PURPOSE Polymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases POLE and POLD1. Manifestations may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not yet accurately quantified. METHODS We sequenced POLE and POLD1 exonuclease domains in 354 individuals with early/familial colorectal cancer (CRC) or adenomatous polyposis. We assessed the pathogenicity of POLE variants with yeast fluctuation assays and structural modeling. We estimated the penetrance function for each cancer site in variant carriers with a previously published nonparametric method based on survival analysis approach, able to manage unknown genotypes. RESULTS Pathogenic POLE exonuclease domain variants P286L, M294R, P324L, N363K, D368N, L424V, K425R, and P436S were found in ten families. The estimated cumulative risk of CRC at 30, 50, and 70 years was 11.1% (95% confidence interval [CI]: 4.2-17.5), 48.5% (33.2-60.3), and 74% (51.6-86.1). Cumulative risk of glioblastoma was 18.7% (3.2-25.8) at 70 years. Variants interfering with DNA binding (P286L and N363K) had a significantly higher mutagenic effect than variants disrupting ion metal coordination at the exonuclease site. CONCLUSION The risk estimates derived from this study provide a rational basis on which to provide genetic counseling to POLE variant carriers.

中文翻译：

---

POLE 聚合酶校对变体的遗传、结构和功能表征可以预测癌症风险。

目的聚合酶校对相关息肉病是一种显性遗传的结直肠癌综合征，由 DNA 聚合酶 POLE 和 POLD1 中的外切核酸酶结构域错义变异体引起。表现也可能包括结肠外部位的恶性肿瘤。这种综合征的癌症风险尚未准确量化。方法 我们对 354 名早期/家族性结直肠癌 (CRC) 或腺瘤性息肉病患者的 POLE 和 POLD1 核酸外切酶结构域进行了测序。我们通过酵母波动测定和结构建模评估了 POLE 变体的致病性。我们使用先前发表的基于生存分析方法的非参数方法估计了变异携带者中每个癌症部位的外显率函数，能够管理未知基因型。结果 致病性 POLE 外切核酸酶结构域变体 P286L、M294R、P324L、N363K、D368N、L424V、K425R 和 P436S 在 10 个家族中被发现。CRC 在 30、50 和 70 年的估计累积风险为 11.1%（95% 置信区间 [CI]：4.2-17.5）、48.5%（33.2-60.3）和 74%（51.6-86.1）。70 岁时胶质母细胞瘤的累积风险为 18.7% (3.2-25.8)。干扰 DNA 结合的变体（P286L 和 N363K）比在外切核酸酶位点破坏离子金属配位的变体具有显着更高的诱变效果。结论 本研究得出的风险评估为向 POLE 变异携带者提供遗传咨询提供了合理的基础。干扰 DNA 结合的变体（P286L 和 N363K）比在外切核酸酶位点破坏离子金属配位的变体具有显着更高的诱变效果。结论 本研究得出的风险评估为向 POLE 变异携带者提供遗传咨询提供了合理的基础。干扰 DNA 结合的变体（P286L 和 N363K）比在外切核酸酶位点破坏离子金属配位的变体具有显着更高的诱变效果。结论 本研究得出的风险评估为向 POLE 变异携带者提供遗传咨询提供了合理的基础。