Levine Cancer Institute, Atrium Health, Charlotte, NC.
Division of Hematology-Oncology, MedStar Georgetown University Hospital, Washington, DC.
JCO Precis Oncol. 2023 Aug;7:e2200695. doi: 10.1200/PO.22.00695.
Among cancer predisposition genes, most direct-to-consumer (DTC) genetic tests evaluate three Ashkenazi Jewish (AJ) founder mutations in , which represent a small proportion of pathogenic or likely pathogenic variants (PLPV) in cancer predisposing genes. In this study, we investigate PLPV in and other cancer predisposition genes that are missed by testing only AJ founder mutations.
Individuals were referred to genetic testing for personal diagnoses of breast and/or ovarian cancer (clinical cohort) or were self-referred (nonindication-based cohort). There were 348,692 participants in the clinical cohort and 7,636 participants in the nonindication-based cohort. Both cohorts were analyzed for AJ founder mutations. Full sequence analysis was done for PLPV in , , , , , , , , , (truncating variants), , , , , , , and 22 other genes.
AJ founder mutations accounted for 10.8% and 29.7% of PLPV in the clinical and nonindication-based cohorts, respectively. AJ founder mutations accounted for 89.9% of PLPV in those of full AJ descent, but only 69.6% of those of partial AJ descent. In total, 0.5% of all individuals had a AJ founder variant, while 7.7% had PLPV in a high-risk breast/ovarian cancer gene. For non-AJ individuals, limiting evaluation to the AJ founder mutations missed >90% of mutations in actionable cancer risk genes. Secondary analysis revealed a false-positive rate of 69% for PLPV outside of non-AJ founder mutations.
DTC genetic testing misses >90% of PLPV in individuals of non-AJ ancestry and about 10% of PLPV among AJ individuals. There is a high false-positivity rate for non-AJ PLPV with DTC genetic testing.
在癌症易感基因中，大多数直接面向消费者（DTC）的基因检测评估三个阿什肯纳兹犹太人（AJ）创始人突变，这仅代表癌症易感基因中致病性或可能致病性变异（PLPV）的一小部分。在这项研究中，我们研究了仅通过检测 AJ 创始人突变而错过的 和其他癌症易感基因中的 PLPV。
个体因个人诊断乳腺癌和/或卵巢癌（临床队列）或自我转诊（非指征性队列）而被转介进行基因检测。临床队列中有 348692 名参与者，非指征性队列中有 7636 名参与者。两个队列均分析了 AJ 创始人突变。对 、、、、、、、、、（截断变异）、、、、、、、和 22 个其他基因中的 PLPV 进行了全序列分析。
AJ 创始人突变分别占临床和非指征性队列中 PLPV 的 10.8%和 29.7%。AJ 创始人突变占完全 AJ 血统的 PLPV 的 89.9%，但仅占部分 AJ 血统的 69.6%。总的来说，所有个体中有 0.5%携带 AJ 创始人变体，而 7.7%携带高风险乳腺癌/卵巢癌基因中的 PLPV。对于非 AJ 个体，将评估仅限于 AJ 创始人 突变会导致 >90%可操作的癌症风险基因中的突变被遗漏。二次分析显示，非 AJ 创始人突变之外的 PLPV 的假阳性率为 69%。
DTC 基因检测会遗漏 >90%非 AJ 血统个体中的 PLPV 以及 AJ 个体中约 10%的 PLPV。DTC 基因检测对非 AJ PLPV 的假阳性率较高。
