biostudies-literaturePinto EMAmerican Lebanese Syrian Associated Charities - ALSACRosetreesNCI NIH HHSWellcome Trusteaba3231https://www.ebi.ac.uk/biostudies/studies/S-EPMC7314530biostudies-literatureUnknown6(26)Cancer risk is highly variable in carriers of the common <i>TP53-</i>R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor <i>XAF1</i> (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 (<i>P</i> = 0.003) and subsequent malignancies (<i>P</i> = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic <i>TP53</i> variants, whereas <i>XAF1</i>-E134* is markedly attenuated in this activity. We propose that cosegregation of <i>XAF1-</i>E134* aScience advancesXAF1 as a modifier of p53 function and cancer susceptibility.PMC7314530P30 CA021765100719/Z/12/ZR01 CA217657M505Vaur DConnelly JPZhang JAchatz MIPappo AWu GParise IZSWang JRampersaud EOdone-Filho VMachado MPinto EMYeager MRamos CRNChen WNichols KELavarino CBittar CMFuster-Soler JLMaxwell KNBrugieres LHamilton KVKorbonits MVogt AElse TKomechen HRodriguez-Galindo CMathias CCosta TEBKowalski LJones KAshton-Prolla PFigueiredo BCLetouze EClay MRRibeiro RCNeale GPruett-Miller SMurphy AJVolc SStoffel EMSoares EWSPalmero EIRibeiro EMSFFormiga MNGalvao HCRAlmeida MQFragoso MCBVSavage SAParaizo MMThomas MGMendonca BBLalli EZambetti GPde Andrade KCZhou WKlincha PPBrondani VBSalvador HFelix GSantiago KMLatronico ACDiekmann YChantada GfalseXAF1 as a modifier of p53 function and cancer susceptibility.Cancer risk is highly variable in carriers of the common <i>TP53-</i>R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor <i>XAF1</i> (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 (<i>P</i> = 0.003) and subsequent malignancies (<i>P</i> = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic <i>TP53</i> variants, whereas <i>XAF1</i>-E134* is markedly attenuated in this activity. We propose that cosegregation of <i>XAF1-</i>E134* a2020-01-01T00:00:00Z2020 Jun2026-05-04T01:00:09.302Z2020-07-10T07:16:42ZS-EPMC73145303263760510.1126/sciadv.aba3231