Position- and base pair-specific comparison of p53 mutation spectra in human tumors: elucidation of relationships between organs for cancer etiology.

A new approach to analyze the p53 mutation database of the European Molecular Biology Laboratory for a comparison of mutation spectra is described, with the aim of investigating organ specificity of etiological factors and putative organ-to-organ relationships in cancer pathogenesis. The number of entries of each nucleotide- and base-pair substitution-specific mutation was divided by the total number of tumors analyzed. For each organ pair, the difference of the mutation-specific frequency differences was calculated. Resulting values could range from 0 (full concordance) to 2 (full discordance). Skin, lung, and urinary bladder showed highly independent mutation spectra (maximum discordance value = 1.48 for skin versus brain), in agreement with the presence of specific factors responsible for a large number of the respective tumors (UV light, smoking, aromatic amines). The three organs with the smallest sum of discordance values were mammary gland (breast), colon and esophagus. The minimum organ-to-organ discordance value was 0.95, for stomach versus colon. For these organs, common, possibly also endogenous, cancer risk factors could be postulated as contributing to the observed mutation spectrum. The remaining cancers (ovary, sarcoma, leukemia/lymphoma, brain, head and neck, and stomach, in order or increasing discordance) were of intermediate range and showed a mix of values. Reasons for close relationship to some of the other organs and marked differences to others are discussed. Exclusion of the "hot-spot" mutations did not markedly alter the observed relationships, indicating that a putative selective growth advantage does not cover up the etiological basis for the observed mutation spectrum. It is expected that much more insight into carcinogenesis and cancer could be gained by further exploratory analyses of mutation databases.