Founder pathogenic variants (PVs) are prevalent in Israel. This study investigated the current practice of offering cancer patients two-step genetic testing, starting with targeted testing for recurring founder PVs, followed, if negative, by next-generation sequencing. A total of 2128 subjects with cancer or a positive family history underwent oncogenetic testing with a panel of 51 recurring PVs at a tertiary medical center in March 2020–January 2023. Those with a known familial PV (n = 370) were excluded from the analysis. Among the remainder, 128/1758 (7%) were heterozygous for at least one variant, and 44 (34%) carried a PV of medium-high penetrance (MHPV). Cancer was diagnosed in 1519/1758 patients (86%). The diagnostic yield of founder MHPV testing was 2% in cancer patients and 4% in healthy individuals with a positive family history. It was higher in Ashkenazi Jews than non-Ashkenazi Jews and Arabs, but not over 10% for any type of cancer, and it was significantly higher in younger (<40 years) than older (>50 years) individuals (7% vs. 1%). Eighty-four of the heterozygotes (66%), mostly Ashkenazi Jews, harbored a low-penetrance variant (LPV) not associated with the diagnosed cancer, usuallyAPCc.3902T>A. These findings question the advantage of two-step testing. LPVs should not be included in targeted testing because this can lead to an overestimation of the yield, and their detection does not preclude further comprehensive testing.
在以色列，创始人致病性变异（PVs）较为普遍。本研究调查了当前对癌症患者提供两步法基因检测的实践情况，即首先针对反复出现的创始人PVs进行靶向检测，若结果为阴性，则进行下一代测序。2020年3月至2023年1月期间，在一家三级医疗中心，共有2128名癌症患者或有阳性家族史的个体接受了包含51种反复出现PVs的肿瘤基因检测。已知有家族性PV的个体（n=370）被排除在分析之外。在其余个体中，128/1758（7%）至少携带一种杂合变异，其中44人（34%）携带中高外显率（MHPV）的PV。1519/1758（86%）的患者被诊断为癌症。在癌症患者中，创始人MHPV检测的诊断率为2%，在有阳性家族史的健康个体中为4%。阿什肯纳兹犹太人的诊断率高于非阿什肯纳兹犹太人和阿拉伯人，但任何类型癌症的诊断率均未超过10%，且在年轻（<40岁）个体中显著高于年长（>50岁）个体（7% vs. 1%）。84名杂合子（66%）携带与所诊断癌症无关的低外显率变异（LPV），通常是APCc.3902T>A，其中大多数为阿什肯纳兹犹太人。这些发现对两步法检测的优势提出了质疑。LPVs不应包含在靶向检测中，因为这可能导致诊断率的高估，且其检测结果并不排除进一步全面检测的必要性。
肿瘤(癌症)患者之家