title: Germ-line splicing mutation of the p53 gene in a cancer-prone family.
abstract: Li-Fraumeni syndrome is a rare autosomal dominant susceptibility to a variety of cancers including carcinomas of the breast and the adrenal cortex, tumors of brain and muscle tissue, and leukemias. Affected individuals develop cancer at a young age and often at multiple primary sites. A study has been conducted into the genetic basis of cancer in a particular Li-Fraumeni syndrome family. Examination of p53 as a candidate susceptibility gene revealed that, in two affected individuals, there was an aberrant larger transcript of 3.6 kilobases present in both tumor and constitutional material in addition to the normal-sized 2.8-kilobase transcript. The additional transcript was not found in three unaffected family members. S1 nuclease mapping localized the insertion toward the 5' end of the p53 transcript near exons 4 and 5, and sequencing revealed a point mutation in the splice donor site of intron 4 in the germ-line of the two affected individuals, which accounted for the presence of the larger transcript. The same splicing mutation was also detected in two obligate carriers and was not found in two unaffected individuals. As no mutations were detected in exons 5-8 in either tumor examined, the second p53 allele was most likely lost during tumorigenesis in both tumors. The demonstration of a germ-line splicing mutation in affected individuals from a Li-Fraumeni syndrome family provides for a novel mechanism of p53 inactivation not seen previously in other affected families, in whom the mutations have all been missense.(ABSTRACT TRUNCATED AT 250 WORDS)
authors: Leukemia Research and Viral Pathology Unit, Children's Medical Research Institute, Westmead, New South Wales, Australia.
authors: S G
authors: SG
authors: Warneford
authors: L J
authors: LJ
authors: Witton
authors: M L
authors: ML
authors: Townsend
authors: P B
authors: PB
authors: Rowe
authors: R R
authors: RR
authors: Reddel
authors: L
authors: L
authors: Dalla-Pozza
authors: G
authors: G
authors: Symonds
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics; D002277:Carcinoma / Q000235:genetics; D015342:DNA Probes; D005260:Female; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009378:Neoplasms, Multiple Primary / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012326:RNA Splicing; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D015342:DNA Probes