Germline TP53 mutations predispose individuals to multiple cancers and are associated with Li-Fraumeni/Li-Fraumeni-Like Syndromes (LFS/LFL). The founder mutation TP53 p.R337H is detected in 0.3% of the general population in southern Brazil. This mutation is associated with an increased risk of childhood adrenal cortical carcinoma (ACC) but is also common in Brazilian LFS/LFL families. Breast Cancer (BC) is one of the most common cancers diagnosed in TP53 mutation carriers. We have assessed the prevalence of p.R337H in two groups: (1) 59 BC affected women with a familial history (FH) suggestive of hereditary cancer syndrome but no LFS/LFL features; (2) 815 BC affected women unselected for cancer FH, diagnosed with BC at or before age 45 or at age 55 or older. Among group 1 and group 2 patients, 2/59 (3.4%, CI95%: 0.4%–11.7%) and 70/815 (8.6%, CI95%: 6.8%–10.7%), respectively, were p.R337H carriers in the germline. The prevalence of p.R337H was higher in women diagnosed with BC at or before age 45 (12.1%, CI95%: 9.1%–15.8%) than at age 55 or older (5.1%, CI95%: 3.2%–7.7%), p<0.001). The Brazilian founder p.R337H haplotype was detected in all carriers analysed. These results suggest that inheritance of p.R337H may significantly contribute to the high incidence of BC in Brazil, in addition to its recently demonstrated impact on the risk of childhood ACC.

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...

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