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.