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Immunohistochemistry and microsatellite instability testing for selecting MLH1, MSH2 and MSH6 mutation carriers in hereditary non-polyposis colorectal cancer.
Oncol Rep. 2004 Sep; 12(3):621-9.OR

Abstract

Hereditary non-polyposis colorectal cancer (HNPCC) represents 1-3% of all colorectal cancers. HNPCC is caused by a constitutional defect in a mismatch repair (MMR) gene, most commonly affecting the genes MLH1, MSH2 and MSH6. The MMR defect results in an increased cancer risk, with the greatest lifetime risk for colorectal cancer and other cancers associated to HNPCC. The HNPCC-associated tumor phenotype is generally characterized by microsatellite instability (MSI) and immunohistochemical loss of expression of the affected MMR protein. The aim of this study was to determine the sensitivity of IHC for MLH1, MSH2 and MSH6, and MSI analysis in tumors from known MMR gene mutation carriers. Fifty-eight paired normal and tumor samples from HNPCC families enrolled in our high-risk colorectal cancer registry were studied for the presence of germline mutations in MLH1, MSH2 and MSH6 by DGGE and direct sequencing. MSI analysis and immunostaining for MLH1, MSH2 and MSH6 were evaluated. Of the 28 patients with a real pathogenic mutation, loss of immunohistochemical expression for at least 1 of these MMR proteins was found, and all except 1 have MSI-H. Sensitivity by MSI analysis was 96%. IHC analysis had a sensitivity of 100% in detecting MMR deficiency in carriers of a pathogenic MMR mutation, and can be used to predict which gene is expected to harbor the mutation for MLH1, MSH2 and MSH6. This study suggests that both analyses are useful for selecting high-risk patients because most MLH1, MSH2 and MSH6 gene carriers will be detected by this 2-step approach. This practical method should have immediate application in the clinical work of patients with inherited colorectal cancer syndromes.

Authors+Show Affiliations

Molecular Oncology Laboratory, Hospital Clínico San Carlos, Martin Lagos s/n, 28040 Madrid, Spain. tcaldes@hcsc.esNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15289847

Citation

Caldés, Trinidad, et al. "Immunohistochemistry and Microsatellite Instability Testing for Selecting MLH1, MSH2 and MSH6 Mutation Carriers in Hereditary Non-polyposis Colorectal Cancer." Oncology Reports, vol. 12, no. 3, 2004, pp. 621-9.
Caldés T, Godino J, Sanchez A, et al. Immunohistochemistry and microsatellite instability testing for selecting MLH1, MSH2 and MSH6 mutation carriers in hereditary non-polyposis colorectal cancer. Oncol Rep. 2004;12(3):621-9.
Caldés, T., Godino, J., Sanchez, A., Corbacho, C., De la Hoya, M., Lopez Asenjo, J., Saez, C., Sanz, J., Benito, M., Ramon Y Cajal, S., & Diaz-Rubio, E. (2004). Immunohistochemistry and microsatellite instability testing for selecting MLH1, MSH2 and MSH6 mutation carriers in hereditary non-polyposis colorectal cancer. Oncology Reports, 12(3), 621-9.
Caldés T, et al. Immunohistochemistry and Microsatellite Instability Testing for Selecting MLH1, MSH2 and MSH6 Mutation Carriers in Hereditary Non-polyposis Colorectal Cancer. Oncol Rep. 2004;12(3):621-9. PubMed PMID: 15289847.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Immunohistochemistry and microsatellite instability testing for selecting MLH1, MSH2 and MSH6 mutation carriers in hereditary non-polyposis colorectal cancer. AU - Caldés,Trinidad, AU - Godino,Javier, AU - Sanchez,Ana, AU - Corbacho,Cesar, AU - De la Hoya,Miguel, AU - Lopez Asenjo,Jose, AU - Saez,Carmen, AU - Sanz,Julian, AU - Benito,Manuel, AU - Ramon Y Cajal,Santiago, AU - Diaz-Rubio,Eduardo, PY - 2004/8/4/pubmed PY - 2004/11/16/medline PY - 2004/8/4/entrez SP - 621 EP - 9 JF - Oncology reports JO - Oncol Rep VL - 12 IS - 3 N2 - Hereditary non-polyposis colorectal cancer (HNPCC) represents 1-3% of all colorectal cancers. HNPCC is caused by a constitutional defect in a mismatch repair (MMR) gene, most commonly affecting the genes MLH1, MSH2 and MSH6. The MMR defect results in an increased cancer risk, with the greatest lifetime risk for colorectal cancer and other cancers associated to HNPCC. The HNPCC-associated tumor phenotype is generally characterized by microsatellite instability (MSI) and immunohistochemical loss of expression of the affected MMR protein. The aim of this study was to determine the sensitivity of IHC for MLH1, MSH2 and MSH6, and MSI analysis in tumors from known MMR gene mutation carriers. Fifty-eight paired normal and tumor samples from HNPCC families enrolled in our high-risk colorectal cancer registry were studied for the presence of germline mutations in MLH1, MSH2 and MSH6 by DGGE and direct sequencing. MSI analysis and immunostaining for MLH1, MSH2 and MSH6 were evaluated. Of the 28 patients with a real pathogenic mutation, loss of immunohistochemical expression for at least 1 of these MMR proteins was found, and all except 1 have MSI-H. Sensitivity by MSI analysis was 96%. IHC analysis had a sensitivity of 100% in detecting MMR deficiency in carriers of a pathogenic MMR mutation, and can be used to predict which gene is expected to harbor the mutation for MLH1, MSH2 and MSH6. This study suggests that both analyses are useful for selecting high-risk patients because most MLH1, MSH2 and MSH6 gene carriers will be detected by this 2-step approach. This practical method should have immediate application in the clinical work of patients with inherited colorectal cancer syndromes. SN - 1021-335X UR - https://www.unboundmedicine.com/medline/citation/15289847/Immunohistochemistry_and_microsatellite_instability_testing_for_selecting_MLH1_MSH2_and_MSH6_mutation_carriers_in_hereditary_non_polyposis_colorectal_cancer_ L2 - http://www.spandidos-publications.com/or/12/3/621 DB - PRIME DP - Unbound Medicine ER -