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

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• 作者：Mayuko Furuta¹ ; Masaki Ueno² ; Akihiro Fujimoto¹ ; Shinya Hayami² ; Satoru Yasukawa³ ; Fumiyoshi Kojima⁴ ; Koji Arihiro⁵ ; Yoshiiku Kawakami⁶ ; Christopher P. Wardell¹ ; Yuichi Shiraishi⁷ ; Hiroko Tanaka⁷ ; Kaoru Nakano¹ ; Kazuhiro Maejima¹ ; Aya Sasaki-Oku¹ ; Naoki Tokunaga¹ ; Keith A. Boroevich⁸ ; Tetsuo Abe⁸ ; Hiroshi Aikata⁶ ; Hideki Ohdan⁹ ; Kunihito Gotoh¹⁰ ; Michiaki Kubo¹¹ ; Tatsuhiko Tsunoda⁸ ; ¹² ; Satoru Miyano⁷ ; Kazuaki Chayama⁶ ; Hiroki Yamaue² ; ^{yamaue-h@wakayama-med.ac.jp} ; Hidewaki Nakagawa¹ ; ^{hidewaki@ims.u-tookoyo.ac.jp}
• 关键词：Liver cancer ; Somatic SNVs ; Multi-centric occurrence ; Intrahepatic metastasis ; Whole genome sequencing ; Hepatocellular Carcinoma
• 刊名：Journal of Hepatology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：66
• 期：2
• 页码：363-373
• 全文大小：2382 K
• 卷排序：66

文摘

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.MethodsWe 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.ResultsSequencing-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.ConclusionsIt 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 summaryWhole 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.