title: A constitutional de novo mutation in exon 8 of the p53 gene in a patient with multiple primary malignancies.
abstract: We report a constitutional point mutation of codon 278 in exon 8 of the TP53 gene that has not yet been described as a germ-line mutation. A 52-year-old female developed multiple primary malignancies (liposarcoma, breast cancer, malignant histiocytoma, occult adenocarcinoma). The mutation found in her tumour and peripheral blood lymphocyte DNA is a cytosine to thymine transition at the second position of codon 278 resulting in an amino acid exchange from proline to leucine in the DNA-binding domain. Evaluation of the patient's family revealed that both of her sons were affected by the same mutation. Although the patient's mother had died already, we were able to demonstrate by polymorphic microsatellite analysis that the defective allele originated from the maternal side. As four brothers and one sister had inherited the same allele, which however was wild type, we were able to show that the mutation must have occurred in the germ cells of the patient's mother and that it may therefore be called de novo. This explains the lack of a high cancer incidence in the family history. All tumours tested showed positive immunohistochemical staining for p53. Loss of heterozygosity was found in five of seven tumours, one showing chromosome 17 monosomy.
authors.affiliation: University Hospital Vienna, Medical School, Department of Obstetrics and Gynecology, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Speiser
authors.forename: E
authors.initials: E
authors.lastname: Gharehbaghi-Schnell
authors.forename: S
authors.initials: S
authors.lastname: Eder
authors.forename: A
authors.initials: A
authors.lastname: Haid
authors.forename: J
authors.initials: J
authors.lastname: Kovarík
authors.forename: R
authors.initials: R
authors.lastname: Nenutil
authors.forename: G
authors.initials: G
authors.lastname: Sauter
authors.forename: C H
authors.initials: CH
authors.lastname: Schneeberger
authors.forename: B
authors.initials: B
authors.lastname: Vojtesek
authors.forename: C H
authors.initials: CH
authors.lastname: Wiltschke
authors.forename: R
authors.initials: R
authors.lastname: Zeillinger
mesh_terms: D000483:Alleles; D001483:Base Sequence; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D004276:DNA, Satellite / Q000032:analysis / Q000235:genetics; D005091:Exons; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D016158:Genes, p53; D018095:Germ-Line Mutation; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009378:Neoplasms, Multiple Primary / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D011110:Polymorphism, Genetic; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D004273:DNA, Neoplasm; D004276:DNA, Satellite; D016159:Tumor Suppressor Protein p53