XAF1 as a modifier of p53 function and cancer susceptibility
Pinto, Emilia-M; Figueiredo, Bonald-C; Chen, Wenan; Galvao, Henrique-CR; Formiga, María-Nirvana; Fragoso, María-Candida-B; Ashton-Prolla, Patricia; Ribeiro, Enilze-MSF; Felix, Gabriela; Costa, Tatiana-EB; Savage, Sharon-A; Yeager, Meredith; Palmero, Edenir; Volc, Sahlua; Salvador, Hector; Fuster-Soler, José-Luis; Lavarino, Cinzia; Chantada, Guillermo; Vaur, Dominique; Odone-Filho, Vicente; Brugieres, Laurence; Else, Tobias; Stoffel, Elena-M; Maxwell, Kara-N; Achatz, María-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-WS; Mathias, Carolina; Ramos, Cintia-RN; Machado, Moara; Zhou, Weiyin; Jones, Kristine; Vogt, Aurelie; Klincha, Payal-P; Santiago, Karina-M; Komechen, Heloisa; Paraizo, Mariana-M; Parise, Ivy-ZS; Hamilton, Kayla; Wang, Jinling; Rampersaud, Evadnie; Clay, Michael-R; Murphy, Andrew-J; Lalli, Enzo; Nichols, Kim-E; Ribeiro, Raúl-C; Rodríguez-Galindo, Carlos; Korbonits, Marta; Zhang, Jinghui; Thomas, Mark-G; Connelly, Jon-P; Pruett-Miller, Shondra; Diekmann, Yoan; Neale, Geoffrey; Wu, Gang; Zambetti, Gerard-P
Fecha:
2020-06
Resumen:
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.
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