Prevalence of TP53 p.R337H mutation in children with cancer from a public hospital in southern Brazil.

Abstract

10593 Background: Childhood cancers are a common feature in Li-Fraumeni/Li Fraumeni-Like Syndromes (LFS/LFL), associated with the inheritance of a germline TP53 mutation. Recently, a specific germline mutation in exon 10 of the TP53 gene, p.R337H, has been reported at a high prevalence in Southeastern Brazil. Initial studies on this mutation claimed that the main, if not exclusive, cancer risk in carriers is childhood adrenocortical carcinoma (ADR). However, others recent reports identified p.R377H carriers among LFL families and among a larger spectrum of tumors, such as choroid plexus carcinoma (CPC) and osteosarcoma. The aim of this study was to assess the frequency of the p.R337H mutation in children diagnosed with tumors of the LFS/LFL spectrum: ADR, sarcoma, central nervous system tumors, leukemia, germline cell tumors and Wilm’s tumor) at the Children’s Cancer Institute of Rio Grande do Sul (Brazil) between 1998 and 2011. Methods: Family history (FH) was recorded in pedigrees, and DNA was extracted from peripheral blood and FFPE samples by standard methods. Screening for the p.R337H mutation was performed by allelic discrimination (TaqMan assay) and by TP53 exon 10 sequencing. Results: Analysis of 295 children diagnosed with tumors of the LFS/LFL spectrum identified the p.R337H mutation in 9/11 (81,8%) children with ADR (including a homozygous p.R337H individual) and in 2/2 (100%) children with CPC. All individuals had loss of heterozygosity in the tumor and in all cases the mutant allele occurred on the same founder haplotype. One hundred fourth-six (49,5%) patients had a cancer FH in first or second degree relatives, 47 (16,0%) had a FH of breast cancer and 49 (16,6%) had FH of LFL consistent with Chompret and/or Birch criteria. Conclusions: These results confirm the strong association of p.R337H with ADR and CPC. A FH consistent with LFL syndrome is present in a high proportion of children diagnosed with tumors of the LFS/LFL spectrum in Southern Brazil. Financial support: FIPE-HCPA, CAPES, FAPERGS and Glaxo Smith Kline.