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 Tsunoda12, Satoru Miyano7, Kazuaki Chayama6, Hiroki Yamaue13, Hidewaki Nakagawa14. 1. Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan. 2. Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan. 3. Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto 602-8565, Japan. 4. Department of Pathology, Wakayama Medical University, Wakayama 641-8510, Japan. 5. Department of Anatomical Pathology, Hiroshima University, Hiroshima 734-8551, Japan. 6. Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima 734-8551, Japan. 7. Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. 8. Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan. 9. Department of Gastroenterological Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan. 10. Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan. 11. Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan. 12. Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. 13. Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan. Electronic address: yamaue-h@wakayama-med.ac.jp. 14. Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan. Electronic address: hidewaki@ims.u-tookoyo.ac.jp.
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 withIM 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/MCdiagnosis. 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 accuratediagnosis ofmulti-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.
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 withIM 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/MCdiagnosis. Divergent alterations between IMtumors 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 IMtumors, 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 accuratediagnosis ofmulti-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.
Authors: L X Xu; M H He; Z H Dai; J Yu; J G Wang; X C Li; B B Jiang; Z F Ke; T H Su; Z W Peng; Y Guo; Z B Chen; S L Chen; S Peng; M Kuang Journal: Ann Oncol Date: 2019-06-01 Impact factor: 32.976