title: Molecular genetics of microsatellite-unstable colorectal cancer for pathologists.
abstract: BACKGROUND
  Microsatellite-unstable colorectal cancers (CRC) that are due to deficient DNA mismatch repair (dMMR) represent approximately 15% of all CRCs in the United States. These microsatellite-unstable CRCs represent a heterogenous group of diseases with distinct oncogenesis pathways. There are overlapping clinicopathologic features between some of these groups, but many important differences are present. Therefore, determination of the etiology for the dMMR is vital for proper patient management and follow-up.
  
  
  METHODS
  Epigenetic inactivation of MLH1 MMR gene (sporadic microsatellite-unstable CRC) and germline mutation in an MMR gene (Lynch syndrome, LS) are the two most common mechanisms in the pathogenesis of microsatellite instability in CRC. However, in a subset of dMMR CRC cases that are identified by screening tests, no known LS-associated genetic alterations are appreciated by current genetic analysis. When the etiology for dMMR is unclear, it leads to patient anxiety and creates challenges for clinical management.
  
  
  CONCLUSIONS
  It is critical to distinguish LS patients from other patients with tumors due to dMMR, so that the proper screening protocol can be employed for the patients and their families, with the goal to save lives while avoiding unnecessary anxiety and costs. This review summarizes the major pathogenesis pathways of dMMR CRCs, their clinicopathologic features, and practical screening suggestions. In addition, we include frequently asked questions for MMR immunohistochemistry interpretation.
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, S301 Rhodes Hall, 450 W. 10th Ave, Columbus, Ohio, 43210, USA.|Department of Pathology, The Ohio State University Wexner Medical Center, 129 Hamilton Hall, Columbus, Ohio, 43210, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Swanson
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, S301 Rhodes Hall, 450 W. 10th Ave, Columbus, Ohio, 43210, USA. Wendy.Frankel@osumc.edu.|Department of Pathology, The Ohio State University Wexner Medical Center, 129 Hamilton Hall, Columbus, Ohio, 43210, USA. Wendy.Frankel@osumc.edu.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Frankel
mesh_terms: D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D000072142:Pathologists; D012007:Rectum / Q000473:pathology
keywords: Colorectal cancer; Immunohistochemistry; Lynch syndrome; MMR; MSI; Microsatellite instability; Mismatch repair protein; Molecular genetics