A NOVEL P53 GERMLINE ALTERATION IDENTIFIED IN A LATE-ONSET BREAST-CANCER KINDRED

Germline mutations in the p53 tumor suppressor gene are associated wit h the Li-Fraumeni syndrome, characterized by childhood sarcoma, leukem ia and early onset breast cancer and has occasionally been found also in familial breast-ovarian cancer. Most mutations found are of missens e type and located in the central region of the gene (exons 5 to 8). I n the present study, a germline p53 alteration was identified in a lat e onset breast cancer family (kindred Lund 5; mean age 58 years) using single stranded conformation polymorphism and sequence analysis. The mutation (a CCG to CTG transition) at codon 82 in exon 4, resulting in a proline to leucine substitution, has not previously been reported a nd was not present in a control set of 60 healthy individuals. Three o f five woman with breast cancer (45, 57 and 65 years) were carriers of the alteration. Loss of heterozygosity at the p53 locus was not seen in the primary tumors of these women, but appeared as a partial loss o f the wildtype allele in subsequent recurrent lesions of two gene carr iers. The family manifested no linkage to the p53 gene (a two-point LO D-score of -0.41), and has previously also been excluded for linkage t o the BRCA1 and BRCA2 loci, as well as being carrier of a BRCA1 germli ne mutation. Although it seems unlikely that the p53 germline mutation is the major cause of disease predisposition in Lund 5, the data sugg est that some p53 alteration may confer a subtle influence on breast c ancer development and progression.