PURPOSE Despite advances in DNA sequencing technology and expanded medical guidelines, the vast majority of individuals carrying pathogenic variants of common cancer susceptibility genes have yet to be identified. An alternative to population-wide genetic screening of healthy individuals would exploit the trend for genetic testing at the time of cancer diagnosis to guide therapy and prevention, combined with augmented familial diffusion or “cascade” of genomic risk information. METHODS Using a multiple linear regression model, we derived the time interval to detect an estimated 3.9 million individuals in the United States with a pathogenic variant in 1 of 18 cancer susceptibility genes. We analyzed the impact of the proportion of incident patients sequenced, varying observed frequencies of pathogenic germline variants in patients with cancer, differential rates of diffusion of genetic information in families, and family size. RESULTS The time to detect inherited cancer predisposing variants in the population is affected by the extent of cascade to first-, second-, and third-degree relatives (FDR, SDR, TDR, respectively), family size, prevalence of mutations in patients with cancer, and the proportion of patients with cancer sequenced. In a representative scenario, assuming a 7% prevalence of pathogenic variants across cancer types, an average family size of 3 per generation, and 15% of incident patients with cancer in the United States undergoing germline testing, the time to detect all 3.9 million individuals with pathogenic variants in 18 cancer susceptibility genes would be 46.2, 22.3, 13.6, and 9.9 years if 10%, 25%, 50%, and 70%, respectively, of all FDR, SDR, and TDR were tested for familial mutations. CONCLUSION Peridiagnostic and cascade cancer genetic testing offers an alternative strategy to achieve population-wide identification of cancer susceptibility mutations.

中文翻译：

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诊断前后癌症基因检测的级联：基于人群的筛查的替代方案


目的尽管 DNA 测序技术取得了进步，医疗指南也得到了扩展，但绝大多数携带常见癌症易感基因致病变异的个体尚未被识别。对健康个体进行全民基因筛查的替代方案是利用癌症诊断时基因检测的趋势来指导治疗和预防，并结合增强的家族传播或基因组风险信息的“级联”。方法 使用多元线性回归模型，我们得出了检测美国大约 390 万人的时间间隔，该人群的 18 个癌症易感基因中的 1 个基因中存在致病性变异。我们分析了测序患者比例、癌症患者致病种系变异的不同观察频率、家庭中遗传信息扩散率的差异以及家庭规模的影响。结果 检测人群中遗传性癌症易感性变异的时间受到一级、二级和三级亲属（分别为 FDR、SDR、TDR）级联程度、家庭规模、患者突变患病率的影响。癌症，以及癌症患者的测序比例。在一个代表性的场景中，假设各种癌症类型的致病性变异患病率为 7%，平均家庭规模为每代 3 人，并且美国 15% 的癌症患者接受种系检测，那么检测所有 390 万人的时间如果对所有 FDR、SDR 和 TDR 中的 10%、25%、50% 和 70% 分别进行家族突变检测，则 18 个癌症易感基因中存在致病性变异的人的寿命将分别为 46.2、22.3、13.6 和 9.9 年。 结论 诊断期间和级联癌症基因检测提供了一种替代策略，以实现全人群癌症易感性突变的识别。