Microsatellite Instability and hMLH1 and hMSH2 Expression Analysis in Familial and Sporadic Colorectal Cancer

Salahshor, Sima; Koelble, Konrad; Rubio, Carlos A.; Lindblom, Annika

doi:10.1038/labinvest.3780262

Cited by 97 publications

(86 citation statements)

References 28 publications

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“…19,20,[31][32][33][34][35][36] Clearly, mutation analysis cannot be applied at a large scale and should only be offered to patients with substantial risk of having a deleterious mutation. Also, microsatellite analysis and immunohistochemistry, which have been shown to allow effective enrichment of high-risk patients, are presently not recommended for all cases of colorectal tumors.…”

Section: Discussionmentioning

confidence: 99%

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Engel

Forberg

Holinski‐Feder

et al. 2005

Intl Journal of Cancer

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Clinical criteria, microsatellite analysis (MSA) and immunohistochemistry (IHC) are important diagnostic tools for identification of hereditary nonpolyposis colorectal cancer (HNPCC) patients who are likely to carry pathogenic germline mutations in mismatch repair genes. Based on MSA and IHC results and subsequent mutation analyses of 1,119 unrelated index patients meeting the Amsterdam II criteria or the classical Bethesda guidelines, we analyzed the value of these tools to predict MLH1 and MSH2 mutations with the aim of establishing optimal strategies for their most efficient sequential use. The overall prevalence of pathogenic germline mutations in our cohort was 20.6% (95% CI 5 18.3-23.0%) and 61.8% (95% CI 5 56.8-66.6%), respectively, after MSA/IHC-based preselection. IHC was highly predictive (99.1%) and specific (99.6%) with regard to MSA. However, 14 out of 230 mutations (6%) escaped detection by IHC. Thus, IHC cannot be recommended to substitute MSA fully. Nonetheless, IHC is important to indicate the gene that is likely to be affected. To combine both methods efficiently, we propose a novel screening strategy that provides 2 alternative ways of sequential IHC and MSA application, either using IHC or MSA in the first place. A logistic regression model based on the age of the index patient at first tumor diagnosis and the number of fulfilled HNPCC criteria is used to allocate individual patients to that alternative pathway that is expected to be least expensive. A cost analysis reveals that about 25% of the costs can be saved using this strategy. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Engel

Forberg

Holinski‐Feder

et al. 2005

Intl Journal of Cancer

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“…Since approximately 90% of medullary-type carcinomas showed an absence of hMLH1 protein expression together with microsatellite instability, immunohistochemistry for the detection of hMLH1 protein may be useful in predicting the tumor type. 12,32 However, immunohistochemistry cannot replace testing for microsatellite instability to identify microsatellite-unstable sporadic colorectal cancer, 33 and morphological prediction of microsatellite-unstable cancer has low sensitivity. 34 Thus, we emphasize that both hMLH1 immunohistochemistry and a histopathological evaluation can predict medullary-type carcinomas, but they may miss some cases.…”

Section: Discussionmentioning

confidence: 99%

“…34 Thus, we emphasize that both hMLH1 immunohistochemistry and a histopathological evaluation can predict medullary-type carcinomas, but they may miss some cases. 32,33 Molecular analysis is required for therapeutic decisions. 34 Colorectal adenocarcinoma are graded predominantly on the basis of the extent of glandular appearances.…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly

Arai

Esaki²,

Sawabe

et al. 2004

Modern Pathology

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To clarify the significance of hMLH1 promoter hypermethylation in the development of medullary-type poorly differentiated colorectal adenocarcinoma, we studied the status of promoter methylation and hMLH1 expression in 23 medullary-type and 12 pleomorphic-type carcinomas, as well as the pathology and microsatellite status. In medullary-type carcinomas, the percentages of cases with promoter methylation (83%) and an absence of hMLH1 expression (91%) were significantly higher than in pleomorphic-type carcinomas (14 and 17%), respectively. The rate of microsatellite instability in the medullary type was significantly higher than that of the pleomorphic type (87 vs 40%, Po0.01). Compared with pleomorphic-type carcinomas, medullary-type carcinomas were significantly associated with hMLH1 promoter methylation, absent expression of hMLH1 protein, microsatellite instability, as well as a proximal location, a Crohn's-like lymphoid reaction, a low incidence of lymph node metastasis, and a favorable outcome. Medullary-type carcinomas accumulated with advancing age, especially in the female. These results indicated that hMLH1 hypermethylation, concurrent with a lack of its protein expression, may play an important role in the development of medullary-type poorly differentiated colorectal adenocarcinomas in the elderly.

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“…19,20 In 1998, five "Bethesda MSI markers" were recommended by a National Cancer Institute workshop on MSI, which are considered to be able to detect MSI-H cancers with high reliability. 21 hMLH1 expression determined by immunohistochemistry (IHC) has been compared to MSI testing in sporadic CRC and HNPCC, and a correlation was found in detecting the loss of hMLH1 expression and MSI-H. 22,23,24 However, these strategies could not exclude the possibility of missing some cases of MSI-H cancers when IHC was used as a solitary technique. Recently, much emphasis has also been placed on studying hMLH1 methylation in CRCs.…”

Section: 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 Nmentioning

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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Microsatellite Instability and hMLH1 and hMSH2 Expression Analysis in Familial and Sporadic Colorectal Cancer

Cited by 97 publications

References 28 publications

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly

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

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