Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
JAMA Oncol. 2018 Nov 1;4(11):1589-1593. doi: 10.1001/jamaoncol.2018.2297.
Although clonal hematopoiesis (CH) is well described in aging healthy populations, few studies have addressed the practical clinical implications of these alterations in solid-tumor sequencing.
To identify and quantify CH-related mutations in patients with solid tumors using matched tumor-blood sequencing, and to establish the proportion that would be misattributed to the tumor based on tumor-only sequencing (unmatched analysis).
DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of samples from 17 469 patients with solid cancers who underwent prospective clinical sequencing of DNA isolated from tumor tissue and matched peripheral blood using the MSK-IMPACT assay between January 2014 and August 2017.
We identified the presence of CH-related mutations in each patient's blood leukocytes and quantified the fraction of DNA molecules harboring the mutation in the corresponding matched tumor sample.
The mean age of the 17 469 patients with cancer at sample collection was 59.2 years (range, 0.3-98.9 years); 53.6% were female. We identified 7608 CH-associated mutations in the blood of 4628 (26.5%) patients. A total of 1075 (14.1%) CH-associated mutations were also detectable in the matched tumor above established thresholds for calling somatic mutations. Overall, 912 (5.2%) patients would have had at least 1 CH-associated mutation erroneously called as tumor derived in the absence of matched blood sequencing. A total of 1061 (98.7%) of these mutations were absent from population scale databases of germline polymorphisms and therefore would have been challenging to filter informatically. Annotating variants with OncoKB classified 534 (49.7%) as oncogenic or likely oncogenic.
This study demonstrates how CH-derived mutations could lead to erroneous reporting and treatment recommendations when tumor-only sequencing is used.
虽然克隆性造血（CH）在老年健康人群中已有很好的描述，但很少有研究探讨这些改变在实体瘤测序中的实际临床意义。
通过匹配的肿瘤-血液测序，在患有实体瘤的患者中识别和量化与 CH 相关的突变，并根据肿瘤的测序结果（不匹配分析）确定这些突变被错误归因于肿瘤的比例。
设计、地点和参与者：回顾性分析了 17469 名患有实体癌的患者的样本，这些患者在 2014 年 1 月至 2017 年 8 月期间接受了前瞻性临床 DNA 测序，这些样本是使用 MSK-IMPACT 检测法从肿瘤组织和配对的外周血中分离出来的。
我们在每位患者的血液白细胞中确定了与 CH 相关的突变的存在，并量化了相应匹配肿瘤样本中携带该突变的 DNA 分子的比例。
在样本采集时，17469 名癌症患者的平均年龄为 59.2 岁（范围，0.3-98.9 岁）；53.6%为女性。我们在 4628 名（26.5%）患者的血液中发现了 7608 个与 CH 相关的突变。在建立了体细胞突变检测标准的情况下，在匹配的肿瘤中还可检测到 1075 个（14.1%）与 CH 相关的突变。总的来说，如果不进行配对血液测序，912 名（5.2%）患者至少会有 1 个 CH 相关的突变被错误地报告为肿瘤来源。这些突变中共有 1061 个（98.7%）不存在于种系多态性的大规模数据库中，因此很难通过信息学方法进行过滤。使用 OncoKB 注释变异体将 534 个（49.7%）归类为致癌或可能致癌。
这项研究表明，当仅使用肿瘤测序时，CH 衍生的突变可能导致错误的报告和治疗建议。
