Biological background of the genomic variations of cf-DNA in healthy individuals

作者：J. Liu, X. Chen, J. Wang, Shumin Zhou, C.L. Wang, Muying Ye, X.Y. Wang, Yijun Song, Youwei Wang, liuping zhang, Renhua Wu, Huanming Yang, Shida Zhu, Mengyu Zhou, Xue Zhang, Hongmei Zhu, Zhaoyang Qian · 发表于：Annals of Oncology · 年份：2018 · DOI：10.1093/annonc/mdy513 · 被引用次数：116 · 研究领域：Cancer Genomics and Diagnostics、Hematopoietic Stem Cell Transplantation、Blood groups and transfusion

BACKGROUND: Cell-free DNA (cf-DNA)-based liquid biopsy is emerging as a revolutionary new method in individualized cancer treatment and prognosis monitoring, although detecting early-stage cancers using cf-DNA remains challenging, partially because of the undefined biological background of cf-DNA. MATERIALS AND METHODS: We investigated somatic mutations in the cf-DNA of 259 cancer-free individuals with a median age of 47 years using an endogenous barcoding duplex method with an ultralow base error rate (2 × 10-7) and compared the variant allele frequencies (VAFs) of these mutations between the cf-DNA and the corresponding blood cell DNA. RESULTS: Sixty percent (155/259) of the samples showed at least one nonsynonymous mutation on either of two similar target panels covering 508 and 559 cancer-related genes. For individuals older than 50 years of age, the positive rate increased to 76%. Most cf-DNA mutations were also present at similar VAFs in the paired blood cell DNA. The most frequently mutated genes were driver genes of hematologic malignancies, including DNMT3A, TET2, AXSL1, and JAK2. However, the other 58.4% (192/329) of the mutations were likely 'passenger mutations' of clonal hematopoiesis, including mutations in NOTCH2, FAT3, EXT2, ERBB4, and ARID2, which are driver genes of solid tumors. CONCLUSION: Hematopoietic clone-derived mutations, including 'driver mutations' and 'passenger mutations', are prevalent in the cf-DNA of both healthy individuals and cancer patient...