Abstract 5598: Germline TP53 mutation in very early onset breast cancer patients without BRCA1 and BRCA2 mutation in Brazilian population
Authors: Cannavan Marina C. , Lisboa Bianca CG , Brentani Maria M. , Palmero Edenir I. , Martel-Planche Ghyslaine , Hainaut Pierre , Carraro Dirce M. , Achatz Maria Isabel W. 
Published: June 2012

Germline mutations in TP53 gene are the main cause of cancer susceptibility in the Li-Fraumeni syndrome (LFS) and its variant, Li-Fraumeni-like syndrome (LFL). It is associated with the development of early-onset cancers, including early onset breast cancer, sarcomas, brain tumors and adrenocortical carcinoma. Breast cancer is the most common tumor found in the LFS/LFL accounting for more than 27% of all tumors described. Recently, the 2010 National Comprehensive Cancer Network guidelines for Hereditary Cancer indicated that TP53 germline mutation testing should be considered for women with breast cancer before age 30 years without a BRCA1/BRCA2 mutation detected. The aim of this study is to identify the role of germline mutations in TP53 gene in women with early onset breast cancer who do not carry a BRCA1 or BRCA2 mutation, regardless of family history. Germline DNA was obtained from peripheral blood, collected after genetic counseling and signature of informed consent. TP53 mutation status was assessed by DNA sequencing of the entire coding region of TP53 gene (exons 2-11). A total of 41 females who developed ductal invasive breast cancer were selected, including (a) 15 women diagnosed with very early breast cancer (VEBC), before age 30, regardless of family history of cancer and (b) 26 women diagnosed with early breast cancer (EBC), between ages 30 and 36 years old, regardless of family history of cancer. One patient from the VEBC was found to be carrier of a germline missense mutation detected occurred in the DNA binding domain of the TP53 gene, p.V143M, (GTG&lt;ATG), accounting for 6.7% of the VEBC group. No mutation was found in the EBC group. This mutation p.V143M has not been previously reported as a germline mutation but has been detected in 28 tumors of various types as a somatic mutation. Using Sorting Intolerant From Tolerant software (SIFT) and Align GVGD software, the mutation is predicted to be deleterious (SIFT) or neutral (Align-GVGD). In yeast functional assays, the mutant p.V143M protein shows a clear loss of transactivation function. Overall, these predictive and functional data suggest that p.V143M is a loss-of-function p53 mutant. Our results support recent observations that germline TP53 mutations may be present in a small but significant proportion of patients with very early onset breast cancer. Given the risk for development of multiple primary cancers associated with TP53 mutation inheritance, the possible benefit of early detection through surveillance and the impact on treatment decisions, we support that it is important to offer TP53 testing in patients who develop breast cancer before age 30 without detected BRCA1/BRCA2 mutation.

Financial support: FAPESP

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5598. doi:10.1158/1538-7445.AM2011-5598