A NEW GERMLINE TP53 GENE MUTATION IN A FAMILY WITH LI-FRAUMENI SYNDROME

This report describes an unusual clinical presentation of Li-Fraumeni syndrome. Family history revealed a mild aggregation of adult cancers in one generation, and an unusual clustering of brain tumours of early childhood in the following generation. In order to evaluate the genet ic basis for cancer predisposition in this family, molecular genetic a nalysis for the occurrence of germline TP53 tumour suppressor gene mut ations was performed on 12 siblings of two generations. Indirect mutat ion analysis was performed by the single-strand conformation polymorph ism (SSCP) technique. Alterations were characterised by automated dire ct fluorescence sequencing analysis. Tumour material was also examined for p53 protein accumulation by immunohistochemistry. Initially, a TP 53 gene germline missense mutation was detected in an 11-year-old kind red with acute myeloid leukaemia (AML) following intensive treatment o f a brain tumour. In peripheral blood and bone marrow samples of this proband, a reduction to hemizygosity occurred. During AML treatment, d etection of LOH of 17p was used as a marker for clonality and treatmen t control. The mutation was found to be inherited from the proband's m other, who was diagnosed with breast cancer at the age of 48 years. Fu rther, three siblings were carriers, and two are apparently healthy at the age of 21 and 23 years. Knowledge of germline mutations may allow accurate DNA-based carrier diagnosis which is of important clinical s ignificance for treatment strategy and control. Furthermore, the occur rence of unaffected carriers in this family raises questions about app ropriate methods of cancer surveillance and counselling for these peop le. Copyright (C) 1996 Elsevier Science Ltd