XAF1 as a modifier of p53 function and cancer susceptibility

PINTO, EMILIA M.; FIGUEIREDO, BONALD C.; CHEN, WENAN; GALVAO, HENRIQUE C.R.; FORMIGA, MARIA NIRVANA; FRAGOSO, MARIA CANDIDA B.V.; ASHTON-PROLLA, PATRICIA; RIBEIRO, ENILZE M.S.F.; FELIX, GABRIELA; COSTA, TATIANA E.B.; SAVAGE, SHARON A.; YEAGER, MEREDITH; PALMERO, EDENIR I.; VOLC, SAHLUA; SALVADOR, HECTOR; FUSTER-SOLER, JOSE LUIS; LAVARINO, CINZIA; CHANTADA, GUILLERMO; VAUR, DOMINIQUE; ODONE-FILHO, VICENTE; BRUGIÈRES, LAURENCE; ELSE, TOBIAS; STOFFEL, ELENA M.; MAXWELL, KARA N.; ACHATZ, MARIA ISABEL; KOWALSKI, LUIS; DE ANDRADE, KELVIN C.; PAPPO, ALBERTO; LETOUZE, ERIC; LATRONICO, ANA CLAUDIA; MENDONCA, BERENICE B.; ALMEIDA, MADSON Q.; BRONDANI, VANIA B.; BITTAR, CAMILA M.; SOARES, EMERSON W.S.; MATHIAS, CAROLINA; RAMOS, CINTIA R.N.; MACHADO, MOARA; ZHOU, WEIYIN; JONES, KRISTINE; VOGT, AURELIE; KLINCHA, PAYAL P.; SANTIAGO, KARINA M.; KOMECHEN, HELOISA; PARAIZO, MARIANA M.; PARISE, IVY Z.S.; HAMILTON, KAYLA V.; WANG, JINLING; RAMPERSAUD, EVADNIE; CLAY, MICHAEL R.; MURPHY, ANDREW J.; LALLI, ENZO; NICHOLS, KIM E.; R

Science Advances

Science Advances is the American Association for the Advancement of Science

Año: 2020 vol. 6

2375-2548

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.