A Li-Fraumeni syndrome family with retained heterozygosity for a germline TP53 mutation in two tumors

• Published in: Cancer genetics and cytogenetics Vol. 145; no. 1; pp. 60 - 64
• Main Authors: Trkova, Marie, Foretova, Lenka, Kodet, Roman, Hedvicakova, Petra, Sedlacek, Zdenek
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.08.2003; Elsevier Science
• Subjects: Amino Acid Sequence; Biological and medical sciences; Female; General aspects. Genetic counseling; Genes, p53; Germ-Line Mutation; Humans; Li-Fraumeni Syndrome - genetics; Loss of Heterozygosity; Medical genetics; Medical sciences; Pedigree; Tumor Suppressor Protein p53 - metabolism; Human; Multiple; Rectal disease; Carcinoma; Pathophysiology; Sarcoma; Family study; p53 Protein; Exploration; Malignant tumor; Genetic disease; Heterozygosity; Colonic disease; TP53 Gene; Li Fraumeni syndrome; Germ line; Liposarcoma; Rectum; Digestive diseases; Adipose tissue disorders; Colon; Mutation; Molecular biology
• ISSN: 0165-4608; 1873-4456
• DOI: 10.1016/S0165-4608(03)00031-1

We identified a missense germline mutation (Gly245Ser) in one of the mutation hot spots of the TP53 gene in two affected members of a Li-Fraumeni syndrome family. We also analyzed their tumors, a liposarcoma and a colorectal carcinoma. Both tumors exhibited p53 protein accumulation but none of them showed loss of the wild-type allele of the TP53 gene. We reviewed all published cases of tumors in germline TP53 mutation carriers where loss of heterozygosity data were available and identified 84 tumors with loss of the wild-type allele, 57 tumors with retention of heterozygosity, and 9 tumors with loss of the allele harboring the germline mutation. Among the tumors showing p53 accumulation, we observed a significant difference in the fraction of tumors showing p53 protein accumulation between the tumors with loss of the wild-type allele and those with retention of TP53 heterozygosity. This supports the idea that the pathogenesis of tumors in germline TP53 mutation carriers does not have to be associated with loss of the wild-type TP53 allele. The product of the normal allele can potentially be inactivated by a variety of other mechanisms or, as suggested by the analysis, many of these tumors may even preserve the activity of the wild-type p53 protein.