The topographical distribution of a mutation provides insight into past patterns of tumor evolution. This approach was applied to two loci commonly mutated in adenocarcinoma of the lung--p53 and c-K-ras. In 41 primary adenocarcinomas, c-K-ras codon 12 point mutations were detected in 8 (19.5%) tumors and p53 point mutations were detected in 10 (24.4%) tumors, with one tumor harboring both mutations. These mutations were only detected in malignant cells and with a homogeneous topographical distribution throughout 16 tumors, including metastasis. Intratumor heterogeneity was detected in only one tumor in which a small portion lacked the specific p53 mutation. Based on this topographical analysis, it is likely that when these mutations occur in adenocarcinoma of the lung, they are usually acquired during the very earliest phases of tumor formation before the bulk of clonal expansion, and in very small precursor lesions.