Determination of the replication error phenotype in human tumors without the requirement for matching normal DNA by analysis of mononucleotide repeat microsatellites

Zhou, Xiaoping; Hoang, Jean-Marc; Li, Youjun; Seruca, Raquel; Carneiro, Fátima; Sobrinho‐Simöes, Manuel; Lothe, Ragnhild; Gleeson, C. M.; Russell, S. E. H.; Muzeau, Françoise; Fléjou, Jean‐François; Hoang-Xuân, Khê; Lidereau, Rosette; Thomas, Gilles; Hamelin, Richard

doi:10.1002/(sici)1098-2264(199802)21:2<101::aid-gcc4>3.0.co;2-4

Cited by 211 publications

(169 citation statements)

References 19 publications

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“…Previous studies have reported a high accuracy of specific MSI markers in detecting the MSI-H phenotype, especially for the highly monomorphic mononucleotide marker BAT26. 28 We compared the sensitivity and specificity of each individual marker of the Bethesda panel for its ability to define the MSI-H (n = 45) phenotype based on all 5 markers. All 45 MSI-H tumors (from CALGB and UCSD) were included in this analysis.…”

Section: Msi Status Correlation With Hmlh1 Promoter Methylation and mentioning

confidence: 99%

Evaluation of Microsatellite Instability, hMLH1 Expression and hMLH1 Promoter Hypermethylation in Defining the MSI Phenotype of Colorectal Cancer

Arnold¹,

Goel²,

Compton³

et al. 2004

Cancer Biology & Therapy

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B i o s c i e n c e . N o t f o r d i s t r i b u t i o n . KEY WORDShMLH1, microsatellite instability, promoter methylation, colorectal cancer, immunohistochemistry ACKNOWLEDGEMENTSThe research for CALGB study 9865 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, Chairman). This work was also sponsored by a grant from the NIH (RO1-CA 72851) to C.R.B and in part by an American Cancer Society-IRG award to A.G. C.N.A. was funded by a grant of the Dr. MildredScheel-Stiftung, Germany. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. For further information regarding who participated in this study, please see table on p. 78. ABSTRACTIntroduction: About 15% of all colorectal cancers (CRCs) demonstrate high levels of microsatellite instability (MSI-H) and are currently best identified by molecular analysis of microsatellite markers. Most sporadic CRCs with MSI-H are known to be associated with the methylation of the hMLH1 promoter. Promoter methylation coincided with lack of hMLH1 expression. We aimed to investigate the association between MSI status, hMLH1 protein expression and methylation status of the hMLH1 promoter, and to determine the usefulness of each method in defining the MSI phenotype in sporadic CRCs. Materials and Methods: CRCs from 173 patients from the Cancer and Leukemia Group B (CALGB) were assessed for their MSI status. An additional cohort of 18 MSI-H tumors from the University of California San Diego (UCSD) was included in the analysis of the MSI-H subgroup. MSI testing was performed by PCR using five standard MSI markers. hMLH1 promoter analysis was investigated by methylation specific PCR (MSP), and expression of the MMR genes hMLH1 and hMSH2 was examined by immunohistochemistry (IHC). Results: Of the 173 CALGB tumors, 111 (64%) were MSS, 35 (20%) were MSI-L and 27 (16%) MSI-H, respectively. Data on hMLH1 protein expression, hMSH2 protein expression and hMLH1 methylation are available on 128, 173 and 81 of these tumors, respectively. Presence of hMLH1 and hMSH2 protein expression was significantly associated with MSI status. Four of 45 (8.9%) MSI-H tumors and 0 of 146 (0%) MSS/MSI-L tumors did not express hMSH2 (p = 0.0028). hMLH1 protein expression was present in 107 of 108 (99%) MSS and MSI-L tumors versus 11 of 20 (55%) MSI-H tumors (p < 0.0001). Of 61 MSS and MSI-L cancers studied for methylation, 11 (18%) were methylated at the hMLH1 promoter whereas 14 of 20 (70%) MSI-H cancers were methylated (p = 0.0001). In 27 MSI-H tumors studied for hMLH1 protein expression and methylation, 93% of tumors with loss of expression (93%) were also methylated while 42% (5/12) with positive immunostaining for hMLH1 were methylated at the hMLH1 promoter (p = 0.009). Conclusions: Promoter methylation and hMLH1 expression are significantly associated with the MSI-H phenotype in CRC. Promoter methylation analysis p...

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Section: Msi Status Correlation With Hmlh1 Promoter Methylation and mentioning

confidence: 99%

Evaluation of Microsatellite Instability, hMLH1 Expression and hMLH1 Promoter Hypermethylation in Defining the MSI Phenotype of Colorectal Cancer

Arnold¹,

Goel²,

Compton³

et al. 2004

Cancer Biology & Therapy

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“…The MSI status of the 100 tumours in the first series were analysed by the two mononucleotide repeats, BAT-25 and BAT-26, which are robust markers for MSI-H detection (Loukola et al, 2001;Zhou et al, 1998). Tumours with mutation in both markers were defined MSI-H (10 cases) and the rest were put in the MSS/MSI-L group.…”

Section: Msi Statusmentioning

confidence: 99%

Strong HLA-DR expression in microsatellite stable carcinomas of the large bowel is associated with good prognosis

et al. 2002

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Progression of colorectal cancer may follow either of two main genetic routes: the chromosome- or microsatellite-instability pathways. Association between the patients' prognosis and microsatellite instability has been questioned. Improved survival has previously been found in patients with expression of HLA-DR antigens on their tumour cells. In this study, the expression of HLA-DR antigen was investigated by immunohistochemistry in 357 large bowel carcinomas stratified by microsatellite instability status. Sixteen per cent of the tumours showed strong HLA-DR expression and 35% had weak DR expression. We confirmed that patients with strong positive HLA-DR staining had improved survival ( P <0.001) compared to patients with no HLA-DR expression. Strong epithelial HLA-DR staining was significantly associated with high level of microsatellite instability ( P <0.001). In the subgroup of tumours with characteristics typical of the chromosomal instability phenotype, i.e. in microsatellite-stable tumours, the patients positive for the HLA-DR determinants showed better survival than those without HLA-DR expression. The protective effect of HLA-DR expression on survival was confirmed by multivariate analysis, both in the whole patient group and in the microsatellite-stable/microsatellite instability-low group. This might be explained by enhanced T-cell mediated anti-tumour immune responses against tumour cells in the HLA-DR positive tumours. The finding of better patient survival in the subgroup of strong HLA-DR positive microsatellite-stable tumours may have clinical implications for these patients. British Journal of Cancer (2002) 87 , 756–762. doi: 10.1038/sj.bjc.6600507 www.bjcancer.com © 2002 Cancer Research UK

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“…All the samples were tested at ®ve microsatellite loci including the highly unstable BAT-26 locus, claimed to be su cient alone for identifying the RER status (Zhou et al, 1998;Hoang et al, 1997). The other 4 loci included L-myc, TGFbRII, D13S160, and D2S123 using the primers and conditions described elsewhere (Young et al, 1995;Huang et al, 1996).…”

Section: Rer Status Analysismentioning

confidence: 99%

Role of BAX mutations in mismatch repair-deficient colorectal carcinogenesis

et al. 1999

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BAX gene mutations occur in approximately 50% of RER+ colorectal cancers. To determine the role of these mutations in tumour progression we analysed multiple di erent tumour sites from RER+ colorectal cancers for BAX mutations. Sixty colorectal carcinomas were analysed for microsatellite instability at loci BAT-26, L-myc, TGFbRII, D13S160 and D2S123. Twelve out of 60 tumours (20%) were RER+. Forty-®ve di erent tumour sites from the 12 RER+ carcinomas were analysed for BAX mutations at the [(G)8] tract in exon 3. Six out of 12 (50%) RER+ tumours showed BAX mutations, four of which showed a homogenous pattern of such mutations detected in all tumour sites. In the other two cases, BAX mutations were present in some but not all tumour sites sampled from the same patient. In contrast, TGFbRII mutations were found in 9/12 cases (75%) and in each of these were present in all the sampled sites. Two cases showed neither BAX nor TGFbRII mutation. These data suggest that mutations in TGFbRII may occur at a very early stage in tumour progression, perhaps in the founder clone. BAX mutations, however, are clearly not necessary for formation of the founder clone and can occur for the ®rst time later in tumour progression.

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Determination of the replication error phenotype in human tumors without the requirement for matching normal DNA by analysis of mononucleotide repeat microsatellites

Cited by 211 publications

References 19 publications

Evaluation of Microsatellite Instability, hMLH1 Expression and hMLH1 Promoter Hypermethylation in Defining the MSI Phenotype of Colorectal Cancer

Evaluation of Microsatellite Instability, hMLH1 Expression and hMLH1 Promoter Hypermethylation in Defining the MSI Phenotype of Colorectal Cancer

Strong HLA-DR expression in microsatellite stable carcinomas of the large bowel is associated with good prognosis

Role of BAX mutations in mismatch repair-deficient colorectal carcinogenesis

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