Microsatellite instability accounts for tumor site-related differences in clinicopathologic variables and prognosis in human colon cancers

Am J Gastroenterol. 2006 Dec;101(12):2818-25. doi: 10.1111/j.1572-0241.2006.00845.x. Epub 2006 Oct 6.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Aged
  • Carrier Proteins / metabolism
  • Cell Proliferation
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • DNA-Binding Proteins / metabolism
  • Female
  • Humans
  • Male
  • Microsatellite Instability*
  • Middle Aged
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein / metabolism
  • Nuclear Proteins / metabolism
  • Ploidies
  • Prognosis
  • Tumor Suppressor Protein p53 / metabolism


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MLH1 protein, human
  • Nuclear Proteins
  • Tumor Suppressor Protein p53
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein