XAF1 as a modifier of p53 function and cancer susceptibility
A partir de l'analyse de l'ADN génomique de 203 patients atteints d'un cancer, de 582 personnes apparentées et de 42 438 nouveaux-nés, cette étude identifie un variant du gène du suppresseur de tumeur XAF1 qui augmente le caractère agressif des tumeurs chez les personnes porteuses d'une substitution R337H sur la protéine TP53
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.