title: Challenges in the identification of MSH6-associated colorectal cancer: rectal location, less typical histology, and a subset with retained mismatch repair function.
abstract: Identification of Lynch syndrome tumors is challenging. This relates particularly to MSH6-associated cases, which show reduced penetrance of colorectal cancer and a higher age at diagnosis. We recorded the clinical and morphologic features of 52 MSH6-associated colorectal cancers in comparison with MLH1/MSH2-mutant tumors and sporadic mismatch repair-deficient cancers. In the MSH6 subset, we confirmed a higher age (median, 56 y) at diagnosis and found a significantly larger proportion (25%) of rectal cancers. Presence of dirty necrosis was the sole histologic component that significantly differed between MSH6 and MLH1/MSH2 tumors. Compared with the sporadic mismatch repair-defective cohort, MSH6 cases had a lower prevalence of tumor-infiltrating lymphocytes and Crohn-like reactions. Mismatch repair defects were identified in 92% of MSH6 tumors, with high concordance between microsatellite instability and loss of immunohistochemical MSH6 expression. The remaining 8% showed a mismatch repair-stable phenotype, which suggests that analysis of additional tumors might be considered in families suspected of Lynch syndrome.
authors.affiliation: Clinical Research Center, Department of Pathology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Sweden. louise.klarskov@dadlnet.dk
authors.forename: Louise
authors.initials: L
authors.lastname: Klarskov
authors.forename: Susanne
authors.initials: S
authors.lastname: Holck
authors.forename: Inge
authors.initials: I
authors.lastname: Bernstein
authors.forename: Henrik
authors.initials: H
authors.lastname: Okkels
authors.forename: Eva
authors.initials: E
authors.lastname: Rambech
authors.forename: Bo
authors.initials: B
authors.lastname: Baldetorp
authors.forename: Mef
authors.initials: M
authors.lastname: Nilbert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D016009:Chi-Square Distribution; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000235:genetics; D003718:Denmark; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation; D009336:Necrosis; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D011237:Predictive Value of Tests; D012007:Rectum / Q000473:pathology*; D012042:Registries
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein