title: Integrated analysis of whole genome and transcriptome sequencing reveals diverse transcriptomic aberrations driven by somatic genomic changes in liver cancers.
abstract: Recent studies applying high-throughput sequencing technologies have identified several recurrently mutated genes and pathways in multiple cancer genomes. However, transcriptional consequences from these genomic alterations in cancer genome remain unclear. In this study, we performed integrated and comparative analyses of whole genomes and transcriptomes of 22 hepatitis B virus (HBV)-related hepatocellular carcinomas (HCCs) and their matched controls. Comparison of whole genome sequence (WGS) and RNA-Seq revealed much evidence that various types of genomic mutations triggered diverse transcriptional changes. Not only splice-site mutations, but also silent mutations in coding regions, deep intronic mutations and structural changes caused splicing aberrations. HBV integrations generated diverse patterns of virus-human fusion transcripts depending on affected gene, such as TERT, CDK15, FN1 and MLL4. Structural variations could drive over-expression of genes such as WNT ligands, with/without creating gene fusions. Furthermore, by taking account of genomic mutations causing transcriptional aberrations, we could improve the sensitivity of deleterious mutation detection in known cancer driver genes (TP53, AXIN1, ARID2, RPS6KA3), and identified recurrent disruptions in putative cancer driver genes such as HNF4A, CPS1, TSC1 and THRAP3 in HCCs. These findings indicate genomic alterations in cancer genome have diverse transcriptomic effects, and integrated analysis of WGS and RNA-Seq can facilitate the interpretation of a large number of genomic alterations detected in cancer genome.
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIEKN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan; Laboratory for Medical Science Mathematics, RIEKN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fujimoto
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIEKN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Furuta
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory for Medical Science Mathematics, RIEKN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Boroevich
authors.affiliation: Laboratory for Medical Science Mathematics, RIEKN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Medicine & Molecular Science, Hiroshima University School of Medicine, Hiroshima, 734-8551, Japan.
authors.forename: Yoshiiku
authors.initials: Y
authors.lastname: Kawakami
authors.affiliation: Second Department of Surgery, Wakayama Medical University, Wakayama, 641-8510, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 537-8511, Japan.
authors.forename: Kunihito
authors.initials: K
authors.lastname: Gotoh
authors.affiliation: Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
authors.forename: Shun-ichi
authors.initials: S
authors.lastname: Ariizumi
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shibuya
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIEKN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIEKN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Sasaki
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIEKN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Maejima
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIEKN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Kitada
authors.affiliation: Second Department of Surgery, Wakayama Medical University, Wakayama, 641-8510, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Hayami
authors.affiliation: Second Department of Surgery, Wakayama Medical University, Wakayama, 641-8510, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Shigekawa
authors.affiliation: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 537-8511, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Marubashi
authors.affiliation: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 537-8511, Japan.
authors.forename: Terumasa
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Laboratory for Genotyping Development, RIEKN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 537-8511, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ishikawa
authors.affiliation: Department of Medicine & Molecular Science, Hiroshima University School of Medicine, Hiroshima, 734-8551, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aikata
authors.affiliation: Department of Anatomical Pathology, Hiroshima University School of Medicine, Hiroshima, 734-8551, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Arihiro
authors.affiliation: Department of Gastroenterological Surgery, Hiroshima University School of Medicine, Hiroshima, 734-8551, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohdan
authors.affiliation: Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Second Department of Surgery, Wakayama Medical University, Wakayama, 641-8510, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamaue
authors.affiliation: Department of Medicine & Molecular Science, Hiroshima University School of Medicine, Hiroshima, 734-8551, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.affiliation: Laboratory for Medical Science Mathematics, RIEKN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan; Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIEKN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
authors.forename: Hidewaki
authors.initials: H
authors.lastname: Nakagawa
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D060965:Clonal Evolution; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009857:Oncogenes / Q000235:genetics; D059467:Transcriptome