1. XAF1 as a modifier of p53 function and cancer susceptibility
- Author
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Patricia Ashton-Prolla, Tatiana Ei-Jaick B Costa, Madson Q. Almeida, Maria Nirvana Formiga, Berenice B. Mendonca, Kara N. Maxwell, Geoffrey Neale, Mariana M Paraizo, Andrew J. Murphy, Enzo Lalli, Meredith Yeager, Jinghui Zhang, Laurence Brugières, Ana Claudia Latronico, Jinling Wang, Wenan Chen, Carolina Mathias, Evadnie Rampersaud, Gang Wu, Dominique Vaur, Sharon A. Savage, Sahlua Volc, Vania Balderrama Brondani, Gabriela E. S. Felix, Camila Matzenbacher Bittar, Elena M. Stoffel, Enilze Maria de Souza Fonseca Ribeiro, Hector Salvador, Vicente Odone-Filho, Kristine Jones, Tobias Else, Kayla V. Hamilton, Alberto S. Pappo, Edenir Inêz Palmero, Guillermo L. Chantada, Karina Miranda Santiago, Emerson Wander Silva Soares, Moara Machado, Kim E. Nichols, Maria Isabel Achatz, Payal P. Klincha, Cintia Regina Niederauer Ramos, Kelvin C. de Andrade, Luis Kowalski, Raul C. Ribeiro, Heloisa Komechen, Aurelie Vogt, Jon P. Connelly, Yoan Diekmann, Márta Korbonits, Eric Letouzé, Maria Candida Barisson Villares Fragoso, Bonald C. Figueiredo, Carlos Rodriguez-Galindo, Ivy Zortéa S Parise, Cinzia Lavarino, Gerard P. Zambetti, Henrique de Campos Reis Galvão, Weiyin Zhou, Shondra M. Pruett-Miller, Michael R. Clay, Emilia M. Pinto, Mark G. Thomas, and Jose Luis Fuster-Soler
- Subjects
Cosegregation ,endocrine system diseases ,Genetic counseling ,Mutant ,Biology ,03 medical and health sciences ,Transactivation ,0302 clinical medicine ,stomatognathic system ,medicine ,Allele ,neoplasms ,Research Articles ,030304 developmental biology ,Cancer ,0303 health sciences ,Multidisciplinary ,Haplotype ,SciAdv r-articles ,Human Genetics ,medicine.disease ,Phenotype ,030220 oncology & carcinogenesis ,Cancer research ,Research Article - Abstract
The XAF1-E134* variant increases the cancer risk for carriers of the TP53-R337H allele., 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.
- Published
- 2020