title: Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2 (POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma.
abstract: Follicular lymphoma (FL) constitutes the second most common non-Hodgkin lymphoma in the western world. FL carries characteristic recurrent structural genomic aberrations. However, information regarding the coding genome in FL is still evolving. Here, we describe the results of massively parallel exome sequencing and single nucleotide polymorphism 6.0 array genomic profiling of 11 highly purified FL cases, and 1 transformed FL case and the validation of selected mutations in 102 FL cases. We report the identification of 15 novel recurrently mutated genes in FL. These include frequent mutations in the linker histone genes HIST1H1 B-E (27%) and mutations in OCT2 (also known as POU2F2; 8%), IRF8 (6%), and ARID1A (11%). A subset of the mutations in HIST1H1 B-E affected binding to DNMT3B, and mutations in HIST1H1 B-E and in EZH2 or ARID1A were largely mutually exclusive, implicating HIST1H1 B-E in epigenetic deregulation in FL. Mutations in OCT2 (POU2F2) affected its transcriptional and functional properties as measured through luciferase assays, the biological analysis of stably transduced cell lines, and global expression profiling. Finally, multiple novel mutated genes located within regions of acquired uniparental disomy in FL are identified. In aggregate, these data substantially broaden our understanding of the genomic pathogenesis of FL.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Li
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kaminski
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Li
authors.forename: Mehmet
authors.initials: M
authors.lastname: Yildiz
authors.forename: Peter
authors.initials: P
authors.lastname: Ouillette
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.forename: Heather
authors.initials: H
authors.lastname: Fox
authors.forename: Kathryn
authors.initials: K
authors.lastname: Jacobi
authors.forename: Kamlai
authors.initials: K
authors.lastname: Saiya-Cork
authors.forename: Dale
authors.initials: D
authors.lastname: Bixby
authors.forename: Daniel
authors.initials: D
authors.lastname: Lebovic
authors.forename: Diane
authors.initials: D
authors.lastname: Roulston
authors.forename: Kerby
authors.initials: K
authors.lastname: Shedden
authors.forename: Michael
authors.initials: M
authors.lastname: Sabel
authors.forename: Lawrence
authors.initials: L
authors.lastname: Marentette
authors.forename: Vincent
authors.initials: V
authors.lastname: Cimmino
authors.forename: Alfred E
authors.initials: AE
authors.lastname: Chang
authors.forename: Sami N
authors.initials: SN
authors.lastname: Malek
mesh_terms: D000595:Amino Acid Sequence; D050882:CREB-Binding Protein / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D059472:Exome; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008224:Lymphoma, Follicular / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D050813:Octamer Transcription Factor-2; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics; D016415:Sequence Alignment; D014157:Transcription Factors; D015533:Transcriptional Activation; D000099185:Interferon Regulatory Factor-8
chemical_list: D050882:CREB-Binding Protein; D004268:DNA-Binding Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D006657:Histones; D050835:Interferon Regulatory Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D050813:Octamer Transcription Factor-2; D063151:Polycomb Repressive Complex 2; D019253:Proto-Oncogene Proteins c-bcl-2; D053240:Receptors, Tumor Necrosis Factor, Member 14; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8; C112476:ARID1A protein, human; C120898:KMT2D protein, human; C506028:TNFRSF14 protein, human; C498409:EZH2 protein, human; C494363:CREBBP protein, human