title: Immunohistochemical detection of the hMLH1 and hMSH2 proteins in hereditary non-polyposis colon cancer and sporadic colon cancer.
abstract: Defects in DNA mismatch repair system are involved in carcinogenesis of sporadic and inherited human cancers. We assessed the feasibility of using immunohistochemistry to detect tumors with DNA mismatch repair deficiency. We analyzed 81 samples (74 colon cancers (CC), 1 colon dysplasia and 6 extracolonic cancers) for hMLH1 and hMSH2 protein expression, microsatellite instability (MSI) and/or mutational analysis. A meta-analysis of the published data on immunohistochemistry of hMLH1/hMSH2 proteins was performed. Sensitivity and specificity of the method was calculated. Twenty four of 29 tumors from hMLH1/hMSH2 mutation carriers and 10 of 13 sporadic high frequency MSI tumors lost one of the proteins. None of the 42 tumors with stable microsatellites or low frequency MSI lost the proteins. Based on literature review of 49 publications on colorectal cancer, hMLH1 immunohistochemistry was able to detect 136 of 154 tumors from hMLH1 germline mutation carriers (the sensitivity of 88.3% [95%CI, 85.8-90.8%]), hMSH2 immunohistochemistry detected 99 of 109 tumors from hMSH2 mutation carriers (the sensitivity of 90.8% [95%CI, 88.5-93.1%]), and hMLH1/hMSH2 immunohistochemistry identified 1262 of 1382 tumors with high-frequency microsatellite instability not correlated with mutational analysis (the sensitivity of 91.3% [95%CI, 90.4-92.2%]). The specificity of the method was 99.4% (95%CI, 99.2-99.6%). In conclusion, immunohistochemistry of hMLH1 and hMSH2 proteins is a useful method to predict the presence of mismatch repair deficiency, although its sensitivity is lower than that of MSI analysis.
authors.affiliation: Institute of Pathology, Medical Faculty of the Palacký University, 775 15 Olomouc, Czech Republic. pavlina.plevova@volny.cz
authors.forename: P
authors.initials: P
authors.lastname: Plevová
authors.forename: A
authors.initials: A
authors.lastname: Krepelová
authors.forename: M
authors.initials: M
authors.lastname: Papezová
authors.forename: E
authors.initials: E
authors.lastname: Sedláková
authors.forename: R
authors.initials: R
authors.lastname: Curík
authors.forename: L
authors.initials: L
authors.lastname: Foretová
authors.forename: M
authors.initials: M
authors.lastname: Navrátilová
authors.forename: J
authors.initials: J
authors.lastname: Novotný
authors.forename: J
authors.initials: J
authors.lastname: Zapletalová
authors.forename: J
authors.initials: J
authors.lastname: Palas
authors.forename: J
authors.initials: J
authors.lastname: Nieslanik
authors.forename: J
authors.initials: J
authors.lastname: Horácek
authors.forename: J
authors.initials: J
authors.lastname: Dvorácková
authors.forename: Z
authors.initials: Z
authors.lastname: Kolár
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics*; D005091:Exons; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D007438:Introns; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics*; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics*; D012680:Sensitivity and Specificity
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein