TY - JOUR
T1 - Circulating Tumor DNA Analysis for Liver Cancers and Its Usefulness as a Liquid Biopsy
AU - Ono, Atsushi
AU - Fujimoto, Akihiro
AU - Yamamoto, Yujiro
AU - Akamatsu, Sakura
AU - Hiraga, Nobuhiko
AU - Imamura, Michio
AU - Kawaoka, Tomokazu
AU - Tsuge, Masataka
AU - Abe, Hiromi
AU - Hayes, C. Nelson
AU - Miki, Daiki
AU - Furuta, Mayuko
AU - Tsunoda, Tatsuhiko
AU - Miyano, Satoru
AU - Kubo, Michiaki
AU - Aikata, Hiroshi
AU - Ochi, Hidenori
AU - Kawakami, Yoshi iku
AU - Arihiro, Koji
AU - Ohdan, Hideki
AU - Nakagawa, Hidewaki
AU - Chayama, Kazuaki
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - Background & Aims: Circulating tumor DNA (ctDNA) carrying tumor-specific sequence alterations has been found in the cell-free fraction of blood. Liver cancer tumor specimens are difficult to obtain, and noninvasive methods are required to assess cancer progression and characterize underlying genomic features. Methods: We analyzed 46 patients with hepatocellular carcinoma who underwent hepatectomy or liver transplantation and for whom whole-genome sequencing data was available. We designed personalized assays targeting somatic rearrangements of each tumor to quantify serum ctDNA. Exome sequencing was performed using cell-free DNA paired primary tumor tissue DNA from a patient with recurrent liver cancer after transcatheter arterial chemoembolization (TACE). Results: We successfully detected ctDNA from 100 μL of serum samples in 7 of the 46 patients before surgery, increasing with disease progression. The cumulative incidence of recurrence and extrahepatic metastasis in the ctDNA-positive group were statistically significantly worse than in the ctDNA-negative group (. P= .0102 and .0386, respectively). Multivariate analysis identified ctDNA (OR 6.10; 95% CI, 1.11-33.33, P= .038) as an independent predictor of microscopic vascular invasion of the portal vein (VP). We identified 45 nonsynonymous somatic mutations in cell-free DNA after TACE and 71 nonsynonymous somatic mutations in primary tumor tissue by exome sequencing. We identified 25 common mutations in both samples, and 83% of mutations identified in the primary tumor could be detected in the cell-free DNA. Conclusions: The presence of ctDNA reflects tumor progression, and detection of ctDNA can predict VP and recurrence, especially extrahepatic metastasis within 2 years. Our study demonstrated the usefulness of ctDNA detection and sequencing analysis of cell-free DNA for personalized treatment of liver cancer.
AB - Background & Aims: Circulating tumor DNA (ctDNA) carrying tumor-specific sequence alterations has been found in the cell-free fraction of blood. Liver cancer tumor specimens are difficult to obtain, and noninvasive methods are required to assess cancer progression and characterize underlying genomic features. Methods: We analyzed 46 patients with hepatocellular carcinoma who underwent hepatectomy or liver transplantation and for whom whole-genome sequencing data was available. We designed personalized assays targeting somatic rearrangements of each tumor to quantify serum ctDNA. Exome sequencing was performed using cell-free DNA paired primary tumor tissue DNA from a patient with recurrent liver cancer after transcatheter arterial chemoembolization (TACE). Results: We successfully detected ctDNA from 100 μL of serum samples in 7 of the 46 patients before surgery, increasing with disease progression. The cumulative incidence of recurrence and extrahepatic metastasis in the ctDNA-positive group were statistically significantly worse than in the ctDNA-negative group (. P= .0102 and .0386, respectively). Multivariate analysis identified ctDNA (OR 6.10; 95% CI, 1.11-33.33, P= .038) as an independent predictor of microscopic vascular invasion of the portal vein (VP). We identified 45 nonsynonymous somatic mutations in cell-free DNA after TACE and 71 nonsynonymous somatic mutations in primary tumor tissue by exome sequencing. We identified 25 common mutations in both samples, and 83% of mutations identified in the primary tumor could be detected in the cell-free DNA. Conclusions: The presence of ctDNA reflects tumor progression, and detection of ctDNA can predict VP and recurrence, especially extrahepatic metastasis within 2 years. Our study demonstrated the usefulness of ctDNA detection and sequencing analysis of cell-free DNA for personalized treatment of liver cancer.
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U2 - 10.1016/j.jcmgh.2015.06.009
DO - 10.1016/j.jcmgh.2015.06.009
M3 - Article
AN - SCOPUS:84939250466
SN - 2352-345X
VL - 1
SP - 516
EP - 534
JO - CMGH
JF - CMGH
IS - 5
ER -