title: Identification of cancer patients with Lynch syndrome: clinically significant discordances and problems in tissue-based mismatch repair testing.
abstract: Tissue-based microsatellite instability (MSI) analysis and immunohistochemistry for DNA mismatch repair proteins are accepted screening tools to evaluate patients with cancer for Lynch syndrome. These laboratory analyses are thus important tools in cancer prevention. Quality assurance review was conducted to identify test discordances and problems. These results were then analyzed in conjunction with genetic testing outcomes. Six hundred and forty-six consecutive tumors from 2002 to 2010 were examined. MSI-low tumors were excluded so that 591 tumors comprised the final analyses. Discordance was defined as a discrepancy between immunohistochemical and MSI analysis. Problem was defined as indeterminate or questionable immunohistochemical or MSI results. All results and clinical and family histories were centrally reviewed by two pathologists and one genetics counselor. Discordances and problems were identified in 23 of 591 (3.9%) of the tumors. Twelve of 102 MSI-high carcinomas (11.8%) and one of 489 microsatellite stable tumors had discordant immunohistochemistry. Of these 13 tumors, 11 were from patients who had personal and/or family cancer histories concerning for a germline mismatch repair gene mutation. In addition to discordances, 10 tumors with problematic immunohistochemical profiles were identified. Accurate evaluation of MSI was possible in all tumors. In summary, concordance between immunohistochemistry and MSI was high, particularly for tumors that are microsatellite stable. Greater frequency of test discordance was identified in the tumors that were MSI-high. Thus, a major consequence of the use of immunohistochemistry by itself as a screen is the failure to identify colorectal and endometrial cancer patients who likely have Lynch syndrome.
authors.affiliation: Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Angela N
authors.initials: AN
authors.lastname: Bartley
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.forename: Devki S
authors.initials: DS
authors.lastname: Saraiya
authors.forename: Diana L
authors.initials: DL
authors.lastname: Urbauer
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009369:Neoplasms / Q000175:diagnosis* / Q000209:etiology*; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011379:Prognosis; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
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