In:
Science Advances, American Association for the Advancement of Science (AAAS), Vol. 6, No. 26 ( 2020-06-26)
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 of Medium:
Online Resource
ISSN:
2375-2548
DOI:
10.1126/sciadv.aba3231
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2020
detail.hit.zdb_id:
2810933-8
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