A NOVEL GERM-LINE MUTATION IN THE NONCODING REGION OF THE P53 GENE INA LI-FRAUMENI FAMILY

We identified a novel germ-line p53 mutation in the noncoding, nonspli cing regions of a Li-Fraumeni family. Patients belonging to this famil y included pediatric medulloblastoma and rhabdomyosarcoma patients and a breast carcinoma patient. Three positions in the p53 gene were anal yzed for loss of heterozygosity (LOH). One of the three loci retained heterozygosity, whereas the other two exhibited LOH. Sequence analysis of the third locus identified a change of 5'-CCGGGTGA-3' to 5'-CCAGGT TGGA-3', 63 bp downstream of exon 6. The mutation was identified in th e germ line of the two pediatric patients and in each of the related p arents. We excluded any additional mutation in the entire coding regio n of the p53 gene, including splice-site intronic sequences. Strong po sitive nuclear staining of the p53 protein was detected in both normal and tumor paraffin-embedded tissues. Eighty five normal persons were negative for this alteration, which thus supports it as a mutation. Th ese results may indicate that genetic changes within the noncoding reg ion of the p53 gene may serve as an alternative mechanism of activatin g this gene. Mutations in the noncoding region of this gene should be further studied. (C) Elsevier Science Inc., 1998.