Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors

Mayuko Furuta, Masaki Ueno, Akihiro Fujimoto, Shinya Hayami, Satoru Yasukawa, Fumiyoshi Kojima, Koji Arihiro, Yoshiiku Kawakami, Christopher P. Wardell, Yuichi Shiraishi, Hiroko Tanaka, Kaoru Nakano, Kazuhiro Maejima, Aya Sasaki-Oku, Naoki Tokunaga, Keith A. Boroevich, Tetsuo Abe, Hiroshi Aikata, Hideki Ohdan, Kunihito Gotoh & 6 others Michiaki Kubo, Tatsuhiko Tsunoda, Satoru Miyano, Kazuaki Chayama, Hiroki Yamaue, Hidewaki Nakagawa

Research output: Contribution to journalArticle

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Abstract

Background & Aims Patients with hepatocellular carcinoma (HCC) have a high-risk of multi-centric (MC) tumor occurrence due to a strong carcinogenic background in the liver. In addition, they have a high risk of intrahepatic metastasis (IM). Liver tumors with IM or MC are profoundly different in their development and clinical outcome. However, clinically or pathologically discriminating between IM and MC can be challenging. This study investigated whether IM or MC could be diagnosed at the molecular level. Methods We performed whole genome and RNA sequencing analyses of 49 tumors including two extra-hepatic metastases, and one nodule-in-nodule tumor from 23 HCC patients. Results Sequencing-based molecular diagnosis using somatic single nucleotide variation information showed higher sensitivity compared to previous techniques due to the inclusion of a larger number of mutation events. This proved useful in cases, which showed inconsistent clinical diagnoses. In addition, whole genome sequencing offered advantages in profiling of other genetic alterations, such as structural variations, copy number alterations, and variant allele frequencies, and helped to confirm the IM/MC diagnosis. Divergent alterations between IM tumors with sorafenib treatment, long time-intervals, or tumor-in-tumor nodules indicated high intra-tumor heterogeneity, evolution, and clonal switching of liver cancers. Conclusions It is important to analyze the differences between IM tumors, in addition to IM/MC diagnosis, before selecting a therapeutic strategy for multiple tumors in the liver. Lay summary Whole genome sequencing of multiple liver tumors enabled the accurate diagnosis of multi-centric occurrence and intrahepatic metastasis using somatic single nucleotide variation information. In addition, genetic discrepancies between tumors help us to understand the physical changes during recurrence and cancer spread.

Original languageEnglish
Pages (from-to)363-373
Number of pages11
JournalJournal of Hepatology
Volume66
Issue number2
DOIs
Publication statusPublished - 01-02-2017

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Hepatocellular Carcinoma
Genome
Neoplasm Metastasis
Neoplasms
Liver
Nucleotides
Clonal Evolution
RNA Sequence Analysis
Liver Neoplasms
Gene Frequency
Recurrence
Mutation

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Furuta, Mayuko ; Ueno, Masaki ; Fujimoto, Akihiro ; Hayami, Shinya ; Yasukawa, Satoru ; Kojima, Fumiyoshi ; Arihiro, Koji ; Kawakami, Yoshiiku ; Wardell, Christopher P. ; Shiraishi, Yuichi ; Tanaka, Hiroko ; Nakano, Kaoru ; Maejima, Kazuhiro ; Sasaki-Oku, Aya ; Tokunaga, Naoki ; Boroevich, Keith A. ; Abe, Tetsuo ; Aikata, Hiroshi ; Ohdan, Hideki ; Gotoh, Kunihito ; Kubo, Michiaki ; Tsunoda, Tatsuhiko ; Miyano, Satoru ; Chayama, Kazuaki ; Yamaue, Hiroki ; Nakagawa, Hidewaki. / Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors. In: Journal of Hepatology. 2017 ; Vol. 66, No. 2. pp. 363-373.
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title = "Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors",
abstract = "Background & Aims Patients with hepatocellular carcinoma (HCC) have a high-risk of multi-centric (MC) tumor occurrence due to a strong carcinogenic background in the liver. In addition, they have a high risk of intrahepatic metastasis (IM). Liver tumors with IM or MC are profoundly different in their development and clinical outcome. However, clinically or pathologically discriminating between IM and MC can be challenging. This study investigated whether IM or MC could be diagnosed at the molecular level. Methods We performed whole genome and RNA sequencing analyses of 49 tumors including two extra-hepatic metastases, and one nodule-in-nodule tumor from 23 HCC patients. Results Sequencing-based molecular diagnosis using somatic single nucleotide variation information showed higher sensitivity compared to previous techniques due to the inclusion of a larger number of mutation events. This proved useful in cases, which showed inconsistent clinical diagnoses. In addition, whole genome sequencing offered advantages in profiling of other genetic alterations, such as structural variations, copy number alterations, and variant allele frequencies, and helped to confirm the IM/MC diagnosis. Divergent alterations between IM tumors with sorafenib treatment, long time-intervals, or tumor-in-tumor nodules indicated high intra-tumor heterogeneity, evolution, and clonal switching of liver cancers. Conclusions It is important to analyze the differences between IM tumors, in addition to IM/MC diagnosis, before selecting a therapeutic strategy for multiple tumors in the liver. Lay summary Whole genome sequencing of multiple liver tumors enabled the accurate diagnosis of multi-centric occurrence and intrahepatic metastasis using somatic single nucleotide variation information. In addition, genetic discrepancies between tumors help us to understand the physical changes during recurrence and cancer spread.",
author = "Mayuko Furuta and Masaki Ueno and Akihiro Fujimoto and Shinya Hayami and Satoru Yasukawa and Fumiyoshi Kojima and Koji Arihiro and Yoshiiku Kawakami and Wardell, {Christopher P.} and Yuichi Shiraishi and Hiroko Tanaka and Kaoru Nakano and Kazuhiro Maejima and Aya Sasaki-Oku and Naoki Tokunaga and Boroevich, {Keith A.} and Tetsuo Abe and Hiroshi Aikata and Hideki Ohdan and Kunihito Gotoh and Michiaki Kubo and Tatsuhiko Tsunoda and Satoru Miyano and Kazuaki Chayama and Hiroki Yamaue and Hidewaki Nakagawa",
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Furuta, M, Ueno, M, Fujimoto, A, Hayami, S, Yasukawa, S, Kojima, F, Arihiro, K, Kawakami, Y, Wardell, CP, Shiraishi, Y, Tanaka, H, Nakano, K, Maejima, K, Sasaki-Oku, A, Tokunaga, N, Boroevich, KA, Abe, T, Aikata, H, Ohdan, H, Gotoh, K, Kubo, M, Tsunoda, T, Miyano, S, Chayama, K, Yamaue, H & Nakagawa, H 2017, 'Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors', Journal of Hepatology, vol. 66, no. 2, pp. 363-373. https://doi.org/10.1016/j.jhep.2016.09.021

Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors. / Furuta, Mayuko; Ueno, Masaki; Fujimoto, Akihiro; Hayami, Shinya; Yasukawa, Satoru; Kojima, Fumiyoshi; Arihiro, Koji; Kawakami, Yoshiiku; Wardell, Christopher P.; Shiraishi, Yuichi; Tanaka, Hiroko; Nakano, Kaoru; Maejima, Kazuhiro; Sasaki-Oku, Aya; Tokunaga, Naoki; Boroevich, Keith A.; Abe, Tetsuo; Aikata, Hiroshi; Ohdan, Hideki; Gotoh, Kunihito; Kubo, Michiaki; Tsunoda, Tatsuhiko; Miyano, Satoru; Chayama, Kazuaki; Yamaue, Hiroki; Nakagawa, Hidewaki.

In: Journal of Hepatology, Vol. 66, No. 2, 01.02.2017, p. 363-373.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors

AU - Furuta, Mayuko

AU - Ueno, Masaki

AU - Fujimoto, Akihiro

AU - Hayami, Shinya

AU - Yasukawa, Satoru

AU - Kojima, Fumiyoshi

AU - Arihiro, Koji

AU - Kawakami, Yoshiiku

AU - Wardell, Christopher P.

AU - Shiraishi, Yuichi

AU - Tanaka, Hiroko

AU - Nakano, Kaoru

AU - Maejima, Kazuhiro

AU - Sasaki-Oku, Aya

AU - Tokunaga, Naoki

AU - Boroevich, Keith A.

AU - Abe, Tetsuo

AU - Aikata, Hiroshi

AU - Ohdan, Hideki

AU - Gotoh, Kunihito

AU - Kubo, Michiaki

AU - Tsunoda, Tatsuhiko

AU - Miyano, Satoru

AU - Chayama, Kazuaki

AU - Yamaue, Hiroki

AU - Nakagawa, Hidewaki

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Background & Aims Patients with hepatocellular carcinoma (HCC) have a high-risk of multi-centric (MC) tumor occurrence due to a strong carcinogenic background in the liver. In addition, they have a high risk of intrahepatic metastasis (IM). Liver tumors with IM or MC are profoundly different in their development and clinical outcome. However, clinically or pathologically discriminating between IM and MC can be challenging. This study investigated whether IM or MC could be diagnosed at the molecular level. Methods We performed whole genome and RNA sequencing analyses of 49 tumors including two extra-hepatic metastases, and one nodule-in-nodule tumor from 23 HCC patients. Results Sequencing-based molecular diagnosis using somatic single nucleotide variation information showed higher sensitivity compared to previous techniques due to the inclusion of a larger number of mutation events. This proved useful in cases, which showed inconsistent clinical diagnoses. In addition, whole genome sequencing offered advantages in profiling of other genetic alterations, such as structural variations, copy number alterations, and variant allele frequencies, and helped to confirm the IM/MC diagnosis. Divergent alterations between IM tumors with sorafenib treatment, long time-intervals, or tumor-in-tumor nodules indicated high intra-tumor heterogeneity, evolution, and clonal switching of liver cancers. Conclusions It is important to analyze the differences between IM tumors, in addition to IM/MC diagnosis, before selecting a therapeutic strategy for multiple tumors in the liver. Lay summary Whole genome sequencing of multiple liver tumors enabled the accurate diagnosis of multi-centric occurrence and intrahepatic metastasis using somatic single nucleotide variation information. In addition, genetic discrepancies between tumors help us to understand the physical changes during recurrence and cancer spread.

AB - Background & Aims Patients with hepatocellular carcinoma (HCC) have a high-risk of multi-centric (MC) tumor occurrence due to a strong carcinogenic background in the liver. In addition, they have a high risk of intrahepatic metastasis (IM). Liver tumors with IM or MC are profoundly different in their development and clinical outcome. However, clinically or pathologically discriminating between IM and MC can be challenging. This study investigated whether IM or MC could be diagnosed at the molecular level. Methods We performed whole genome and RNA sequencing analyses of 49 tumors including two extra-hepatic metastases, and one nodule-in-nodule tumor from 23 HCC patients. Results Sequencing-based molecular diagnosis using somatic single nucleotide variation information showed higher sensitivity compared to previous techniques due to the inclusion of a larger number of mutation events. This proved useful in cases, which showed inconsistent clinical diagnoses. In addition, whole genome sequencing offered advantages in profiling of other genetic alterations, such as structural variations, copy number alterations, and variant allele frequencies, and helped to confirm the IM/MC diagnosis. Divergent alterations between IM tumors with sorafenib treatment, long time-intervals, or tumor-in-tumor nodules indicated high intra-tumor heterogeneity, evolution, and clonal switching of liver cancers. Conclusions It is important to analyze the differences between IM tumors, in addition to IM/MC diagnosis, before selecting a therapeutic strategy for multiple tumors in the liver. Lay summary Whole genome sequencing of multiple liver tumors enabled the accurate diagnosis of multi-centric occurrence and intrahepatic metastasis using somatic single nucleotide variation information. In addition, genetic discrepancies between tumors help us to understand the physical changes during recurrence and cancer spread.

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U2 - 10.1016/j.jhep.2016.09.021

DO - 10.1016/j.jhep.2016.09.021

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JO - Journal of Hepatology

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