Circulating Tumor DNA Analysis for Liver Cancers and Its Usefulness as a Liquid Biopsy

Atsushi Ono, Akihiro Fujimoto, Yujiro Yamamoto, Sakura Akamatsu, Nobuhiko Hiraga, Michio Imamura, Tomokazu Kawaoka, Masataka Tsuge, Hiromi Abe, C. Nelson Hayes, Daiki Miki, Mayuko Furuta, Tatsuhiko Tsunoda, Satoru Miyano, Michiaki Kubo, Hiroshi Aikata, Hidenori Ochi, Yoshi iku Kawakami, Koji Arihiro, Hideki Ohdan & 2 others Hidewaki Nakagawa, Kazuaki Chayama

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)516-534
Number of pages19
JournalCMGH
Volume1
Issue number5
DOIs
Publication statusPublished - 01-09-2015
Externally publishedYes

Fingerprint

Liver Neoplasms
Biopsy
DNA
Neoplasms
Exome
Mutation
Neoplasm Metastasis
Recurrence
Hepatectomy
Portal Vein
Serum
DNA Sequence Analysis
Liver Transplantation

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Ono, A., Fujimoto, A., Yamamoto, Y., Akamatsu, S., Hiraga, N., Imamura, M., ... Chayama, K. (2015). Circulating Tumor DNA Analysis for Liver Cancers and Its Usefulness as a Liquid Biopsy. CMGH, 1(5), 516-534. https://doi.org/10.1016/j.jcmgh.2015.06.009
Ono, Atsushi ; Fujimoto, Akihiro ; Yamamoto, Yujiro ; Akamatsu, Sakura ; Hiraga, Nobuhiko ; Imamura, Michio ; Kawaoka, Tomokazu ; Tsuge, Masataka ; Abe, Hiromi ; Hayes, C. Nelson ; Miki, Daiki ; Furuta, Mayuko ; Tsunoda, Tatsuhiko ; Miyano, Satoru ; Kubo, Michiaki ; Aikata, Hiroshi ; Ochi, Hidenori ; Kawakami, Yoshi iku ; Arihiro, Koji ; Ohdan, Hideki ; Nakagawa, Hidewaki ; Chayama, Kazuaki. / Circulating Tumor DNA Analysis for Liver Cancers and Its Usefulness as a Liquid Biopsy. In: CMGH. 2015 ; Vol. 1, No. 5. pp. 516-534.
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abstract = "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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Ono, A, Fujimoto, A, Yamamoto, Y, Akamatsu, S, Hiraga, N, Imamura, M, Kawaoka, T, Tsuge, M, Abe, H, Hayes, CN, Miki, D, Furuta, M, Tsunoda, T, Miyano, S, Kubo, M, Aikata, H, Ochi, H, Kawakami, YI, Arihiro, K, Ohdan, H, Nakagawa, H & Chayama, K 2015, 'Circulating Tumor DNA Analysis for Liver Cancers and Its Usefulness as a Liquid Biopsy', CMGH, vol. 1, no. 5, pp. 516-534. https://doi.org/10.1016/j.jcmgh.2015.06.009

Circulating Tumor DNA Analysis for Liver Cancers and Its Usefulness as a Liquid Biopsy. / Ono, Atsushi; Fujimoto, Akihiro; Yamamoto, Yujiro; Akamatsu, Sakura; Hiraga, Nobuhiko; Imamura, Michio; Kawaoka, Tomokazu; Tsuge, Masataka; Abe, Hiromi; Hayes, C. Nelson; Miki, Daiki; Furuta, Mayuko; Tsunoda, Tatsuhiko; Miyano, Satoru; Kubo, Michiaki; Aikata, Hiroshi; Ochi, Hidenori; Kawakami, Yoshi iku; Arihiro, Koji; Ohdan, Hideki; Nakagawa, Hidewaki; Chayama, Kazuaki.

In: CMGH, Vol. 1, No. 5, 01.09.2015, p. 516-534.

Research output: Contribution to journalArticle

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

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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Ono A, Fujimoto A, Yamamoto Y, Akamatsu S, Hiraga N, Imamura M et al. Circulating Tumor DNA Analysis for Liver Cancers and Its Usefulness as a Liquid Biopsy. CMGH. 2015 Sep 1;1(5):516-534. https://doi.org/10.1016/j.jcmgh.2015.06.009