title: Microsatellite instability accounts for tumor site-related differences in clinicopathologic variables and prognosis in human colon cancers.
abstract: OBJECTIVE
  Colon cancers with high frequency microsatellite instability (MSI-H) are preferentially located in the proximal colon. Given that 15-20% of sporadic colon cancers are MSI-H, we determined whether tumor site-specific differences in clinicopathological variables, biomarkers, and prognosis are due to inclusion of MSI-H cases.
  
  
  METHODS
  TNM stage II and III primary colon carcinomas (N = 528) from patients enrolled in 5-fluorouracil-based adjuvant trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for DNA mismatch repair (hMLH1, hMSH2, hMSH6) and p53 proteins was performed. DNA ploidy (diploid vs aneuploid/tetraploid) and proliferative indices (PI: S-phase + G(2)M) were analyzed by flow cytometry.
  
  
  RESULTS
  MSI-H was found in 95 (18%) colon cancers. Proximal tumors (N = 286) were associated with MSI-H, older age (>65 yr), poor differentiation, and diploid DNA content compared with distal tumors (all P< or = 0.016). Nuclear p53 staining was more frequent in distal tumors (P= 0.002); PI was unrelated to tumor site. When MSI-H tumors were excluded, no tumor site-related differences were found except for age, which remained associated with proximal cancers (P= 0.030). Proximal site was associated with improved disease-free survival in all patients (P= 0.042), but not when MSI-H cases were excluded (P= 0.236). MSI-H status or loss of mismatch repair proteins, diploidy, and lower PI were associated with improved survival rates.
  
  
  CONCLUSIONS
  Tumor site-related differences in clinicopathological variables, biomarkers, and prognosis of sporadic colon cancers can be explained by the inclusion of MSI-H cases. Older age, however, is associated with proximal tumor site independent of MSI status.
authors.affiliation: Mayo Clinic and Mayo College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
authors.forename: Rafaela L
authors.initials: RL
authors.lastname: Rego
authors.forename: Nathan
authors.initials: N
authors.lastname: Foster
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.forename: Harold E
authors.initials: HE
authors.lastname: Windschitl
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Burgart
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000368:Aged; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011003:Ploidies; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein