LINKAGE STUDIES IN A LI-FRAUMENI FAMILY WITH INCREASED EXPRESSION OF P53 PROTEIN BUT NO GERMLINE MUTATION IN P53

We report a family with the Li-Fraumeni syndrome (LFS) in whom we have been unable to detect a mutation in the coding sequence of the p53 ge ne. Analysis of linkage to three polymorphic markers within p53 enable d direct involvement of p53 to be excluded. This is the first example of a LFS family in whom exclusion of p53 has been possible. Four affec ted members of the family with sarcoma or premenopausal breast cancer showed increased expression of p53 protein in their normal tissues as detected by immunohistochemistry. It therefore appears that the LFS ph enotype has been conferred by an aberrant gene, showing a dominant pat tern of inheritance, which may be acting to compromise normal p53 func tion rather than by a mutation in p53 itself. In order to try to deter mine the chromosomal location of this putative gene, we have carried o ut studies of linkage to candidate loci. By these means we have exclud ed involvement of Rbl and BRCA1 on chromosomes 13q and 17q respectivel y. The MDM2 oncogene on chromosome 12q was considered to be the prime candidate as MDM2 is amplified in sarcomas and the MDM2 product binds to p53. Furthermore, p53 mutation and amplification of MDM2 have been shown to be mutually exclusive events in tumour development. Linkage a nalysis to two polymorphic markers within MDM2 yielded a three-point L OD score of -5.4 at a recombination fraction theta equal to zero. Ther efore MDM2 could be excluded. It is possible that the gene which is re sponsible for cancer susceptibility in this family, possibly via inter action with p53, will be important in the histogenesis of breast cance r in general. We are now carrying out further studies to locate and id entify this gene.