Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, Maryland.
Cancer Epidemiol Biomarkers Prev. 2019 Feb;28(2):293-302. doi: 10.1158/1055-9965.EPI-18-0584. Epub 2019 Jan 28.
Eligibility guidelines for genetic testing may be revisited, given technological advances, plummeting costs, and proposals for population mutation screening. A key property of eligibility criteria is the tradeoff between the number of mutation carriers identified versus population members tested. We assess the fractions of mutation carriers identified, versus women undergoing mutation testing, for founder mutation screening in U.S. Ashkenazi-Jewish women.
carrier probabilities, based on personal/family history, were calculated using the risk-prediction tool BRCAPRO for 4,589 volunteers (102 mutation carriers) in the population-based Washington Ashkenazi Study. For each carrier-probability threshold between 0% and 10%, we compared the percentage of founder mutations detected versus the percentage of women requiring mutation testing. PCR mutation testing was conducted at the NIH for the 3 Ashkenazi-Jewish founder mutations (5382insC and 185delAG in , and 6174delT in ).
Identifying 90% of founder mutations required testing the 60% of Ashkenazi-Jewish women with carrier probabilities exceeding 0.56%, potentially avoiding mutation testing for approximately 0.7 to 1.1 million U.S. Ashkenazi-Jewish women. Alternatively, testing the 44% whose carrier probability exceeded 0.78% identified 80% of mutation carriers, increasing to 89% of mutation carriers when accounting for cascade testing triggered after mutation-positive daughters were identified by screening. We present data on all carrier-probability thresholds, e.g., a 5% threshold identified 46% of mutation carriers while testing 10% of women.
Different carrier-probability thresholds offered diverse tradeoffs between numbers of identified mutation carriers versus women tested. Low carrier-probability thresholds identified 90% of founder mutation carriers, without testing approximately 1 million U.S. Ashkenazi-Jewish women with lowest carrier probabilities.
In general, this risk-based framework could provide useful new options to consider during eligibility-criteria development for population mutation screening.
鉴于技术进步、成本降低以及对人群突变筛查的提议，基因检测的资格标准可能需要重新审视。资格标准的一个关键特性是在鉴定的突变携带者数量与接受测试的人群成员数量之间进行权衡。我们评估了在美国的美国阿什肯纳兹裔犹太女性中，针对 创始人突变筛查的突变携带者鉴定率与接受突变测试的女性比例。
使用基于个人/家族史的风险预测工具 BRCAPRO，为基于人群的华盛顿阿什肯纳兹研究中的 4589 名志愿者（102 名突变携带者）计算了携带者概率。对于 0%至 10%之间的每个携带者概率阈值，我们比较了检测到的 创始人突变的百分比与需要进行突变测试的女性的百分比。在 NIH 对 3 种阿什肯纳兹裔犹太裔创始人突变（ 中的 5382insC 和 185delAG 以及 中的 6174delT）进行了 PCR 突变测试。
确定 90%的 创始人突变需要对携带者概率超过 0.56%的 60%的阿什肯纳兹裔犹太女性进行测试，这可能避免了约 70 万至 110 万美国阿什肯纳兹裔犹太女性的突变测试。或者，对携带者概率超过 0.78%的 44%的女性进行测试，可以鉴定出 80%的突变携带者，当考虑到通过筛查发现突变阳性女儿后触发的级联测试时，这一比例增加到 89%的突变携带者。我们提供了所有携带者概率阈值的数据，例如，5%的阈值可以鉴定出 46%的突变携带者，而只测试了 10%的女性。
不同的携带者概率阈值在鉴定的突变携带者数量与接受测试的女性数量之间提供了不同的权衡。低携带者概率阈值可以鉴定出 90%的 创始人突变携带者，而无需对携带者概率最低的约 100 万美国阿什肯纳兹裔犹太女性进行测试。
一般来说，这种基于风险的框架可以为人群突变筛查的资格标准制定提供有用的新选择。
