title: Systematic discovery of complex insertions and deletions in human cancers.
abstract: Complex insertions and deletions (indels) are formed by simultaneously deleting and inserting DNA fragments of different sizes at a common genomic location. Here we present a systematic analysis of somatic complex indels in the coding sequences of samples from over 8,000 cancer cases using Pindel-C. We discovered 285 complex indels in cancer-associated genes (such as PIK3R1, TP53, ARID1A, GATA3 and KMT2D) in approximately 3.5% of cases analyzed; nearly all instances of complex indels were overlooked (81.1%) or misannotated (17.6%) in previous reports of 2,199 samples. In-frame complex indels are enriched in PIK3R1 and EGFR, whereas frameshifts are prevalent in VHL, GATA3, TP53, ARID1A, PTEN and ATRX. Furthermore, complex indels display strong tissue specificity (such as VHL in kidney cancer samples and GATA3 in breast cancer samples). Finally, structural analyses support findings of previously missed, but potentially druggable, mutations in the EGFR, MET and KIT oncogenes. This study indicates the critical importance of improving complex indel discovery and interpretation in medical research.
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.|Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Ye
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Wang
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.|Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Reyka
authors.initials: R
authors.lastname: Jayasinghe
authors.affiliation: Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Eric-Wubbo
authors.initials: EW
authors.lastname: Lameijer
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Joshua F
authors.initials: JF
authors.lastname: McMichael
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Ning
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.|Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Mingchao
authors.initials: M
authors.lastname: Xie
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Cao
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.|Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Venkata
authors.initials: V
authors.lastname: Yellapantula
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.|Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Kuan-lin
authors.initials: KL
authors.lastname: Huang
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.|Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Scott
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.|Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Foltz
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Beifang
authors.initials: B
authors.lastname: Niu
authors.affiliation: Brown School Master of Public Health Program, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Johnson
authors.affiliation: Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Matthijs
authors.initials: M
authors.lastname: Moed
authors.affiliation: Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.|Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.|Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, USA.|Department of Mathematics, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wendl
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.|Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, USA.|Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.|Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
mesh_terms: D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D057225:Data Mining / Q000379:methods*; D066246:ErbB Receptors / Q000235:genetics; D050990:GATA3 Transcription Factor / Q000235:genetics; D023281:Genomics / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D000075924:X-linked Nuclear Protein
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D066246:ErbB Receptors; D050990:GATA3 Transcription Factor; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit; D019859:Proto-Oncogene Proteins c-met; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000075924:X-linked Nuclear Protein; C112476:ARID1A protein, human; C494749:GATA3 protein, human; C120898:KMT2D protein, human; C495901:TP53 protein, human; C588001:PIK3R1 protein, human; C512478:EGFR protein, human; C491743:MET protein, human; C494929:PTEN protein, human; C092332:ATRX protein, human; C497446:VHL protein, human