Germ-line TP53 mutations in Finnish cancer families exhibiting features ofthe Li-Fraumeni syndrome and negative for BRCA1 and BRCA2

Mutations in BRCA1 and BRCA2 account for a large portion of the inherited p redisposition to breast and ovarian cancer. If runs recently discovered tha t mutations in these two genes are less common in the Finnish population th an expected, Because the genetic background of breast cancer, in particular , is largely obscure, it became necessary to search for mutations in other susceptibility genes. Because seven of our BRCA1 and BRCA2 mutation-negativ e families fulfilled the criteria of either Li-Fraumeni syndrome (LFS) or L i-Fraumeni-like syndrome (LFL), we decided to screen them for germ-line TP5 3 mutations in exons 5-8 using a dual-temperature single-strand conformatio n polymorphism assay (SSCP). Two missense mutations (Asn235Ser and Ty220Cys ) were identified. The clinical significance of these findings was evaluate d by comparison to previously reported germ-line TP53 mutation data, and by using the tumor loss of heterozygosity (LOH) analysis. In addition, an imm unohistochemical analysis of tumor specimens from mutation-positive individ uals was performed. Our results suggest that the observed missense mutation s confer susceptibility: to cancer, and that germ-line TP53 mutations would therefore explain an additional fraction of hereditary breast cancer in Fi nland. (C) Elsevier Science Inc., 1999. All rights reserved.