FREQUENT TP53 GENE ALTERATIONS (MUTATION, ALLELIC LOSS, NUCLEAR ACCUMULATION) IN PRIMARY NON-SMALL-CELL LUNG-CANCER

Mutations of the TP53 tumour suppressor gene have been reported for ma ny human cancers. A variety of TP53 mutations have also been reported for both primary non-small cell lung cancer (NSCLC) and associated met astases. To assess the pathogenetic significance of TP53 gene alterati ons in NSCLC, 24 paired samples of primary NSCLC and the corresponding normal lung tissue were analysed for mutations of the TP53 gene (exon s 5-8) using exon-specific PCR, single-strand conformation polymorphis m PCR (SSCP-PCR) and direct DNA sequencing; for p53 protein accumulati on by immunohistochemistry and for 17p allelic loss using restriction fragment length polymorphism (RFLP) probes on Southern blots and ampli fied fragment length polymorphism-PCR. TP53 point mutations were obser ved in 9/24 (38%) tumours encompassing a total of 14 mutations. Two tu mours displayed the same double mutation while a third harboured four different mutations. Seventeen of 24 NSCLCs (71%) overexpressed p53 pr otein and all 17 immunopositive tumours (100%) showed a mutation and/o r allelic loss at the D17S30 locus. Of the 17 NSCLCs informative at th e DS17S30 locus, 10 (59%) showed allelic loss, of which five (50%) wer e also mutated on the remaining TP53 allele. These results suggest tha t TP53 gene alterations are involved in the pathogenesis of primary NS CLC and that such alterations may serve a selective role in the develo pment of NSCLC by diminishing the apoptotic potential of bronchial epi thelial cells heterozygous for a TP53 point mutation. This may also ex plain the accumulation of multiple TP53 point mutations in 3/24 of our NSCLC samples.