The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.

BACKGROUND: Pediatric cancers are a feature in patients with Li-Fraumeni syndrome and its variant Li-Fraumeni-like syndrome (LFS=LFL). To the best of the authors' knowledge, TP53 germline mutations are currently the only molecular defect known to be associated with this disease. Recently, a specific germline mutation in this gene, p.R337H, has been reported at a high prevalence in Brazil. METHODS: The prevalence of LFS=LFL was investigated in children with cancer who were diagnosed with tumors on the LFS=LFL spectrum and in a small consecutive series of controls without cancer. The prevalence of the germline p.R337H mutation and of other germline TP53 mutations was investigated in a general group of children with cancer and exclusively in children fulfilling the clinical criteria for LFS=LFL, respectively. RESULTS: Among the 65 children without cancer, 1.5% had a family history of LFL whereas of the 292 children with cancer, 25.3% had a family history of LFL (P <.001). Screening for the p.R337H mutation identified 11 carriers (3.7%), 9 of whom were diagnosed with adrenocortical carcinomas (ACC) and 2 of whom were diagnosed with choroid plexus carcinomas. One of the ACC probands was homozygous mutant. The Brazilian founder haplotype and loss of heterozygosity at the p.R337H locus were present in all carriers. In addition, direct sequencing of the entire TP53 coding region and gene rearrangement analysis of probands fulfilling the criteria for LFL (Eeles 2 criteria, Birch and=or Chompret criteria) and who were negative for the p.R337H mutation revealed a DNA-binding domain pathogenic mutation, p.G245S, in 1 child. CONCLUSIONS: TP53 p.R337H testing should be offered to Brazilian children diagnosed with ACC and choroid plexus carcinoma. A significant percentage of children with cancer in southern Brazil fulfill the criteria for LFL and should be referred for genetic risk assessment. Cancer 2013;119:4341-9. V C 2013 American Cancer Society.KEYWORDS: childhood cancer, Li-Fraumeni syndrome, Li-Fraumeni-like syndrome, TP53 mutations, TP53 p.R337H mutation. INTRODUCTIONPediatric cancer is one of the more frequent causes of nontraumatic deaths in children, representing 1% to 3% of all cancer diagnoses worldwide. [1][2][3][4][5] The Brazilian National Cancer Institute estimates that approximately 384,340 new cancer diagnoses will have been made in Brazil in 2012, including 11,530 (3%) diagnosed in children and adolescents aged < 19 years. 5 Childhood cancers that arise within the context of a genetic predisposition are rare events, and are estimated to account for approximately 5% to 10% of all pediatric cancer cases. 5 However, with increased awareness of cancer family history and advanced technologies in mutation detection, this percentage will likely increase, 6 facilitating the presymptomatic identification of high-risk individuals and ultimately decreasing cancer-related mortality in this setting.Childhood cancers are a common feature in patients with Li-Fraumeni syndrome and its variant Li-Fraumeni-like syndrome (LFS...

Background: Retinoblastoma (Rb) is the most common intraocular tumor diagnosed in children in Brazil. However, detailed information is lacking regarding patient clinical demographics. This study aimed to determine the clinical profile of patients with Rb who were treated in a public university hospital in southern Brazil from 1983 to 2012. Methods: Patients' medical records were reviewed to retrospectively identify patients with a principal diagnosis of Rb. Rb was classified as hereditary or non-hereditary. Clinical staging was reviewed by an ophthalmologist. Statistical analysis was performed using SPSS. Results: Of 165 patients with a diagnosis of Rb during this period, 140 were included in the study. Disease was unilateral in 65.0 % of patients, bilateral in 32.9 %, and trilateral in 2.1 %. The mean age at onset of the first sign/ symptom was 18.1 month, and 35.7 % of patients were diagnosed during the first year of life. The most common presenting signs were leukocoria (73.6 %) and strabismus (20.7 %). The mean age at diagnosis was 23.5 months, and time to diagnosis was 5.4 months. In patients with clinical features of hereditary Rb, both onset of the first sign/symptom and diagnosis were at an earlier age than in patients without these features (12.3 vs 21.6 months [P = 0.001] and 15.9 vs 28.0 months [P < 0.001], respectively). However, there was no significant difference in overall survival between the two groups. Ocular stage at diagnosis was advanced in 76.5 % (Reese V) and 78.1 % (International Classification D or E). Of patients with unilateral and bilateral disease, 35.2 % and 34.8 %, respectively, had extraocular disease at diagnosis; 10.7 % had metastatic disease at diagnosis. Enucleation was observed in 88.1 % and exenteration in 11.9 % of patients; 93.6 % patients were followed until 2012, and 22.9 % relapsed. Overall survival was 86.4 %. Conclusions: Most Rb diagnoses are still diagnosed in advanced stages of the disease, considerably reducing overall survival time and the rate of eye and vision preservation.