p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: Further evidence of CHK2 in inherited cancer predisposition

Germ-line mutations in the p53 gene predispose individuals to Li-Fraumeni s yndrome (LFS). The cell cycle checkpoint kinases CHK1 and CHK2 act upstream of p53 in DNA damage responses, and recently rare germ-line mutations in C HK2 were reported in LFS families. We have analyzed CHK1, CHK2, and p53 gen es for mutations in 44 Finnish families with LFS, Li-Fraumeni-like syndrome , or families phenotypically suggestive of LFS with conformation-sensitive gel electrophoresis. Five different disease-causing mutations were observed in 7 families (7 of 44 families; 15.9%): 4 in the p53 gene (5 of 44 famili es; 11.4%) and 1 in the CHK2 gene (2 of 44 families; 4.5%). Interestingly, the other CHK2-mutation carrier also has a mutation in the MSH6 gene. The c ancer phenotype in the CHK2-families was not characteristic of LFS, and may indicate variable phenotypic expression in the rare families with CHK2 mut ations. No mutations in the CHK1 gene were identified. Additional work is n ecessary to completely unravel the molecular background of LFS.