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Comparative analysis between telomere length and clinical features of carriers of the germline TP53 p.R337H mutation

Grant number: 14/14319-1
Support type:Scholarships abroad - Research Internship - Master's degree
Effective date (Start): March 02, 2015
Effective date (End): September 01, 2015
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Maria Isabel Alves de Souza Waddington Achatz
Grantee:Kelvin César de Andrade
Supervisor abroad: Sharon A. Savage
Home Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
Local de pesquisa : National Cancer Institute (NCI), United States  
Associated to the scholarship:14/03279-9 - Comparative analysis between telomere length and clinical features of carriers of the germline p.R337H TP53 mutation, BP.MS


Li-Fraumeni syndrome is a hereditary cancer predisposition disorder related to germline TP53 mutations. Although it is considered to be a rare condition, a high occurrence of a founder mutation, the p.R337H TP53, is present in 0.3% of Southern Brazilian population. This mutation occurs in the oligomerization domain of the p53 protein and differs from the majority of germline mutations, commonly found in the DNA binding domain. In a subgroup of asymptomatic carriers of the p.R337H mutation, specific characteristics were clinically observed, with a lower frequency of metabolic alterations and diseases typical of aging, when compared to general population. These observations provided the first evidence that the p.R337H carriers may have genetic factors modulating cellular senescence. Given the interaction between the p53 protein, telomere pathway and senescence, the hypothesis of this project is that asymptomatic carriers of the p.R337H mutation will have longer telomeres when compared to both carriers affected by cancer and control group (asymptomatic and without any mutation described). This fact would differentiate asymptomatic p.R337H carriers from patients with other mutations in the TP53 gene who have shorter telomeres (when compared to the population of corresponding age). Through analysis of telomere length by Q-PCR, we will evaluate 40 p.R337H mutation carriers, including 20 patients who previously developed a cancer and 20 without cancer. In addition, these groups will be compared to 40 control individuals. A questionnaire will be used to characterize clinically all participants. Therefore, this study will provide a better understanding of the biological consequences of germline TP53 p.R337H mutation, as well as additional information about the characteristics of patients positive for the most prevalent mutation already described in the Brazilian population. (AU)