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Doctoral Thesis
DOI
10.11606/T.5.2008.tde-29012009-172419
Document
Author
Full name
Maria Isabel Alves de Souza Waddington Achatz
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2008
Supervisor
Committee
Brentani, Ricardo Renzo (President)
Ashton-prolla, Patricia
Brunoni, Decio
Carvalho, André Lopes
Hainaut, Pierre
Title in Portuguese
Modificadores de penetrância de mutações germinativas no gene TP53 em famílias brasileiras com diagnóstico clínico da síndrome de Li-Fraumeni e Li-Fraumeni like: impacto dos polimorfismos intragênicos do TP53 e de genes
Keywords in Portuguese
Carcinoma adrenocortical
Deleção de genes
Mutação em linhagem germinativa
Polimorfismo genético
Predisposição genética para doença
Proteína supressora de tumor p53
Proteínas proto-oncogênicas c-mdm2
Síndrome de Li-Fraumeni
Abstract in Portuguese
A síndrome de Li-Fraumeni (LFS) e sua variante like (LFL) são associadas a mutações germinativas no gene TP53 e predispõe ao alto risco para múltiplos tumores em idade jovem. Analisamos 91 famílias LFS/LFL do sul/sudeste do Brasil para mutações germinativas e haplótipos de TP53 (PIN2, PIN3 e PEX4) e MDM2 (309T-G). A mutação R337H ocorreu em 44,4% das famílias avaliadas. Em 750 controles da região a freqüência populacional da mutação foi 0,3%. A genotipagem de oito indivíduos não relacionados R337H-positivos para 29 TAG SNPs intragênicos demonstrou o mesmo haplótipo raro estabelecendo efeito fundador para R337H. O alelo duplicado no PIN3 apresenta impacto modificador e retardo de 17,1 anos na ocorrência de tumores em famílias com mutação no TP53, enquanto o SNP309 MDM2 modula a idade dos sarcomas de partes moles.
Title in English
Genetic modifiers of germline TP53 mutation in Brazilian families with Li-Fraumeni and Li-Fraumeni Like syndromes: impact of TP53 intragenic polymorphisms and p53 regulatory genes
Keywords in English
Adrenocortical carcinoma
Gene deletion
Genetic polymorphism
Genetic predisposition to disease
Germline mutation
Li-Fraumeni syndrome
Proto-oncogene proteins c-mdm2
Tumor suppressor protein p53
Abstract in English
Li-Fraumeni syndrome (LFS) and its variant like (LFL) are associated with germline mutations in the TP53 gene and predispose to a variety of cancers at an earlier age. We analyzed 91 LFS/LFL families from southern Brazil for germline mutations in TP53 and polymorphisms in TP53 (PIN2, PIN3, PEX4) and MDM2 (309T-G). The germline TP53 mutation R337H was found in 44.4% of all families included. In 750 controls from the same region, mutation prevalence was 0.3%. Genotyping of eight unrelated R337H-positive individuals for 29 intragenic TAG SNPs showed that they all shared the same rare haplotype confirming the founder effect for the mutation. Duplication of PIN3 had a modifier effect on the age of tumor onset (delay of 17.1 years) in TP53 mutation carriers whereas MDM2 SNP309 modulated age of onset for soft-tissue sarcomas.
 
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MariaIsabelACHATZ.pdf (3.90 Mbytes)
Publishing Date
2009-02-04
 
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