Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location PURPOSE: To examine studies of normal colon and colorectal cancer for evidence that the location of the primary tumor proximal or distal to the splenic flexure of the colon may determine distinct genetic categories of this disease. DATA IDENTIFICATION: Studies were identified through a manual search of journals, through MEDLINE, and through review of bibliographies in identified articles. STUDY SELECTION: Approximately 300 articles were examined. About 150 articles were excluded because tumor location was not reported or was reported in a way that did not permit correlation with results or conclusions. DATA EXTRACTION: Articles were selected either because the presentation of data permitted correlation of results with anatomic regions of the colon or because they were relevant to inherited colorectal cancer. RESULTS OF THE ANALYSIS: Differences were noted in biologic properties of proximal and distal segments of normal fetal and adult colonic epithelium and in the epidemiologic, pathologic, cytogenetic, and molecular features of proximal and distal colorectal cancer. Some differences correlated with the features of inherited colorectal cancer (proximal, nonpolyposis or distal, and polyposis forms). CONCLUSIONS: Developmental and biologic differences in proximal and distal colon may reflect differing susceptibilities to neoplastic transformation. Differences in proximal and distal colorectal cancer suggest that each may arise through different pathogenetic mechanisms. Proximal tumors appear to represent a genetically more stable form of the disease and may arise through the same mechanisms that underlie inherited nonpolyposis colon cancer. Distal tumors show evidence of greater genetic instability and may develop through the same mechanisms that underlie polyposis-associated colorectal cancer syndromes. 