Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing

Terdiman, Jonathan P.; Gum, James R.; Conrad, Peggy; Miller, Glenn A.; Weinberg, Vivian; Crawley, Suzanne C.; Levin, Theodore R.; Reeves, Cynthia; Schmitt, Anna; Hepburn, M B S Lisa; Sleisenger, Marvin H.; Kim, Young S.

doi:10.1053/gast.2001.20874

Cited by 141 publications

(87 citation statements)

References 25 publications

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“…23,29,30 First, we demonstrated the expected frequency of the MSI phenotype in sporadic colorectal cancer with 16% of all cancers being MSI-H. Interestingly, only 45% of these cancers showed absence of hMLH1 expression. Earlier studies have estimated sensitivity between 75% and 100% for negative immunostaining and the MSI-H phenotype.…”

Section: Discussionmentioning

confidence: 67%

“…This is in accordance with others, all showing a specificity of 100% of immunohistochemistry in correctly diagnosing the MSS phenotype in cancers with positive hMLH1 and hMSH2 expression. 22,23,[29][30][31] Despite this, an important issue still remains as to how the difference in sensitivity of immunohistochemistry in MSI-H cancers demonstrated in our and previous studies can be best explained. One issue is the definition of the MSI phenotype itself.…”

Section: Discussionmentioning

confidence: 75%

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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: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 75%

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 same yield of about 50% is found for families with less clinical indications of HNPCC but which, in addition, have MSI-high tumours (Terdiman et al, 2001;Raedle et al, 2001). Among families that only fulfil clinical criteria, usually not as stringent as the Amsterdam criteria, mutations are detected in about 30% of kindreds (Wijnen et al, 1998a;Bapat et al, 1999;Lamberti et al, 1999;Syngal et al, 2000;Wahlberg et al, 2002).…”

Section: Discussionmentioning

confidence: 78%

Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

et al. 2002

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Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatchrepair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer.

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“…A small proportion of HNPCC cases appear to be caused by germ line mutations in two other MMR genes, Msh6 and Pms2, and mutations in Msh6 are also found in familial non-HNPCC cases (17)(18)(19)(20)(21). Tumors from HNPCC patients often exhibit microsatellite instability (MSI) (22)(23)(24)(25)(26). MSI results from expansion or contraction of mono-or multinucleotide repeats due to failure to repair insertion͞ deletion mismatches in DNA.…”

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confidence: 99%

Haploinsufficiency of Flap endonuclease ( Fen1 ) leads to rapid tumor progression

Kucherlapati

Yang

Kuraguchi

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

227

188

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Flap endonuclease (Fen1) is required for DNA replication and repair, and defects in the gene encoding Fen1 cause increased accumulation of mutations and genome rearrangements. Because mutations in some genes involved in these processes cause cancer predisposition, we investigated the possibility that Fen1 may function in tumorigenesis of the gastrointestinal tract. Using gene knockout approaches, we introduced a null mutation into murine Fen1. Mice homozygous for the Fen1 mutation were not obtained, suggesting absence of Fen1 expression leads to embryonic lethality. Most Fen1 heterozygous animals appear normal. However, when combined with a mutation in the adenomatous polyposis coli (Apc) gene, double heterozygous animals have increased numbers of adenocarcinomas and decreased survival. The tumors from these mice show microsatellite instability. Because one copy of the Fen1 gene remained intact in tumors, Fen1 haploinsufficiency appears to lead to rapid progression of cancer

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Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing

Cited by 141 publications

References 25 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

Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

Haploinsufficiency of Flap endonuclease ( Fen1 ) leads to rapid tumor progression

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