Tailor Tina D, Rao Xiayu, Campa Michael J, Wang Jing, Gregory Simon G, Patz Edward F
Department of Radiology, Duke University Medical Center, Durham, NC, United States.
Division of Quantitative Sciences, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Front Oncol. 2019 Apr 24;9:317. doi: 10.3389/fonc.2019.00317. eCollection 2019.
Indeterminate pulmonary lesions (IPL) detected by CT pose a significant clinical challenge, frequently necessitating long-term surveillance or biopsy for diagnosis. In this pilot investigation, we performed whole exome sequencing (WES) of plasma cell free (cfDNA) and matched germline DNA in patients with CT-detected pulmonary lesions to determine the feasibility of somatic cfDNA mutations to differentiate benign from malignant pulmonary nodules. 33 patients with a CT-detected pulmonary lesions were retrospectively enrolled ( = with a benign nodule, = with a malignant nodule). Following isolation and amplification of plasma cfDNA and matched peripheral blood mononuclear cells (PBMC) from patient blood samples, WES of cfDNA and PBMC DNA was performed. After genomic alignment and filtering, we looked for lung-cancer associated driver mutations and next identified high-confidence somatic variants in both groups. Somatic cfDNA mutations were observed in both groups, with the cancer group demonstrating more variants than the benign group (1083 ± 476 versus 553 ± 519, < 0.0046). By selecting variants present in >2 cancer patients and not the benign group, we accurately identified 82% (14/17) of cancer patients. This study suggests a potential role for cfDNA for the early identification of lung cancer in patients with CT-detected pulmonary lesions. Importantly, a substantial number of somatic variants in healthy patients with benign pulmonary nodules were also found. Such "benign" variants, while largely unexplored to date, have widespread relevance to all liquid biopsies if cfDNA is to be used accurately for cancer detection.
CT检测出的肺部不确定病变（IPL）带来了重大的临床挑战，常常需要进行长期监测或活检以明确诊断。在这项初步研究中，我们对CT检测出肺部病变的患者进行了血浆游离细胞DNA（cfDNA）和匹配的种系DNA的全外显子组测序（WES），以确定体细胞cfDNA突变用于区分良性和恶性肺结节的可行性。回顾性纳入了33例CT检测出肺部病变的患者（良性结节患者 = 例，恶性结节患者 = 例）。从患者血液样本中分离并扩增血浆cfDNA和匹配的外周血单核细胞（PBMC）后，对cfDNA和PBMC DNA进行了WES。经过基因组比对和筛选，我们在两组中寻找与肺癌相关的驱动突变，接着鉴定出高可信度的体细胞变异。两组均观察到体细胞cfDNA突变，癌症组的变异比良性组更多（1083 ± 476对553 ± 519，P < 0.0046）。通过选择在2例以上癌症患者中存在而良性组中不存在的变异，我们准确识别出了82%（14/17）的癌症患者。这项研究表明cfDNA在CT检测出肺部病变的患者中对肺癌早期识别具有潜在作用。重要的是，在患有良性肺结节的健康患者中也发现了大量体细胞变异。这些“良性”变异，虽然迄今为止在很大程度上尚未被探索，但如果要将cfDNA准确用于癌症检测，它们与所有液体活检都广泛相关。
