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. 2024 Jan 11;5(1):100244.
doi: 10.1016/j.xhgg.2023.100244. Epub 2023 Oct 4.

Multiple TP53 p.R337H haplotypes and implications for tumor susceptibility

Emilia M Pinto  1 , Cintia Fridman  2 , Bonald C Figueiredo  3 , Hector Salvador  4 , Manuel R Teixeira  5 , Carla Pinto  6 , Manuela Pinheiro  6 , Christian P Kratz  7 , Cinzia Lavarino  4 , Edith A M F Legal  3 , Anh Le  8 , Gregory Kelly  8 , Erika Koeppe  9 , Elena M Stoffel  9 , Kelsey Breen  10 , Stefanie Hahner  11 , Britta Heinze  11 , Piti Techavichit  12 , Amanda Krause  13 , Tsutomu Ogata  14 , Yasuko Fujisawa  14 , Michael F Walsh  10 , Huma Q Rana  15 , Kara N Maxwell  8 , Judy E Garber  15 , Carlos Rodriguez-Galindo  16 , Raul C Ribeiro  17 , Gerard P Zambetti  18
Affiliations

Multiple TP53 p.R337H haplotypes and implications for tumor susceptibility

Emilia M Pinto et al. HGG Adv. .

Abstract

The germline TP53 p.R337H mutation is reported as the most common germline TP53 variant. It exists at a remarkably high frequency in the population of southeast Brazil as founder mutation in two distinct haplotypes with the most frequent co-segregating with the p.E134∗ variant of the XAF1 tumor suppressor and an increased cancer risk. Founder mutations demonstrate linkage disequilibrium with neighboring genetic polymorphic markers that can be used to identify the founder variant in different geographic regions and diverse populations. We report here a shared haplotype among Brazilian, Portuguese, and Spanish families and the existence of three additional distinct TP53 p.R337H alleles. Mitochondrial DNA sequencing and Y-STR profiling of Brazilian carriers of the founder TP53 p.R337H allele reveal an excess of Native American haplogroups in maternal lineages and exclusively European haplogroups in paternal lineages, consistent with communities established through male European settlers with extensive intermarriage with Indigenous women. The identification of founder and independent TP53 p.R337H alleles underlines the importance for considering the haplotype as a functional unit and the additive effects of constitutive polymorphisms and associated variants in modifier genes that can influence the cancer phenotype.

Keywords: Brazil; Iberian Peninsula; R337H; Sephardic Jewish; Y-STR; ancestry; cancer predisposition; founder mutation; haplotype; mitochondrial DNA.

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Conflict of interest statement

Declaration of interests K.B. reports an immediate family member on the scientific advisory board of Emendo Biotherapeutics, Karyopharm Therapeutics, Imago BioSciences, and DarwinHealth; is co-founder of Isabl Technologies; and has equity interest in Imago BioSciences, Emendo Biotherapeutics, and Isabl Technologies.

Figures

Figure 1
Figure 1
Diagram of five distinct TP53 p.R337H alleles (A) Five distinct haplotypes were identified based on TP53 internal polymorphisms and microsatellite markers on chromosome 17p13. (B) Identical DNA sequences shared among the five haplotypes are identified by solid blue bars and blue dashed lines. Polymorphic markers distinguishing the five haplotypes are highlighted in purple [Hap3, VNTRp53(n) and p53CA(n)], red [Hap4 P72R, PIN3, VNTRp53(n) and p53CA(n)], orange (Hap5, de novo, P72/A2), and green (Hap1, DNA sequence spanning D17S796 to D17S952 containing XAF1 p.E134∗ variant) solid bars.
Figure 2
Figure 2
World map showing the distribution of TP53 p.R337H alleles and their constitutive haplotypes Known migration routes of carriers from Brazil to the United States, Portugal, and Japan are highlighted by purple (Hap1) and blue (Hap2) arrows with dotted lines.
See this image and copyright information in PMC

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