Purpose: Germline mutations of the p53 coding region are present in approximately 50-70% of patients with Li-Fraumeni Syndrome (LFS), a rare hereditary disorder of familial and intraindividual clustering of different malignancies such as sarcoma (index tumor), breast cancer, brain tumors, leukemias, and adrenocortical carcinomas, the latter usually in young children. Both onset and spectrum of malignancies in individuals with LFS are thus heterogenous and may, less frequently, also include other epithelial and mesenchymal tumors. A 32-year-old female presented for genetic counseling with a history of leiomyosarcoma at age 22, malignant melanoma (a rare component of LFS) at age 26, and breast cancer at age 30. All three tumors had been treated surgically. Astrocytoma and breast cancer, respectively, had been diagnosed in her brother and mother before age 30. Other malignancies diagnosed early in life in relatives of the mother were: prostate cancer, stomach cancer, and carcinoma of the larynx.
Methods: Upon written informed consent, DNA was extracted from peripheral blood mononuclear cells of the proband, and p53 exons 4-8 analyzed for mutations by SSCP and DNA sequencing.
Results: A G:C to A:T mutation at codon 175 of p53 resulting in an arginine --> histidine substitution was detected, confirming the clinical diagnosis of LFS.
Conclusions: The patient and her family are being followed further, but testing of her children for the presence of this mutation is currently being withheld. The difficulties in the management and treatment of patients with this clinically heterogenous disorder are discussed.