title: Screening for germline mismatch repair mutations following diagnosis of sebaceous neoplasm.
abstract: IMPORTANCE Sebaceous neoplasms (SNs) define the Muir-Torre syndrome variant of Lynch syndrome (LS), which is associated with increased risk for colon and other cancers necessitating earlier and more frequent screening to reduce morbidity and mortality.Immunohistochemical (IHC) staining for mismatch repair (MMR) proteins in SNs can be used to screen for LS, but data on subsequent germline genetic testing to confirm LS diagnosis are limited.OBJECTIVE To characterize the utility of IHC screening of SNs in identification of germline MMR mutations confirming LS.DESIGN, SETTING, AND PARTICIPANTS Retrospective study at 2 academic cancer centers of 86 adult patients referred for clinical genetics evaluation after diagnosis of SN.MAIN OUTCOMES AND MEASURES Results of tumor IHC testing and germline genetic testing were reviewed to determine positive predictive value and sensitivity of IHC testing in diagnosis of LS. Clinical variables, including age at diagnosis of SN, clinical diagnostic criteria for LS and Muir-Torre syndrome, and family history characteristics were compared between mutation carriers and noncarriers.RESULTS Of 86 patients with SNs, 25 (29%) had germline MMR mutations confirming LS.Among 77 patients with IHC testing on SNs, 38 (49%) had loss of staining of 1 or more MMR proteins and 14 had germline MMR mutations. Immunohistochemical analysis correctly identified 13 of 16 MMR mutation carriers, corresponding to 81% sensitivity. Ten of 12 patients(83%) with more than 1 SN had MMR mutations. Fifty-two percent of MMR mutation carriers did not meet clinical diagnostic criteria for LS, and 11 of 25 (44%) did not meet the clinical definition of Muir-Torre syndrome. CONCLUSIONS AND RELEVANCE Immunohistochemical screening of SNs is effective in identifying patients with germline MMR mutations and can be used as a first-line test when LSis suspected. Abnormal IHC results, including absence of MSH2, are not diagnostic of LS and should be interpreted cautiously in conjunction with family history and germline genetic testing. Use of family history to select patients for IHC screening has substantial limitations,suggesting that universal IHC screening of SNs merits further study. Clinical genetics evaluation is warranted for patients with abnormal IHC test results, normal IHC test results with personal or family history of other LS-associated neoplasms, and/or multiple SNs.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Everett
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Raymond
authors.forename: Monica
authors.initials: M
authors.lastname: Dandapani
authors.forename: Monica
authors.initials: M
authors.lastname: Marvin
authors.forename: Wendy
authors.initials: W
authors.lastname: Kohlmann
authors.forename: Anu
authors.initials: A
authors.lastname: Chittenden
authors.forename: Erika
authors.initials: E
authors.lastname: Koeppe
authors.forename: Shanna L
authors.initials: SL
authors.lastname: Gustafson
authors.forename: Tobias
authors.initials: T
authors.lastname: Else
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Fullen
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Johnson
authors.forename: Sapna
authors.initials: S
authors.lastname: Syngal
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.forename: Elena M
authors.initials: EM
authors.lastname: Stoffel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000032:analysis / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000951:Antigens, Neoplasm / Q000032:analysis / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D055653:Muir-Torre Syndrome / Q000175:diagnosis* / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000032:analysis / Q000235:genetics; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics; D011237:Predictive Value of Tests; D012189:Retrospective Studies
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C094443:G-T mismatch-binding protein; 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