POSITION-SPECIFIC 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 Mo lecular Biology Laboratory for a comparison of mutation spectra is des cribed, with the aim of investigating organ specificity of etiological factors and putative organ-to-organ relationships in cancer pathogene sis. The number of entries of each nucleotide- and base-pair substitut ion-specific mutation was divided by the total number of tumors analyz ed. For each organ pair, the difference of the frequencies was calcula ted (absolute values) and, goings through all mutations, the sum of th e mutation-specific frequency differences was calculated. Resulting va lues could range from 0 (full concordance) to 2 (full discordance). Sk in, lung, and urinary bladder showed highly independent mutation spect ra (maximum discordance value = 1.48 for skin versus brain), in agreem ent with the presence of specific factors responsible for a large numb er 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 disco rdance value was 0.95, for stomach versus colon. For these organs, com mon, possibly also endogenous, cancer risk factors could be postulated as contributing to the observed mutation spectrum. The remaining canc ers (ovary, sarcoma, leukemia/lymphoma brain, head and neck, and stoma ch, in order of 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. Exclusio n of the ''hot-spot'' mutations did not markedly alter the observed re lationships, indicating that a putative selective growth advantage doe s not coverup 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 .