Research Papers:

Noninvasive detection of tumor-associated mutations from circulating cell-free DNA in hepatocellular carcinoma patients by targeted deep sequencing

Wenjun Liao _, Huayu Yang, Haifeng Xu, Yanan Wang, Penglei Ge, Jinjun Ren, Wei Xu, Xin Lu, Xinting Sang, Shouxian Zhong, Hongbing Zhang and Yilei Mao

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Oncotarget. 2016; 7:40481-40490. https://doi.org/10.18632/oncotarget.9629

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Wenjun Liao1, Huayu Yang1, Haifeng Xu1, Yanan Wang2, Penglei Ge1, Jinjun Ren1, Wei Xu1, Xin Lu1, Xinting Sang1, Shouxian Zhong1, Hongbing Zhang2, Yilei Mao1

1Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing, China

2State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, PUMC & Chinese Academy of Medical Sciences, Beijing, China

Correspondence to:

Yilei Mao, email: [email protected]

Keywords: circulating cell-free DNA, circulating tumor DNA, hepatocellular carcinoma, tumor-associated mutation, MiSeq sequencing

Received: December 02, 2015    Accepted: May 02, 2016    Published: May 26, 2016


Background: Detection of circulating cell-free DNA (cfDNA) has potential clinical value for assessing tumor biology in patients with hepatocellular carcinoma (HCC), yet many traditional assays lack robustness. This study was the first to apply a high-throughput sequencing platform to detect tumor-associated mutations in HCC from circulating tumor-derived DNA (ctDNA) and to evaluate the utility and feasibility of this approach.

Methods: Using the MiSeq™ system, plasma and matched tumor DNA samples were analyzed for hotspot mutations in the TERT, CTNNB1, and TP53 genes that had been verified as the most prevalent mutations in HCC. We compared tumor and plasma data and prospectively investigated the association between significant mutations detected in ctDNA and the patients’ clinical outcomes.

Results: In 41 patients, we detected tumor-associated mutations for HCC in 8 (19.5%) plasma samples. Among them, one showed a tumor-associated mutation in ctDNA but not in the tumor tissue which we used to detect. We also found that ctDNA with mutations could be detected more easily in patients who suffered vascular invasion (P=0.041) and predicted a shorter recurrence-free survival time (P<0.001). There was no relationship between detectable mutations and concentration of cfDNA (P=0.818).

Conclusions: The results of our study suggest that tumor-associated mutations detected in plasma are associated with vascular invasion and might be used to predict a shorter recurrence-free survival time for HCC patients. This kind of biomarker can overcome the limitations of tumor heterogeneity. Moreover, the diagnostic performance is improved if multiple mutations in different genes are combined.

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