Detailed haplotype analysis at theTP53locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect

Abstract

Due to patterns of migration, selection, and population expansion, founder effects are common among humans. In Southern Brazil, a recurrent TP53 mutation, p.R337H, is detected in families with cancer predisposition. We have used whole locus resequencing and high-density single nucleotide polymorphism (SNP) genotyping to refine TP53 locus haplotype definitions. Haplotyping of 12 unrelated p.R337H carriers using a set of 29 tag SNPs, revealed that all subjects carried the same haplotype, and presence of the mutation on this haplotype was confirmed by allele-specific PCR. The probability that this haplotype occurs independently in all index cases was of 3.1x10(-9), demonstrating a founder effect. Analysis of the patterns of 103 tumors diagnosed in 12 families showed that the presence of p.R337H is associated with multiple cancers of the Li-Fraumeni Syndrome (LFS) spectrum, with relatively low penetrance before the age of 30 but a lifetime risk comparable to classical LFS. The p.R337H families are mostly distributed along a road axis historically known as the main route used by merchants of Portuguese origin in the XVIII and XIX century. This historical circumstance and the relatively low penetrance before the age of 30 may have contributed to the maintenance of this pathogenic mutation in a large, open population.

Recent developments in brain tumor predisposing syndromes

“…Carriers of this specific TP53 mutation (R337H) have a low risk of developing cancer before the age of 30, but a lifetime cancer risk comparable to classic LFS [105,106]. Interestingly, 90-95% of all patients with adrenocortical carcinomas have the TP53-R337H mutation leading to a drastic increase of this cancer form in the southern provinces of Brazil [107].…”

Szlaki molekularne w raku kory nadnercza — od wiedzy o sygnalizacji komórkowej do metod diagnostyki i leczenia

“…Despite the previous alternative theories, a recent study has confirmed that the high prevalence of this mutation, around 0.3% in the population of this region, results from the occurrence of a founder effect in the Brazilian population. In Southern Brazil the incidence of childhood ACC is 10-15 higher compared with other parts of the world, being strongly associated with the p.R337H mutation [115][116][117].…”

“…Pomimo wcześniejszych alternatywnych teorii, ostatnie badania potwierdzają, że wysoki współczyn-nik występowania tej mutacji u około 0,3% populacji tego regionu wynika z wystąpienia efektu założyciela w populacji Brazylii. W południowej Brazylii częstość występowania ACC u dzieci jest 10-15-krotnie wyższa niż w innych częściach świata i jest silnie związana z mutacją p.R337H [115][116][117].…”

The Role of New Sequencing Technology in Identifying Rare Mutations in New Susceptibility Genes for Cancer

“…biallelic MUTYH mutation associated colon cancer) [33,38]. Further developments in high-throughput, cost-effective mutation screening methods that generally applied Sanger sequencing in a validation phase made possible considerable candidate gene sequencing and resequencing that further defined mutation frequency and associated cancer risks [39][40][41][42][43][44][45] (see Fig. 1).…”