Novel p53 splice site mutations in three families with Li-Fraumeni syndrome

Abstract

Germline mutations in the p53 tumor suppressor gene predispose to a variety of cancers in families with LiFraumeni syndrome. Most germline p53 mutations observed to date cause amino acid substitutions in the protein's central sequence-speci®c DNA binding domain. Outside this conserved core region, however, we found novel alterations in sequences that regulate precursor mRNA splicing in three Li-Fraumeni syndrome families. Two splice site mutations a ected the consensus sequence at the splice donor sites of introns 1 and 9, and produced unstable variant transcripts in normal cells. A third mutation at the splice acceptor site of intron 9 generated splicing at a cryptic acceptor site in intron 9. These splice site alterations emphasize the need to examine both noncoding and untranslated regions of the p53 gene for germline mutations in Li-Fraumeni syndrome families. Oncogene (2000) 19, 4230 ± 4235.

Relative frequency and morphology of cancers in carriers of germline TP53 mutations

“…Six of the 28 families (21%) carried splicing mutations (Varley et al, 2001). Such mutations are under-represented among published families and patients since in many studies intron-exon boundaries were not included in gene sequence analyses (Frebourg et al, 1995;Verselis et al, 2000). This may account for the paucity of Wilms' tumour cases in published families.…”

Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour

“…109 110 Wilms tumour is not one of the cardinal tumours included in the diagnostic criteria for this syndrome, but has been reported in at least six families harbouring TP53 mutations, and in several mutation negative families which fulfil the Li-Fraumeni syndrome and Li-Fraumeni-like diagnostic criteria. [111][112][113][114][115][116][117][118] Five of the six TP53 mutations reported in association with Wilms tumour affect splicing. Such mutations account for only 4% of all reported germline TP53 mutations.…”

The dl1520 Virus Is Found Preferentially in Tumor Tissue after Direct Intratumoral Injection in Oral Carcinoma

“…Of 15 samples assessed, 10 had a mutant p53 sequence, 4 had wild-type gene sequences, and 1 sample was inadequate for assessment. All of the mutations found have been previously described and are known to cause significant dysfunction of the p53 protein (18,19,20). Immunohistochemistry staining (IHC) was also used to detect mutant p53, and we demonstrated a good correlation between this and gene sequencing with all of the samples with a wild-type gene sequence scoring zero for p53 expression (21,22).…”