RT Journal Article SR Electronic T1 XAF1 as a modifier of p53 function and cancer susceptibility JF Science Advances JO Sci Adv FD American Association for the Advancement of Science SP eaba3231 DO 10.1126/sciadv.aba3231 VO 6 IS 26 A1 Pinto, Emilia M. A1 Figueiredo, Bonald C. A1 Chen, Wenan A1 Galvao, Henrique C.R. A1 Formiga, Maria Nirvana A1 Fragoso, Maria Candida B.V. A1 Ashton-Prolla, Patricia A1 Ribeiro, Enilze M.S.F. A1 Felix, Gabriela A1 Costa, Tatiana E.B. A1 Savage, Sharon A. A1 Yeager, Meredith A1 Palmero, Edenir I. A1 Volc, Sahlua A1 Salvador, Hector A1 Fuster-Soler, Jose Luis A1 Lavarino, Cinzia A1 Chantada, Guillermo A1 Vaur, Dominique A1 Odone-Filho, Vicente A1 Brugières, Laurence A1 Else, Tobias A1 Stoffel, Elena M. A1 Maxwell, Kara N. A1 Achatz, Maria Isabel A1 Kowalski, Luis A1 de Andrade, Kelvin C. A1 Pappo, Alberto A1 Letouze, Eric A1 Latronico, Ana Claudia A1 Mendonca, Berenice B. A1 Almeida, Madson Q. A1 Brondani, Vania B. A1 Bittar, Camila M. A1 Soares, Emerson W.S. A1 Mathias, Carolina A1 Ramos, Cintia R.N. A1 Machado, Moara A1 Zhou, Weiyin A1 Jones, Kristine A1 Vogt, Aurelie A1 Klincha, Payal P. A1 Santiago, Karina M. A1 Komechen, Heloisa A1 Paraizo, Mariana M. A1 Parise, Ivy Z.S. A1 Hamilton, Kayla V. A1 Wang, Jinling A1 Rampersaud, Evadnie A1 Clay, Michael R. A1 Murphy, Andrew J. A1 Lalli, Enzo A1 Nichols, Kim E. A1 Ribeiro, Raul C. A1 Rodriguez-Galindo, Carlos A1 Korbonits, Marta A1 Zhang, Jinghui A1 Thomas, Mark G. A1 Connelly, Jon P. A1 Pruett-Miller, Shondra A1 Diekmann, Yoan A1 Neale, Geoffrey A1 Wu, Gang A1 Zambetti, Gerard P. YR 2020 UL http://advances.sciencemag.org/content/6/26/eaba3231.abstract AB 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.