Schwartz Alison N, Hyman Sophie R, Stokes Samantha M, Castillo Danielle, Tung Nadine M, Weitzel Jeffrey N, Rana Huma Q, Garber Judy E
Division of Cancer Genetics and Prevention, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Division of Clinical Cancer Genomics, Beckman Research Institute, City of Hope, Duarte, CA.
JCO Precis Oncol. 2021 Nov;5:1677-1686. doi: 10.1200/PO.21.00278.
Multigene panel testing (MGPT) identifies pathogenic or likely pathogenic (P/LP) variants in patients with diverse phenotypes, of which only one is classic Li-Fraumeni syndrome. Low variant allelic fraction (VAF) in found on germline testing may suggest aberrant clonal expansion or constitutional mosaicism. We evaluated -positive probands seen in a cancer genetics program to determine germline versus somatic status.
We reviewed -positive probands from 2012 to 2019 identified by MGPT on blood or saliva (N = 84). Available VAFs were collected. Probands with a familial variant, who met Li-Fraumeni syndrome testing criteria or who carried a founder variant, were considered germline. For those with uncertain germline status, variants were further examined using ancillary data of family members and somatic tissue.
Of the 84 probands, 54.7% had germline variants with 33.3% meeting criteria for germline status and 21.4% confirmed through ancillary testing. Aberrant clonal expansion comprised 13.1% with clonal hematopoiesis of indeterminate potential and 2.4% with a hematologic malignancy. Constitutional mosaicism was confirmed in 8.3% probands. Definitive status could not be determined in 3.6% despite ancillary assessment, and 17.9% did not have ancillary testing.
A P/LP variant found on peripheral blood or saliva MGPT does not always originate in the germline. In a clinical cancer genetics cohort, approximately half of the patients had P/LP germline variants; these patients plus those with constitutional mosaicism require intensified surveillance. A framework of multiple strategies enables discernment of germline from constitutional mosaic and acquired variants, which is essential for appropriate management.
多基因panel检测（MGPT）可在具有不同表型的患者中识别出致病性或可能致病性（P/LP）变异，其中只有一种是经典的李-弗劳梅尼综合征。在种系检测中发现的低变异等位基因分数（VAF）可能提示异常的克隆扩增或体细胞镶嵌现象。我们评估了在癌症遗传学项目中检测呈阳性的先证者，以确定种系状态与体细胞状态。
我们回顾了2012年至2019年通过MGPT在血液或唾液中检测呈阳性的先证者（N = 84）。收集可用的VAF。具有家族性变异、符合李-弗劳梅尼综合征检测标准或携带奠基者变异的先证者被视为种系变异。对于种系状态不确定的患者，使用家庭成员和体细胞组织的辅助数据进一步检查变异。
在84名先证者中，54.7%有种系变异，其中33.3%符合种系状态标准，21.4%通过辅助检测得到确认。异常克隆扩增包括13.1%的具有不确定潜能的克隆性造血和2.4%的血液系统恶性肿瘤。8.3%的先证者被确认存在体细胞镶嵌现象。尽管进行了辅助评估，但仍有3.6%的患者无法确定明确状态，17.9%的患者未进行辅助检测。
在外周血或唾液MGPT中发现的P/LP变异并不总是起源于种系。在临床癌症遗传学队列中，约一半的患者具有P/LP种系变异；这些患者以及体细胞镶嵌现象的患者需要加强监测。多种策略的框架能够区分种系变异与体细胞镶嵌变异和获得性变异，这对于适当的管理至关重要。
