美国纪念斯隆-凯特琳癌症中心Jorge S. Reis-Filho研究团队利用深度测序揭示出血浆循环中游离DNA（cfDNA）变异的来源。相关论文于2019年11月25日在线发表于国际学术期刊《自然—医学》。

研究人员在对124例转移性癌症患者以及匹配的肿瘤组织活检和47例无癌症的对照的前瞻性研究中，确定了cfDNA和匹配的白细胞DNA的强度测序测定技术的可行性，该测定涵盖了较大的基因组区域（508个基因；2兆碱基；> 60000倍原始深度）。

该方法显示出高灵敏度和特异性，可以从头检测肿瘤来源的突变，并推断出cfDNA中鉴定的肿瘤突变负担、微卫星不稳定性、突变特征和体细胞突变的来源。绝大多数cfDNA突变（对照组为81.6％，癌症患者为53.2％）具有与克隆性造血一致的特征。

cfDNA测序方法揭示了克隆性造血是一种普遍的生物学现象，并强调了匹配的cfDNA-白细胞测序对于准确解释变异的重要性。

据了解，在血浆循环cfDNA中准确鉴定肿瘤来源的体细胞变异体需要了解不同生物区域对cfDNA库的影响。

附：英文原文

Title: High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants

Author: Pedram Razavi, Bob T. Li, David N. Brown, Byoungsok Jung, Earl Hubbell, Ronglai Shen, Wassim Abida, Krishna Juluru, Ino De Bruijn, Chenlu Hou, Oliver Venn, Raymond Lim, Aseem Anand, Tara Maddala, Sante Gnerre, Ravi Vijaya Satya, Qinwen Liu, Ling Shen, Nicholas Eattock, Jeanne Yue, Alexander W. Blocker, Mark Lee, Amy Sehnert, Hui Xu, Megan P. Hall, Angie Santiago-Zayas, William F. Novotny, James M. Isbell, Valerie W. Rusch, George Plitas, Alexandra S. Heerdt, Marc Ladanyi, David M. Hyman, David R. Jones, Monica Morrow, Gregory J. Riely, Howard I. Scher, Charles M. Rudin, Mark E. Robson, Luis A. Diaz, David B. Solit, Alexander M. Aravanis, Jorge S. Reis-Filho

Issue&Volume: 2019-11-25

Abstract: 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; 2megabases; >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.

DOI: 10.1038/s41591-019-0652-7

Source: https://www.nature.com/articles/s41591-019-0652-7