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Tesi etd-02212009-150152

Thesis type
Tesi di dottorato di ricerca
Re-sequencing TP53: seeking new polymorphisms and haplotypes
Settore scientifico disciplinare
Corso di studi
Relatore Dott. Landi, Stefano
Parole chiave
  • Li-Fraumeni syndrome
  • haplotypes
  • SNPs
  • TP53
Data inizio appello
Data di rilascio
Riassunto analitico
The p53 tumor suppressor serves as one of the major cellular barriers against cancer development. Indeed, as many as 50% of all human tumors contain p53 mutants whereas the other half maintain a wild-type TP53 gene but acquire other genetic or epigenetic alterations that compromise the p53 response. Most of the mutations within the TP53 gene are missense mutations (75%) that results in the expression of full-length mutant p53 (mutp53) proteins lacking its specific DNA-binding activity and accumulating in the nucleus of tumor cells. TP53 germline mutations are seen in 70-80% of patients with Li-Fraumeni syndrome (LFS), a familial cancer predisposition syndrome. Though most of germline mutations occur in one of the six hotspots, a rare germline TP53 mutation at codon 337 (R337H) has been found in a number of apparently unrelated cancer-prone families in Southern Brazil. Moreover, recent studies associated the common polymorphisms, intron3 16bp-duplication, Arg72Pro, and the MspI RFLP in intron 6, with the risk of various types of cancer. Nevertheless, TP53 haplotypic structure is still poorly known. According to this view, it would be desirable to characterize the haplotypic structure of TP53 and find other genetic variants that have not yet been used in association studies. Thus, in the present study we undertook a complete mutation screening of TP53, in order to find new polymorphisms, and finely reconstruct the common haplotypes of TP53. We identified 18 new variants along the gene. After the screening of 192 control samples, we classified these into mutations (i.e., allelic frequency <0.01) or polymorphisms (allelic frequency >0.01, n=6). We determined the haplotypes across the whole gene and we selected 29 tagSNP out of 182 SNPs.Using these 29 tagSNPs we demonstrated that some R337H Brazilian carriers shared the same uncommon haplotype, supporting the hypothesis of founder effect for this mutation.