Microsatellite Instability Accounts for Tumor Site-Related Differences in Clinicopathologic Variables and Prognosis in Human Colon Cancers

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Abstract
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. 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. 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. 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.