Abu Shtaya Aasem, Kedar Inbal, Mattar Samar, Mahamid Ahmad, Basel-Salmon Lina, Farage Barhom Sarit, Naftaly Nathan Sofia, Magal Nurit, Azulay Noy, Levy Zalcberg Michal, Chen-Shtoyerman Rakefet, Segol Ori, Seri Mor, Reznick Levi Gili, Shkedi-Rafid Shiri, Vinkler Chana, Netzer Iris, Hagari Bechar Ofir, Chamma Liat, Liberman Sari, Goldberg Yael
Recanati Genetics Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva 4941492, Israel.
Unit of Gastroenterology, Lady Davis Carmel Medical Center, Haifa 3436212, Israel.
Cancers (Basel). 2023 Dec 24;16(1):94. doi: 10.3390/cancers16010094.
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, usually c.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.
奠基者致病变异（PVs）在以色列很普遍。本研究调查了目前为癌症患者提供两步基因检测的做法，首先针对复发的奠基者PVs进行靶向检测，如果结果为阴性，则进行二代测序。2020年3月至2023年1月期间，共有2128名患有癌症或有阳性家族史的受试者在一家三级医疗中心接受了51种复发PVs的肿瘤基因检测。已知有家族性PV的患者（n = 370）被排除在分析之外。在其余患者中，128/1758（7%）至少有一个变异为杂合子，44名（34%）携带中高外显率（MHPV）的PV。1758名患者中有1519名（86%）被诊断患有癌症。奠基者MHPV检测在癌症患者中的诊断率为2%，在有阳性家族史的健康个体中为4%。在德系犹太人中比在非德系犹太人和阿拉伯人中更高，但在任何类型的癌症中都不超过10%，并且在年龄较小（<40岁）的个体中显著高于年龄较大（>50岁）的个体（7%对1%）。84名杂合子（66%），大多数是德系犹太人，携带与诊断出的癌症无关的低外显率变异（LPV），通常为c.3902T>A。这些发现对两步检测的优势提出了质疑。LPV不应包括在靶向检测中，因为这可能导致对检测率的高估，并且检测到它们并不排除进一步的全面检测。
