Purpose

Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study.

Methods

POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case–control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation.

Results

Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies <1%, were identified. One ED variant (POLE p.Met294Arg) was classified as likely pathogenic, four as likely benign, and seven as variants of unknown significance. The most commonly associated tumor types were colorectal, endometrial and ovarian cancers. Loss-of-function and outside-ED variants are likely not pathogenic for this syndrome.

Conclusions

Polymerase proofreading–associated syndrome constitutes 0.1–0.4% of familial cancer cases, reaching 0.3–0.7% when only CRC and polyposis are considered. ED variant interpretation is challenging and should include multiple pieces of evidence.

中文翻译：

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POLE 和 POLD1 在家族性癌症中的作用。

目的

聚合酶POLE和POLD1的外切核酸酶结构域 (ED) 中的种系致病变异易患腺瘤性息肉、结直肠癌 (CRC)、子宫内膜肿瘤和其他恶性肿瘤，并表现出更高的突变率和高度特异性的相关突变特征。本研究评估了遗传性癌症中POLE和POLD1变体的肿瘤谱和患病率。

方法

POLE和POLD1在 2813 名无关先证者中进行了测序，这些先证者被转介进行遗传咨询（2309 名遗传性癌症患者接受了多基因组，504 名患者根据表型特征选择）。进行了共分离和病例对照研究、基于酵母的功能测定和肿瘤突变分析以进行变异解释。

结果

鉴定了 12 个 ED 错义变体、6 个功能丧失和 23 个外部 ED 预测有害错义变体，所有这些变体的群体等位基因频率均 <1%。一种 ED 变异 ( POLE p.Met294Arg) 被归类为可能致病，四种可能为良性，七种为未知意义的变异。最常见的相关肿瘤类型是结直肠癌、子宫内膜癌和卵巢癌。功能丧失和外部 ED 变异可能对这种综合征没有致病性。

结论

聚合酶校对相关综合征占家族性癌症病例的 0.1-0.4%，仅考虑 CRC 和息肉病时达到 0.3-0.7%。ED 变异解释具有挑战性，应包括多条证据。