Integrated analysis of whole genome and transcriptome sequencing reveals diverse transcriptomic aberrations driven by somatic genomic changes in liver cancers.

Yuichi Shiraishi,Shigeru Marubashi,Hiroko Tanaka,Kazuhiro Maejima,Kazuaki Chayama,Satoru Miyano,Tetsuo Shibuya,Akihiro Fujimoto,Kaoru Nakano,Yoshiiku Kawakami,Mayuko Furuta,Shinya Hayami,Rina Kitada,Hiroki Yamaue,Hidewaki Nakagawa,Hideki Ohdan,Aya Sasaki,Koji Arihiro,Tetsuo Abe,Michiaki Kubo,Kunihito Gotoh,Masakazu Yamamoto,Masaki Ueno,Yoshinobu Shigekawa,Hiroshi Aikata,Tatsuhiko Tsunoda,Osamu Ishikawa,Keith A Boroevich,Terumasa Yamada,Kenichi Chiba ,Shun‐Ichi Ariizumi

doi:10.1371/journal.pone.0114263

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.

Highlights

Each year, more than half a million people worldwide are diagnosed with hepatocellular carcinoma (HCC), the fifth and seventh most common cancer in men and women, respectively [1]
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 whole genome sequencing (WGS) and RNA-Seq can facilitate the interpretation of a large number of genomic alterations detected in cancer genome
Various genetic alternations have been detected in HCCs, such as mutations of TP53 and CTNNB1 encoding b-catenin [2], further detailed characterization of liver cancer genome is required for identification of biomarkers for personalized medicine and more effective therapeutic drug development

Summary

Introduction

More than half a million people worldwide are diagnosed with hepatocellular carcinoma (HCC), the fifth and seventh most common cancer in men and women, respectively [1]. Several examples of splicing aberrations [9, 10] and gene fusions [11] caused by genomic mutations are known, and studies using recent highthroughput sequencing data identified cancer-specific transcriptional aberrations in several cancer types [12, 13].

Results

Conclusion