title: The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells.
abstract: In this study, we define the genetic landscape of mantle cell lymphoma (MCL) through exome sequencing of 56 cases of MCL. We identified recurrent mutations in ATM, CCND1, MLL2, and TP53. We further identified a number of novel genes recurrently mutated in patients with MCL including RB1, WHSC1, POT1, and SMARCA4. We noted that MCLs have a distinct mutational profile compared with lymphomas from other B-cell stages. The ENCODE project has defined the chromatin structure of many cell types. However, a similar characterization of primary human mature B cells has been lacking. We defined, for the first time, the chromatin structure of primary human naïve, germinal center, and memory B cells through chromatin immunoprecipitation and sequencing for H3K4me1, H3K4me3, H3Ac, H3K36me3, H3K27me3, and PolII. We found that somatic mutations that occur more frequently in either MCLs or Burkitt lymphomas were associated with open chromatin in their respective B cells of origin, naïve B cells, and germinal center B cells. Our work thus elucidates the landscape of gene-coding mutations in MCL and the critical interplay between epigenetic alterations associated with B-cell differentiation and the acquisition of somatic mutations in cancer.
authors.affiliation: Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC;
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhang
authors.forename: Dereje
authors.initials: D
authors.lastname: Jima
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Moffitt
authors.forename: Qingquan
authors.initials: Q
authors.lastname: Liu
authors.forename: Magdalena
authors.initials: M
authors.lastname: Czader
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hsi
authors.forename: Yuri
authors.initials: Y
authors.lastname: Fedoriw
authors.forename: Cherie H
authors.initials: CH
authors.lastname: Dunphy
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Richards
authors.forename: Javed I
authors.initials: JI
authors.lastname: Gill
authors.forename: Zhen
authors.initials: Z
authors.lastname: Sun
authors.forename: Cassandra
authors.initials: C
authors.lastname: Love
authors.forename: Paula
authors.initials: P
authors.lastname: Scotland
authors.forename: Eric
authors.initials: E
authors.lastname: Lock
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.forename: David S
authors.initials: DS
authors.lastname: Hsu
authors.forename: David
authors.initials: D
authors.lastname: Dunson
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Dave
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism*; D002051:Burkitt Lymphoma / Q000235:genetics / Q000473:pathology; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D044127:Epigenesis, Genetic; D059472:Exome / Q000235:genetics; D053263:Gene Regulatory Networks; D023281:Genomics; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000473:pathology; D008745:Methylation; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D017422:Sequence Analysis, DNA; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C440849:POT1 protein, human; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C084108:SMARCA4 protein, human; D004265:DNA Helicases