title: Analyzing Somatic Genome Rearrangements in Human Cancers by Using Whole-Exome Sequencing.
abstract: Although exome sequencing data are generated primarily to detect single-nucleotide variants and indels, they can also be used to identify a subset of genomic rearrangements whose breakpoints are located in or near exons. Using >4,600 tumor and normal pairs across 15 cancer types, we identified over 9,000 high confidence somatic rearrangements, including a large number of gene fusions. We find that the 5' fusion partners of functional fusions are often housekeeping genes, whereas the 3' fusion partners are enriched in tyrosine kinases. We establish the oncogenic potential of ROR1-DNAJC6 and CEP85L-ROS1 fusions by showing that they can promote cell proliferation in vitro and tumor formation in vivo. Furthermore, we found that ∼4% of the samples have massively rearranged chromosomes, many of which are associated with upregulation of oncogenes such as ERBB2 and TERT. Although the sensitivity of detecting structural alterations from exomes is considerably lower than that from whole genomes, this approach will be fruitful for the multitude of exomes that have been and will be generated, both in cancer and in other diseases.
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lixing
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul 06351, Korea.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Hengyu
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul 06351, Korea.
authors.forename: Doo-Yi
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea; Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co., Seoul 06351, Korea.
authors.forename: Yeon Jeong
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea; Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co., Seoul 06351, Korea.
authors.forename: Donghyun
authors.initials: D
authors.lastname: Park
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea.
authors.forename: Gahee
authors.initials: G
authors.lastname: Park
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Genomic Medicine and Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Bristow
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Psalm S
authors.initials: PS
authors.lastname: Haseley
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Soohyun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Pantazi
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul 06351, Korea; Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea.
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Scott
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul 06351, Korea; Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea. Electronic address: ylachoi@skku.edu.
authors.forename: Yoon-La
authors.initials: YL
authors.lastname: Choi
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA; Ludwig Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: peter_park@harvard.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Park
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D059472:Exome / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D050939:Gene Fusion / Q000235:genetics*; D015321:Gene Rearrangement; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA / Q000379:methods*; D023041:Xenograft Model Antitumor Assays
chemical_list: C573619:CEP85L protein, human; D003598:Cytoskeletal Proteins; C494652:DNAJC6 protein, human; D050956:HSP40 Heat-Shock Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C078717:ROR2 protein, human; C062333:ROS1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors