title: Immunohistochemistry as first-line screening for detecting colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: a 2-antibody panel may be as predictive as a 4-antibody panel.
abstract: The utility of immunohistochemical detection of DNA mismatch repair proteins in screening colorectal cancer for hereditary nonpolyposis colorectal cancer (HNPCC) is being widely investigated. Currently, in both research and clinical settings, a 4-antibody panel that includes the 4 most commonly affected proteins (MLH1, MSH2, MSH6, and PMS2) is being used generally. On the basis of the biochemical properties of these proteins, we hypothesized that a 2-antibody panel, comprising MSH6 and PMS2, would be sufficient to detect abnormalities in all 4 proteins. We tested this hypothesis on a series of 232 colorectal carcinoma samples derived from 2 patient cohorts: (1) a prospectively accrued series of patients who were judged to carry a higher-than-average risk for HNPCC based on the revised Bethesda guidelines (n=190); and (2) a retrospective series of patients who were 40 years of age or younger (n=42). Immunohistochemical stains were regarded as negative (protein lost), when there was no nuclear labeling in tumor cells (with positive internal control). Overall, 70 of the 232 tumors demonstrated loss of at least one protein. The most common abnormality was concurrent loss of MLH1 and PMS2 (observed in 17% of the cases), followed by concurrent loss of MSH2 and MSH6 (6%). All MLH1 and MSH2-abnormal cases were also abnormal for PMS2 and MSH6, respectively, whereas 9 of 50 (18%) PMS2 and 6 of 20 (30%) MSH6-abnormal cases showed only isolated loss of PMS2 or MSH6 (with normal staining for MLH1 and MSH2). As such, our findings provide evidence that a 2-antibody panel (PMS2 and MSH6) is as effective as the current 4-antibody panel in detecting DNA mismatch repair protein abnormalities. Such a cost-effective approach carries significant implication, as immunohistochemistry is being widely used as first-line screening for HNPCC.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.forename: Laura H
authors.initials: LH
authors.lastname: Tang
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.forename: Jose G
authors.initials: JG
authors.lastname: Guillem
authors.forename: Zsofia K
authors.initials: ZK
authors.lastname: Stadler
authors.forename: Robert A
authors.initials: RA
authors.lastname: Soslow
authors.forename: Nora
authors.initials: N
authors.lastname: Katabi
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weiser
authors.forename: Philip B
authors.initials: PB
authors.lastname: Paty
authors.forename: Larissa K
authors.initials: LK
authors.lastname: Temple
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Nash
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Wong
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D053843:DNA Mismatch Repair / Q000502:physiology; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques / Q000191:economics / Q000379:methods*; D008403:Mass Screening / Q000191:economics / Q000379:methods; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012189:Retrospective Studies
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; 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