TP53, hChk2, and the Li-Fraumeni syndrome.

Abstract

Germline TP53 mutations are responsible for the large majority of classic LFS families, and a smaller proportion of LFL families. In some of the families shown to have no germline TP53 mutation, germline hChk2 mutations have been described. In some cases the functional consequences of the latter have been demonstrated, although there are still relatively few reports of such mutations. Due to the paucity of families currently described with hChk2 mutations, it is not possible to reach any conclusions concerning the phenotypic/clinical differences between the two types of germline mutation. At least one family with a germline hChk2 mutation is a classic LFS family, whereas others are LFL, variant-LFS, or phenotypically suggestive of LFS. However, there is still a significant number of LFS/LFL families for which no underlying genetic determinant has been identified. It will be fascinating to see what genetic defects are responsible, and whether they involve additional components of DNA damage recognition, repair, or cell cycle checkpoint pathways.