Prevalence of Clonal Hematopoiesis Mutations in Tumor-Only Clinical Genomic Profiling of Solid Tumors.
Prevalence of Clonal Hematopoiesis Mutations in Tumor-Only Clinical Genomic Profiling of Solid Tumors.
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DOI：
10.1001/jamaoncol.2018.2297
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发表时间：
2018-11-01
期刊：
影响因子：
28.4
通讯作者：
Zehir A
中科院分区：
文献类型：
--
作者：
Ptashkin RN;Mandelker DL;Coombs CC;Bolton K;Yelskaya Z;Hyman DM;Solit DB;Baselga J;Arcila ME;Ladanyi M;Zhang L;Levine RL;Berger MF;Zehir A
虽然克隆造血（CH）在老年健康人群中得到了很好的描述，但很少有研究讨论这些改变在实体瘤测序中的实际临床意义。使用匹配的肿瘤-血液测序鉴定和定量实体瘤患者中的CH相关突变，并确定基于仅肿瘤测序（不匹配分析）错误归因于肿瘤的比例。回顾性分析了17469例实体癌患者的样本，这些患者在2014年1月至2017年8月期间使用MSK-IMPACT检测对从肿瘤组织和匹配的外周血中分离的DNA进行了前瞻性临床测序。我们确定了每个患者血液白细胞中CH相关突变的存在，并定量了相应匹配肿瘤样本中携带突变的DNA分子的分数。17469例癌症患者在样本采集时的平均年龄为59.2岁（范围0.3-98.9岁）; 53.6%为女性。我们在4628例（26.5%）患者的血液中确定了7608个CH相关突变。在匹配的肿瘤中也检测到总共1075个（14.1%）CH相关突变，高于确定的体细胞突变阈值。总体而言，912例（5.2%）患者至少有1个CH相关突变，在缺乏匹配血液测序的情况下被错误地称为肿瘤来源。这些突变中共有1061个（98.7%）不存在于生殖系多态性的群体规模数据库中，因此在信息过滤方面具有挑战性。用OncoKB注释的变体将534（49.7%）分类为致癌或可能致癌。这项研究表明，当使用仅肿瘤测序时，CH衍生的突变如何导致错误的报告和治疗建议。
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). 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.
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影响因子：
30.8
作者：
Busque L;Patel JP;Figueroa ME;Vasanthakumar A;Provost S;Hamilou Z;Mollica L;Li J;Viale A;Heguy A;Hassimi M;Socci N;Bhatt PK;Gonen M;Mason CE;Melnick A;Godley LA;Brennan CW;Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
影响因子：
12.3
作者：
Li SD;Ma M;Li H;Waluszko A;Sidorenko T;Schadt EE;Zhang DY;Chen R;Ye F
通讯作者：
Ye F
影响因子：
8
作者：
Sholl, Lynette M.;Do, Khanh;MacConaill, Laura E.
通讯作者：
MacConaill, Laura E.
影响因子：
14.9
作者：
Shen R;Seshan VE
通讯作者：
Seshan VE
影响因子：
11.2
作者：
Hartmaier, Ryan J.;Albacker, Lee A.;Lipson, Doron
通讯作者：
Lipson, Doron