P1-09-07: Contribution of TP53 p.R337H Mutation to Breast Cancer Incidence in Brazil.

Abstract

Abstract Background: The exact contribution of TP53 germline mutations, associated with Li Fraumeni Syndrome — LFS, to the overall burden of cancer is still only partially known. Studies in Southern and Southeastern Brazil have shown that a particular mutant, TP53 p.R337H, has incomplete penetrance and may be present in a significant number of subjects (estimated frequency at the populational level of 1:300 individuals). In an exploratory approach, the aim of this study is to assess the prevalence of the TP53 p.R337H mutation in women with breast cancer diagnosed before 46 and after 55 years of age, unselected for family history of cancer and resident in Southern and Southeastern Brazil. Methods: Formalin-fixed paraffin-embedded (FFPE) non-tumoral tissue of 521 women diagnosed with breast cancer between 2000 and 2010 in two pathology laboratories were obtained retrospectively and consecutively, and analyzed after anonimization. Genomic DNA was isolated with the QIAamp DNA Tissue Kit and genotyping performed by allelic discrimination using a TaqMan assay. Confirmation of all mutation-positive and a sample of mutation-negative cases was done by TP53 exon 10 sequencing. Results: Analysis of the first 299 cases identified the TP53 p.R337H mutation in the germline of 15 (5,0%) cases: 13/142 (9,2%) before 46 years and 2/157 (1,3%) diagnosed after 55 years. The p53 expression pattern assessed by immunohistochemistry in the breast tumors was not different between p.R337H mutation carriers and non-carriers. Conclusion: Preliminary analysis in a sample of women with breast cancer in Southern Brazil indicates that the germline TP53 p.R337H founder mutation is present in a high proportion of cases, especially those diagnosed at a young age. Germline TP53 mutations are considered rare, occurring in about 1:5000 individuals of the general population. The occurrence of this founder mutation at such a high frequency in a particular geographic region has important implications for disease management and cancer risk counseling for these patients and families. This mutation likely contributes to a significant proportion of the health burden associated with breast cancer in Southern Brazil. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-09-07.