Abstract 1836: Distinct tumor spectrum and age of onset in a Brazilian cohort of p.R337H TP53 mutation carriers
Authors: Hainaut Hadrien , Nogueira Sonia , Nobrega Amanda , Hainaut Pierre , Achatz Maria I. 
Published: June 2012

Abstract
The Li-Fraumeni syndrome (LFS) and its variant, Li-Fraumeni-like (LFL), are associated with high risk of early-onset tumors, typically breast cancer (BC), soft tissue sarcoma (STS), adrenocortical tumor (ADR) and brain cancer (BT). The major challenge in management of LFS/LFL is to provide screening for early detection due to the wide tumor spectrum and variable age of onset. Germline mutations in the TP53 gene are the only known genetic defect underlying LFS/LFL, detected in about 70% LFS and 20% LFL families. Most mutations occur in the exons encoding the DNA binding domain of p53 protein, whereas mutations outside these exons are rare and may have partial penetrance. A particular germline mutation at codon 337 (c.1010G&gt;1, p.R337H) within the C-terminal, tetramerization domain of p53 is found in 0.3% of South and Southeastern Brazilian populations due to a founder effect. The aim of this study is to compare tumor spectrum in p.R337H carriers to that of other TP53 mutations. A cohort of 345 patients from 131 families was tested for germline TP53 mutations by sequencing the coding region (exons 2-11). Deletions were assessed by Multiple Ligand Polymorphism Assay. Ninety-one patients from 35 families harbored a TP53 mutation and are followed at the Department of Oncogenetics, Hospital A.C. Camargo in São Paulo, Brazil. Mutations were detected in 35/131 families (26.5%) and 88 tumors were documented in TP53 mutation carriers. Subjects and tumor′s data were managed and analyzed with a specifically designed software (HH-LFS) running on Excel (MicrosoftTM) and Visual Basic programming. The most common mutation was the founder p.R337H mutation (FM) p.R337H, present in 54.3% (19/35) of all families. Among 91 subjects found to carry a mutation, 70.3% (64/91) carried FM. Other mutations in the DNA binding domain (OM) were detected in 27 patients and large deletions occurred in two patients. The types of tumors in carriers of FM were similar to OM. However, there were significant differences in prevalence and/or age of occurrence. In both groups, the most common tumor was breast cancer, accounting for 35.4% in FM and 25% in OM. STS were detected in 14,5% in FM and 25% in OM. Interestingly, the third most common tumor among FM was thyroid cancer (TC) (14.5%), present in 7 patients from 3 distinct families whereas no TC were found in OM (p&lt;0.001). BT and ADR were found in both groups with similar frequencies. Age at diagnosis varied between the two groups. Tumors were detected in 22% of FM before the age of 20 compared to 39.5% in OM (p=0.05). Conversely, 15.2% cancers in FM were above age 60 compared to 7.9% in OM. Gender distribution showed a similar predominance of tumors in females in both groups. The tendency of FM to develop a higher proportion of adult cancers as compared to OM suggests specific screening strategies for FM group. Moreover, the high prevalence of TC advocates for anual thyroid ultrasound screening in carriers of the p.R337H mutation.
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 1836. doi:10.1158/1538-7445.AM2011-1836