XAF1 as a modifier of p53 function and cancer susceptibility.
Emilia Modolo PintoBonald C FigueiredoWenan ChenHenrique C R GalvaoMaria Nirvana FormigaMaria Candida B V FragosoPatricia Ashton-ProllaEnilze M S F RibeiroGabriela FelixTatiana E B CostaSharon A SavageMeredith YeagerEdenir I PalmeroSahlua VolcHector SalvadorJose Luis Fuster-SolerCinzia LavarinoGuillermo ChantadaDominique VaurVicente Odone-FilhoLaurence BrugièresTobias ElseElena M StoffelKara N MaxwellMaria Isabel AchatzLuis KowalskiKelvin C de AndradeAlberto PappoEric LetouzeAna Claudia LatronicoBerenice B MendoncaMadson Q AlmeidaVania B BrondaniCamila M BittarEmerson W S SoaresCarolina MathiasCintia R N RamosMoara MachadoWeiyin ZhouKristine JonesAurelie VogtPayal P KlinchaKarina M SantiagoHeloisa KomechenMariana M ParaizoIvy Z S PariseKayla V HamiltonJinling WangEvadnie RampersaudMichael R ClayAndrew J MurphyEnzo LalliKim E NicholsRaul C RibeiroCarlos Rodriguez-GalindoMarta KorbonitsJinghui ZhangMark G ThomasJon P ConnellyShondra Pruett-MillerYoan DiekmannGeoffrey A NealeGang WuGerard P ZambettiPublished in: Science advances (2020)
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.