Increased incidence of choroid plexus carcinoma due to the germline TP53 R337H mutation in southern Brazil

Abstract

Background: Choroid plexus carcinomas (CPC) are rare tumors predominantly found in children. Given the high frequency of the germline R337H mutation in the TP53 gene in southern Brazil, we have evaluated the frequency of the R337H mutation in families with CPC in children.

Methodology/principal findings: The present series included 29 patients that were admitted to the same institution from 1992 to 2010, including 22 children with CPC (0.08-13.6 years of age at diagnosis) and 7 children with papilloma of the choroid plexus (Pp; 0.5-9.8 years of age). Surgical resection was possible in 28 children. Blood and/or tumor DNA was extracted and analyzed using PCR-RFLP and results were confirmed by sequencing 240 bp of the TP53 exon 10. The patients, all parents, and some relatives submitted samples for blood DNA analysis. In addition, we have also examined the presence of the mutation in DNA from paraffin-embedded tumor samples to evaluate loss of heterozygosity. We found 63.3% (14/22) of the CPC patients positive for the germline R337H mutation; CPC samples were either heterozygous (n = 7), lost only the wild-type (n = 4), or only the R337H copy (n = 2). One CPC sample was not available. All Pp cases (7/7, 100%) were negative for R337H. Cure (>5 years survival free of disease) was observed in 18.1% of the CPC cases with the R337H mutation (2/11), 71.4% of the Pp (5/7), and 25% of CPC cases negative for the R337H mutation (2/8). Family history of cancer (with 2 or more cancer cases) was exclusively identified on the parental side segregating the R337H mutation, and 50% (7/14) of them were compatible with Li-Fraumeni-like syndrome.

Significance: Our results show for the first time that the R337H TP53 mutation is responsible for 63% of the CPC cases in children, suggesting a higher incidence of CPC in southern Brazil.

Figure 1. Typical pedigrees.

The pedigrees of families with the germline TP53 R337H mutation illustrate three different patterns of allele combinations shown in the digital photos of the gel, with loss of the wt allele in A (lane 1: DNA ladder; lane 2: PCR product from CPC DNA treated with HhaI and lane 3 with PCR product from the patient's blood DNA treated with HhaI), loss of the R337H copy in B (lane 1: DNA ladder; lane 2: PCR product from CPC DNA treated with HhaI and lane 3 with PCR product from the father's blood DNA treated with HhaI), and without any loss shown in C (lane 1: DNA ladder; lane 2: PCR product from CPC DNA treated with HhaI and lane 3 with PCR product from the patient's blood DNA treated with HhaI).