Pinto, EM;
Figueiredo, BC;
Chen, W;
Galvao, HCR;
Formiga, MN;
Fragoso, MCB;
Ashton-Prolla, P;
... Zambetti, GP; + view all
(2020)
XAF1 as a modifier of p53 function and cancer susceptibility.
Science Advances
, 6
(26)
, Article eaba3231. 10.1126/sciadv.aba3231.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | XAF1 as a modifier of p53 function and cancer susceptibility |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1126/sciadv.aba3231 |
| Publisher version: | https://doi.org/10.1126/sciadv.aba3231 |
| Language: | English |
| Additional information: | This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10105076 |
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