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.

常见 TP53- R337H创始等位基因携带者的癌症风险差异很大，这可能是由于修饰基因的影响。全基因组测序在 R337H 携带者的一个子集中发现了肿瘤抑制基因XAF1 (E134*/Glu134Ter/rs146752602) 的变异。在 203 名癌症患者、582 名亲属和 42,438 名新生儿中验证了单倍型定义变异。复合突变单倍型在癌症患者中富集，赋予肉瘤（P = 0.003）和随后的恶性肿瘤（P = 0.006）的风险。功能分析表明，野生型 XAF1 增强了野生型和亚型TP53变体的反式激活，而XAF1-E134* 在此活动中明显减弱。我们建议XAF1- E134* 和TP53- R337H突变的共分离导致比单独的 TP53-R337H 更具侵袭性的癌症表型，这对亚型TP53突变携带者的遗传咨询和临床管理具有重要意义。