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

Frank A. Sinicrope, Rafaela L. Rego, Nathan Foster, Daniel J. Sargent, Harold E. Windschitl, Lawrence J. Burgart, Thomas E. Witzig, Stephen N. Thibodeau

Research output: Contribution to journalArticle

50 Scopus citations

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 + G2M) 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 ≤ 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.

Original languageEnglish (US)
Pages (from-to)2818-2825
Number of pages8
JournalAmerican Journal of Gastroenterology
Volume101
Issue number12
DOIs
StatePublished - Dec 1 2006

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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