XAF1 as a modifier of p53 function and cancer susceptibility

Abstract

Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma (P = 0.003) and subsequent malignancies (P = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic TP53 variants, whereas XAF1-E134* is markedly attenuated in this activity. We propose that cosegregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone, with implications for genetic counseling and clinical management of hypomorphic TP53 mutant carriers.

What 20 years of research has taught us about the TP53 p.R337H mutation

“…31 Notably, these probands and family members were tested for the constitutive haplotype, and 5 of the 6 index cases testing positive for the TP53 p.R337H variant (the patients with STS [×3], breast cancer, and renal cell carcinoma) shared the extended haplotype cosegregating both TP53 and XAF1 mutated alleles. 20 The pediatric patient with an ACT in this study was positive only for the p.R337H variant. 20 The tumor spectrum for individuals and family members associated with pathogenic germline TP53 variants is wide, but the tumors most closely associated with LFS (core cancers) include premenopausal breast cancer, STS, and osteosarcoma as well as brain tumors and ACTs.…”

“…20 The pediatric patient with an ACT in this study was positive only for the p.R337H variant. 20 The tumor spectrum for individuals and family members associated with pathogenic germline TP53 variants is wide, but the tumors most closely associated with LFS (core cancers) include premenopausal breast cancer, STS, and osteosarcoma as well as brain tumors and ACTs. 10 Palmero et al 32 tested for the p.R337H variant 750 asymptomatic women aged 40 to 69 years who were not selected on the basis of a family history of cancer but had participated in a breast cancer screening program in South Brazil (Rio Grande do Sul State).…”

“…1). 16,19,20 However, it was determined that the constitutive haplotype constructed on the same TP53 p.R337H variant, which occurs in the majority of Brazilian p.R337H carriers, is larger and has a nonsense mutation (p.E134*) in the putative tumor suppressor Cancer November 1, 2020 XAF1 in close proximity to the TP53 locus ( Fig. 1).…”

“…20 The XAF1 p.E134* in concert with the TP53 p.R337H allele leads to a more aggressive cancer phenotype than either variant alone, and this has clear implications for the clinical management of carriers. 20 In the largest population-based screening study, 171,649 newborns from Paraná State were genotyped, and the p.R337H variant was identified in 461 patients (0.27%). 21 Another study assessed the frequency of the TP53 p.R337H variant by screening 32,130 newborns from São Paulo State, and it found that 68 (0.21%) were carriers.…”

“…Although these original studies have not addressed the constitutive haplotype, screening haplotype-defining variants in newborns (n = 42,538) with an unknown history of cancer from South Brazil showed that 69% of p.R337H carriers also have the XAF1 p.E134* variant in the same haplotype. 20 It is also important to consider that the TP53 p.R337H mutation can be observed outside the context of a founder mutation in an independent occurrence as observed in an adult patient with an ACT from Germany. 23 These observations raise the question whether the TP53 p.R337H variant, constitutive haplotype, and associated polymorphisms influence the tumor phenotype.…”