MUTATIONAL SPECTRUM OF THE P53 GENE IN HUMAN SMALL-CELL LUNG-CANCER AND RELATIONSHIP TO CLINICOPATHOLOGICAL DATA

The spectrum of p53 gene mutations was determined in formalin-fixed, paraffin-embedded samples of small-cell lung cancer derived from 28 patients. By direct sequencing of exons 5, 7, and 8, including their flanking intron sequences, 18 mutations were identified in 17 tumors (61%), and in all but two of these the wild type allele was lost. In 8 cases, the mutation detected in the tumor was absent from the corresponding normal tissue, indicating that these mutations were somatically acquired. In two patients, identical mutations were found in the primary tumor and corresponding metastases. In a further case, an intrapulmonary metastasis did not show the mutation detected in the primary tumor. The local distribution of the mutations resembled that reported in non-small cell lung cancer and gave no indication of distinct hot spot regions. G-to-T transversions were the predominant type of mutation, reflecting a possible genotoxic influence of carcinogens contained in tobacco smoke. Mutations were equally distributed among tumors with intermediate and oat cell histology and did not show a significant association to age and gender of the patients. Also, no significant relationship was observed between the presence of a mutation and tumor stage (T, N, M) or survival. However, transitions at CpG dinucleotides were restricted to tumors without detectable metastases at the time of biopsy, whereas all other mutations occurred in metastasing small cell lung cancer.