Two modes of microsatellite instability in human cancer: differential connection of defective DNA mismatch repair to dinucleotide repeat instability

Oda, Shinya; Maehara, Yoshihiko; Ikeda, Yoichi; Oki, Eiji; Egashira, Akinori; Okamura, Yoshikazu; Takahashi, Ikuo; Kakeji, Yoshihiro; Sumiyoshi, Yoshihiro; Miyashita, Kaname; Yamada, Yuichi; Zhao, Yan; Hattori, Hiroyoshi; Taguchi, Ken; Ikeuchi, Tatsuro; Tsuzuki, Teruhisa; Sekiguchi, Mutsuo; Karran, Peter; Yoshida, Mitsuaki A.

doi:10.1093/nar/gki303

Cited by 58 publications

(60 citation statements)

References 41 publications

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“…36,48 Intriguingly, the IC678 tumour also exhibits a MMRdefective phenotype. 49 As shown in Figure 4a, alterations in a human dinucleotide microsatellite, D13S175, were readily detected in the genomic DNA extracted from this tumour. Indeed, a sequence alteration resulting in an amino-acid substitution was found at codon 521 of another essential MMR gene, MLH1 (Figure 4b).…”

Section: Mmr Deficiency In Proofreading-mutant Colorectal Carcinomasmentioning

confidence: 83%

Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer

et al. 2010

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Genomic sequences encoding the 3¢ exonuclease (proofreading) domains of both replicative DNA polymerases, pol delta and pol epsilon, were explored simultaneously in human colorectal carcinomas including six established cell lines. Three unequivocal sequence alterations, including one previously reported, were found, and all these were considered as dysfunctional mutations in light of the local amino-acid sequences. In particular, the F367S mutation found in the POLE gene encoding the pol epsilon catalytic subunit, which includes the proofreading domain, is the first found in human diseases. Surprisingly, the tumours carrying these proofreading domain mutations were all defective in DNA mismatch repair (MMR). In addition to the two cell lines with acknowledged MMR gene mutations, the third tumour was also demonstrated to harbour a distinct mutation in MLH1, and indeed exhibited a microsatellite-unstable phenotype. These findings suggest that, in concert with MMR deficiency, defective polymerase proofreading may also contribute to the mutator phenotype observed in human colorectal cancer. Our observations may suggest previously unrecognised complexities in the molecular abnormalities underlying the mutator phenotype in human neoplasms. Keywords: polymerase delta; polymerase epsilon; proofreading domain; colorectal cancer INTRODUCTION Mutation rates on the genome are invariably regulated and typically suppressed to an extremely low level, such as 10 À10 per base replicated, in the organisms. 1 The high fidelity of DNA replication is achieved by several molecular mechanisms. The frequency of erroneous nucleotide incorporation is indeed extremely low compared with that expected from base-pairing energetics, and the vast reduction of the misincorporation frequency involves three steps of molecular events: (a) correct incorporation of complementary nucleotides by DNA polymerases, (b) removal of the newly added nucleotides, particularly incorrectly paired nucleotides, by the 3¢ exonuclease activities associated with the DNA polymerases (proofreading) and (c) postreplicative scanning of mispaired bases by DNA mismatch repair (MMR). 2,3 Various Escherichia coli (E. coli) mutator strains have been used to study these molecular mechanisms by which organisms maintain their mutation rates at very low levels. The dnaQ + (mutD + ) gene of E. coli encodes the epsilon subunit of the DNA polymerase III holoenzyme that is involved in 3¢ exonuclease proofreading activity, 4 and, therefore, the mutation frequencies in the dnaQ mutators are sometimes 1000-10 000 times higher than the wild-type levels. 4,5 In E. coli, MMR is chiefly directed by the proteins encoded by the three genes: mutS + , mutL + and mutH + . 6 The mutS or mutL mutators exhibit an approximately 100 times increase in the mutation frequency. 7 Thus, polymerase proofreading and MMR are the two major

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Section: Mmr Deficiency In Proofreading-mutant Colorectal Carcinomasmentioning

confidence: 83%

Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer

et al. 2010

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“…56 In this regard, it is known that MSI results are dependent on the markers chosen for analysis, the threshold chosen for instability, and the sensitivity of the assay used. 34 Although other oncogenic tyrosine kinases, such as BCR/ABL, have been reported to suppress MMR, 52 the mechanisms have not been previously studied. We believe that our study has shed light on the possible mechanisms by which oncogenic tyrosine kinases deregulate MMR.…”

Section: Discussionmentioning

confidence: 99%

“…Instead, we chose four additional monomorphic markers that are mono-nucleotide repeats proved to be informative for the detection of microsatellite instability (MSI) in Lynch associated with the loss of MSH6. [33][34][35] DNA samples were isolated from eight normal donors and nine ALK ϩ ALCL tumors. Tumor DNA was isolated from paraffin curls using the Qiagen Blood and Tissue Kit (Qiagen, Mississagua, ON, Canada).…”

Section: Detection Of Microsatellite Instability In Alk ϩ Alcl Tumorsmentioning

confidence: 99%

Fusion Tyrosine Kinase NPM-ALK Deregulates MSH2 and Suppresses DNA Mismatch Repair Function

Young

Bone

Wang

et al. 2011

The American Journal of Pathology

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The fusion tyrosine kinase NPM-ALK is central to the pathogenesis of ALK-positive anaplastic large cell lymphoma (ALK ؉ ALCL). We recently identified that MSH2, a key DNA mismatch repair (MMR) protein integral to the suppression of tumorigenesis, is an NPM-ALK-interacting protein. In this study, we found in vitro evidence that enforced expression of NPM-ALK in HEK293 cells suppressed MMR function. Correlating with these findings, six of nine ALK ؉ ALCL tumors displayed evidence of microsatellite instability, as opposed to none of the eight normal DNA control samples (P ‫؍‬ 0.007, Student's t-test). Using co-immunoprecipitation, we found that increasing levels of NPM-ALK expression in HEK293 cells resulted in decreased levels of MSH6 bound to MSH2, whereas MSH2·NPM-ALK binding was increased. The NPM-ALK·MSH2 interaction was dependent on the activation/autophosphorylation of NPM-ALK, and the Y191 residue of NPM-ALK was a crucial site for this interaction and NPM-ALK-mediated MMR suppression. MSH2 was found to be tyrosine phosphorylated in the presence of NPM-ALK. Finally, NPM-ALK impeded the expected DNA damage-induced translocation of MSH2 out of the cytoplasm. To conclude, our data support a model in which the suppression of MMR by NPM-ALK is attributed to its ability to interfere with normal MSH2 biochemistry and function.

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“…Recently, novel types of MSI have been reported termed type A and type B alterations. 32 Type A alterations are defined as length changes of 6 bp and type B changes are more drastic modification of 8 bp. In our study on UC specimens, all types of MSI we observed belonged to the type A alterations.…”

Section: Discussionmentioning

confidence: 99%

“…Type A MSI may reflect the uncorrected DNA slippage events that may be related to the MSI-L phenotype. 32 Loss of MGMT is a candidate mechanism for MSI-L CRC. However, loss of MGMT expression was not observed in our study.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous microsatellite instability observed within epithelium of ulcerative colitis

Ozaki

Nagasaka

Notohara

et al. 2006

Intl Journal of Cancer

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Microsatellite instability (MSI) has been associated with colitic cancer. However, reported frequency of MSI was varied and the association of MSI with mismatch repair (MMR) deficiency was unclear. In addition, the occurrence of genetic alterations in stromal cells within ulcerative colitis (UC) is still controversial. We therefore sampled 164 microareas in various pathological lesions of UC with or without colitic cancer and studied the MSI status in relation to the DNA repair protein expressions. A total of 129 microfoci from colorectal tissue of 5 colitic cancer patients and 35 microfoci of 7 UC patients (without neoplasm) were carefully sampled by laser-capture microdissection. MSI was analyzed in each microsamples. The protein expression of MMR genes (MLH1, MSH2, MSH6), O 6 -methylguanine-DNA methyltransferase and p53 were assessed by immunohistochemical analysis. Variety of di-nulcleotide microsatellite markers was altered in individual microfoci from different morphological epithelial lesions, in full range of nonneoplastic epithelium to colitic cancer. Interestingly, MSI was not observed in stromal cells at any sites, including those within colitic cancer/dysplasia lesions. Expression of the MMR proteins was not lost in any of the lesions examined. Microsatellite alterations rather seem to be related to the initiation than to the progression of colitic cancer. ' 2006 Wiley-Liss, Inc.Key words: colitic cancer; ulcerative colitis; microsatellite instability; stroma; mismatch repair Colorectal epithelium with a long-standing ulcerative colitis (UC) has an increased risk of developing cancer. 1-6 An invasive colitic cancer often arises from a preceding flat dysplastic epithelium and tend to develop multifocally over the background inflamed epithelium, whilst sporadic colorectal cancer (CRC) develops from a preexisting adenoma, suggesting a dissimilar carcinogenic pathway in colitic cancer. [7][8][9][10][11][12][13][14][15] In lesions undergoing chronic inflammation, microsatellite instability (MSI) is a possible genetic alteration, and high-and low-level of MSI (MSI-H and MSI-L) has been described in UC associated neoplasm (UCAN). [16][17][18][19][20][21][22][23] However, the reported frequency of MSI-H, a consequence of a defective mismatch repair (MMR) system (notably MLH1 or MSH2), and MSI-L, a consequence in part of O 6 -methylguanine-DNA methyltransferase (MGMT) deficiency, 24 has varied considerably from 9 to 50%, and 11 to 85%, respectively. 22,[25][26][27] In situation of considerable genetic heterogeneity within a sample, collection of samples without microdissection could possibly obscure the findings of MSI. 28,29 In fact, analysis of mixed MSI-L components could result in a false diagnosis as MSI-H. To verify true MSI status and to clarify the significance of MSI in colitic carcinogenesis, precise analysis of individual microfoci from various pathological lesions (including stroma) is required. 16,18,19 Accordingly, we sampled 164 microfoci, including nondysplastic epithelium, dysplastic epithel...

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Two modes of microsatellite instability in human cancer: differential connection of defective DNA mismatch repair to dinucleotide repeat instability

Cited by 58 publications

References 41 publications

Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer

Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer

Fusion Tyrosine Kinase NPM-ALK Deregulates MSH2 and Suppresses DNA Mismatch Repair Function

Heterogeneous microsatellite instability observed within epithelium of ulcerative colitis

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