Sinicrope Frank A, Rego Rafaela L, Foster Nathan, Sargent Daniel J, Windschitl Harold E, Burgart Lawrence J, Witzig Thomas E, Thibodeau Stephen N
Mayo Clinic and Mayo College of Medicine, Rochester, Minnesota 55905, USA.
Am J Gastroenterol. 2006 Dec;101(12):2818-25. doi: 10.1111/j.1572-0241.2006.00845.x. Epub 2006 Oct 6.
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 + G(2)M) 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< 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.
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.
高频微卫星不稳定（MSI-H）的结肠癌多位于近端结肠。鉴于15%-20%的散发性结肠癌为MSI-H，我们确定了临床病理变量、生物标志物和预后方面肿瘤部位特异性差异是否归因于MSI-H病例的纳入。
对参加基于5-氟尿嘧啶的辅助试验患者的TNM II期和III期原发性结肠癌（N = 528），使用11个微卫星标记分析MSI。进行DNA错配修复（hMLH1、hMSH2、hMSH6）和p53蛋白的免疫染色。通过流式细胞术分析DNA倍体（二倍体与非整倍体/四倍体）和增殖指数（PI：S期+G(2)M）。
在95例（18%）结肠癌中发现MSI-H。与远端肿瘤相比，近端肿瘤（N = 286）与MSI-H、老年（>65岁）、低分化和二倍体DNA含量相关（所有P<或=0.016）。核p53染色在远端肿瘤中更常见（P = 0.002）；PI与肿瘤部位无关。排除MSI-H肿瘤后，除年龄外未发现与肿瘤部位相关的差异，年龄仍与近端癌相关（P = 0.030）。近端部位与所有患者无病生存期改善相关（P = 0.042），但排除MSI-H病例后则无相关性（P = 0.236）。MSI-H状态或错配修复蛋白缺失、二倍体和较低的PI与生存率提高相关。
散发性结肠癌临床病理变量、生物标志物和预后方面与肿瘤部位相关的差异可通过纳入MSI-H病例来解释。然而，老年与近端肿瘤部位相关，与MSI状态无关。
