in a cohort of Egyptian bladder cancer samples. IHC analysis of 24 TCC and 12 SCC revealed marked- intra and intertumour heterogeneity in the levels of expression of the two MMR proteins. One TCC lost MLH1 expression and one lost MSH2, (1/24, 4%), and one SCC lost MSH2 (1/12, 8%). A large proportion of analysed tumours revealed a percentage positivity of less than 50% for MLH1 and MSH2 expression (44% and 69%, respectively). Complete loss of heterozygosity in three dinucleotide repeats lying within, or in close proximity to, hMLH1 and hMSH2 was rare (2/57, (4%) for MLH1 ; and 1/55, (2%) for MSH2 ), however allelic imbalance was detected in 11/57 ( hMLH1 ) and 10/55 ( hMSH2 ) at any of the informative microsatellite loci. These alterations in structure and expression of DNA MMR genes suggest their possible involvement in the tumorigenesis and/or progression of bladder cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Section: Discussionmentioning

confidence: 79%

Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

et al. 2001

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“…The results suggest that nuclear and mitochondrial genomes partly share the same DNA repair system. In our previous study (Habano et al, 1998), loss of the hMSH2 and hMLH1 genes was observed in 21% and 20% of the same series of colorectal carcinomas, respectively. However, mtDNA instability was not mtDNA instability in colorectal carcinoma W Habano et al associated with these gene defects, suggesting that a certain MMR enzyme other than hMSH2 or hMLH1 may be responsible for maintenance in both nuclear and mitochondrial genomes.…”

Section: Discussionmentioning

confidence: 99%

“…Corresponding tissue specimens were obtained from normal mucosa located distal to the tumor. All specimens were surgically resected at Iwate Medical University Hospital, Morioka, Japan, between 1993 and 1995, as described previously (Habano et al, 1998). Crypt isolation and total cellular DNA extraction were performed as previously described (Habano et al, 1996).…”

Section: Crypt Isolation and Dna Extractionmentioning

confidence: 99%

Microsatellite instability in the mitochondrial DNA of colorectal carcinomas: Evidence for mismatch repair systems in mitochondrial genome

1998

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The role, if any, that mitochondrial (mt) DNA alterations play in the carcinogenic process remains unclear. To determine whether mtDNA instability occurs in cancers, nine microsatellite sequences in the mtDNA were examined in 45 sporadic colorectal carcinomas. Alteration in a polycytidine (C)n tract within a noncoding displacement-loop (D-loop) region was detected in 20 carcinomas (44%), three of which also exhibited frameshift mutations in a polyadenosine (A)8 or polycytidine (C)6 tract within NADH dehydrogenase (ND) genes. Interestingly, all three mutant genes were predicted to encode truncated ND proteins, which lacked a large portion of the C-terminus. These results suggested that certain repair systems, like the mismatch repair systems in the nuclear genome, are required for mtDNA maintenance and that defects in these systems can lead to target mitochondrial gene mutations in colorectal carcinomas.

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“…Plasmacytomas can therefore be added to the plethora of mouse models of human cancer (B cell lymphomas, 31 T cell lymphomas, 32 and other malignancies 33 ) that have been utililized successfully to study clonal diversity during oncogenesis. However, the possibility to associate clonal diversification processes with a pool of tumor/tumor progenitor cells, which is clearly defined by clonotypic T(12;15) translocations and monoclonal Ig production, may be a unique advantage of the BALB/c plasmacytoma system.…”

Section: Figurementioning

confidence: 99%

Clonal diversification of primary BALB/c plasmacytomas harboring T(12;15) chromosomal translocations

2000

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DNA sequence analysis of PCR amplified Igh/c-myc junction fragments of T(12;15) chromosome translocations and immunohistochemical determination of immunoglobulin isotype production were employed to study the clonal diversification of neoplastic translocated plasma cells that resided in peritoneal inflammatory granulomas of BALB/c mice harboring primary plasmacytomas. The diversity of plasma cells was found to take two major forms when the fine structure of the T(12;15) translocation was used as the clonotypic marker. First, mosaics of clones containing translocations that were apparently unrelated to each other were detected in nine out of 17 (53%) mice. Second, subclones derived from common T(12;15) + progenitors by either secondary deletions in translocation breakpoint regions or aberrant isotype switching near translocation breaksites were found in five of 17 (29.5%) mice. When Ig expression was utilized as the clonotypic marker, clonal mosaics were shown to occur in all mice. This was demonstrated by the finding that the prevalent IgA-or IgG-producing plasmacytoma clone was invariably accompanied by smaller clones of IgG-or IgA-expressing neoplastic plasma cells, respectively. These results provided new insights into the clonal diversification at the terminal stage of plasmacytomagenesis. In addition, they suggested that BALB/c plasmacytomas may be uniquely useful for studying clonal diversity during B cell oncogenesis, since clonal evolution can be evaluated in a pool of tumor and tumor precursor cells that is clearly defined by the T(12;15) chromosomal translocation and the production of monoclonal immunoglobulin. Leukemia (2000) 14, 909-921.

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Mismatch repair deficiency leads to a unique mode of colorectal tumorigenesis characterized by intratumoral heterogeneity

Cited by 21 publications

References 29 publications

Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

Microsatellite instability in the mitochondrial DNA of colorectal carcinomas: Evidence for mismatch repair systems in mitochondrial genome

Clonal diversification of primary BALB/c plasmacytomas harboring T(12;15) chromosomal translocations

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