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High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants.
Nature Medicine ( IF 82.9 ) Pub Date : 2019-11-25 , DOI: 10.1038/s41591-019-0652-7 Pedram Razavi 1, 2 , Bob T Li 1 , David N Brown 3 , Byoungsok Jung 4 , Earl Hubbell 4 , Ronglai Shen 5 , Wassim Abida 1 , Krishna Juluru 6 , Ino De Bruijn 7 , Chenlu Hou 4 , Oliver Venn 4 , Raymond Lim 3 , Aseem Anand 1 , Tara Maddala 4 , Sante Gnerre 4 , Ravi Vijaya Satya 4 , Qinwen Liu 4 , Ling Shen 4 , Nicholas Eattock 4 , Jeanne Yue 4 , Alexander W Blocker 4, 8 , Mark Lee 4, 9 , Amy Sehnert 4, 10 , Hui Xu 4 , Megan P Hall 4 , Angie Santiago-Zayas 1 , William F Novotny 4, 11 , James M Isbell 12 , Valerie W Rusch 12 , George Plitas 12 , Alexandra S Heerdt 12 , Marc Ladanyi 3 , David M Hyman 1 , David R Jones 12 , Monica Morrow 12 , Gregory J Riely 1 , Howard I Scher 1 , Charles M Rudin 1 , Mark E Robson 1 , Luis A Diaz 1 , David B Solit 1, 2, 7 , Alexander M Aravanis 4 , Jorge S Reis-Filho 2, 3
Nature Medicine ( IF 82.9 ) Pub Date : 2019-11-25 , DOI: 10.1038/s41591-019-0652-7 Pedram Razavi 1, 2 , Bob T Li 1 , David N Brown 3 , Byoungsok Jung 4 , Earl Hubbell 4 , Ronglai Shen 5 , Wassim Abida 1 , Krishna Juluru 6 , Ino De Bruijn 7 , Chenlu Hou 4 , Oliver Venn 4 , Raymond Lim 3 , Aseem Anand 1 , Tara Maddala 4 , Sante Gnerre 4 , Ravi Vijaya Satya 4 , Qinwen Liu 4 , Ling Shen 4 , Nicholas Eattock 4 , Jeanne Yue 4 , Alexander W Blocker 4, 8 , Mark Lee 4, 9 , Amy Sehnert 4, 10 , Hui Xu 4 , Megan P Hall 4 , Angie Santiago-Zayas 1 , William F Novotny 4, 11 , James M Isbell 12 , Valerie W Rusch 12 , George Plitas 12 , Alexandra S Heerdt 12 , Marc Ladanyi 3 , David M Hyman 1 , David R Jones 12 , Monica Morrow 12 , Gregory J Riely 1 , Howard I Scher 1 , Charles M Rudin 1 , Mark E Robson 1 , Luis A Diaz 1 , David B Solit 1, 2, 7 , Alexander M Aravanis 4 , Jorge S Reis-Filho 2, 3
Affiliation
Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding of the various biological compartments contributing to the cfDNA pool. We sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white blood cell DNA covering a large genomic region (508 genes; 2 megabases; >60,000× raw depth) in a prospective study of 124 patients with metastatic cancer, with contemporaneous matched tumor tissue biopsies, and 47 controls without cancer. The assay displayed high sensitivity and specificity, allowing for de novo detection of tumor-derived mutations and inference of tumor mutational burden, microsatellite instability, mutational signatures and sources of somatic mutations identified in cfDNA. The vast majority of cfDNA mutations (81.6% in controls and 53.2% in patients with cancer) had features consistent with clonal hematopoiesis. This cfDNA sequencing approach revealed that clonal hematopoiesis constitutes a pervasive biological phenomenon, emphasizing the importance of matched cfDNA-white blood cell sequencing for accurate variant interpretation.
中文翻译:
高强度测序揭示了血浆循环游离 DNA 变体的来源。
准确识别血浆循环游离 DNA (cfDNA) 中肿瘤衍生的体细胞变异体需要了解构成 cfDNA 库的各种生物区室。我们试图在一项对 124 名转移性癌症患者进行的前瞻性研究中确定覆盖大基因组区域(508 个基因;2 兆碱基;>60,000× 原始深度)的 cfDNA 和匹配的白细胞 DNA 的高强度测序分析的技术可行性,同时进行匹配的肿瘤组织活检,以及 47 名没有癌症的对照。该测定显示出高灵敏度和特异性,允许从头检测肿瘤衍生的突变和推断肿瘤突变负荷、微卫星不稳定性、突变特征和 cfDNA 中鉴定的体细胞突变来源。绝大多数 cfDNA 突变 (81. 6% 的对照组和 53.2% 的癌症患者)具有与克隆性造血一致的特征。这种 cfDNA 测序方法揭示了克隆造血是一种普遍存在的生物学现象,强调了匹配的 cfDNA-白细胞测序对准确变异解释的重要性。
更新日期:2019-11-26
中文翻译:
高强度测序揭示了血浆循环游离 DNA 变体的来源。
准确识别血浆循环游离 DNA (cfDNA) 中肿瘤衍生的体细胞变异体需要了解构成 cfDNA 库的各种生物区室。我们试图在一项对 124 名转移性癌症患者进行的前瞻性研究中确定覆盖大基因组区域(508 个基因;2 兆碱基;>60,000× 原始深度)的 cfDNA 和匹配的白细胞 DNA 的高强度测序分析的技术可行性,同时进行匹配的肿瘤组织活检,以及 47 名没有癌症的对照。该测定显示出高灵敏度和特异性,允许从头检测肿瘤衍生的突变和推断肿瘤突变负荷、微卫星不稳定性、突变特征和 cfDNA 中鉴定的体细胞突变来源。绝大多数 cfDNA 突变 (81. 6% 的对照组和 53.2% 的癌症患者)具有与克隆性造血一致的特征。这种 cfDNA 测序方法揭示了克隆造血是一种普遍存在的生物学现象,强调了匹配的 cfDNA-白细胞测序对准确变异解释的重要性。