Dukes B colorectal cancer - Distinct genetic categories and clinical outcome based on proximal or distal tumor location

PURPOSE: The aim of this study was to determine whether turner location pro ximal or distal to the splenic flexure is associated with distinct molecula r patterns and can predict clinical outcome in a homogeneous group of patie nts with Dukes B (T3-T4, N0, M0) colorectal cancer. It has been hypothesize d that proximal and distal colorectal cancer may arise through different pa thogenetic mechanisms. Although p53 and Ki-ras gene mutations occur frequen tly in distal tumors, another form of genomic instability associated with d efective DNA mismatch repair has been predominantly identified in the proxi mal colon. To date, however, the clinical usefulness of these molecular cha racteristics remains unproven. METHODS: A total of 126 patients with a lymp h node-negative sporadic colon or rectum adenocarcinoma were prospectively assessed with the endpoint of death by cancer. No patient received either r adiotherapy or chemotherapy. p53 protein was studied by immunohistochemistr y using DO-7 monoclonal antibody, and p53 and Ki-ras gene mutations were de tected by single strand con formation polymorphism assay. RESULTS: During a mean follow-up of 67 months, the overall five-year survival was 70 percent . Nuclear p53 staining was found in 57 tumors (47 percent), and was more fr equent in distal than in proximal tumors (55 vs. 21 percent; chi-squared te st, P < 0.001). For the whole group, p53 protein expression correlated with poor survival in univariate and multivariate analysis (log-rank rest, P = 0.01; hazard ratio = 2.16; 95 percent confidence interval = 1.12-4.11, P = 0.02). Distal colon tumors and rectal tumors exhibited similar molecular pa tterns and showed no difference in clinical outcome. In comparison with dis tal colorectal cancer, proximal tumors were found to be statistically signi ficantly different on thr following factors: mucinous content (P = 0.008), degree of histologic differentiation (P = 0.012), p53 protein expression, a nd gene mutation (P = 0.001 and 0.01 respectively). Finally, patients with proximal tumors had a marginally better survival than those with distal col on or rectal cancers (log-rank test, P = 0.045). CONCLUSION: In this series of Dukes B colorectal cancers, p53 protein expression was an independent f actor for survival, which also correlated with tumor location. Eighty-six p ercent of p53-positive tumors were located in the distal colon and rectum, Distal colon and rectum tumors had similar molecular and clinical character istics. In contrast, proximal neoplasms seem to represent a distinct entity , with specific histopathologic characteristics, molecular patterns, and cl inical outcome. Location of the neoplasm in reference to the splenic flexur e should be considered before group stratification in future trials of adju vant chemotherapy in patients; with Dukes B tumors.