title: The E3 ubiquitin ligase UBR5 is recurrently mutated in mantle cell lymphoma.
abstract: We have recently reported the application of RNAseq to mantle cell lymphoma (MCL) transcriptomes revealing recurrent mutations in NOTCH1. Here we describe the targeted resequencing of 18 genes mutated in this discovery cohort using a larger cohort of MCL tumors. In addition to frequent mutations in ATM, CCND1, TP53, and NOTCH1, mutations were also observed recurrently in MEF2B, TRAF2, and TET2. Interestingly, the third most frequently mutated gene was UBR5, a gene encoding a 2799aa protein, with multiple functions, including E3 ligase activity based on a conserved cysteine residue at the C-terminus. Nonsynonymous mutations were detected in 18% (18/102) of tumors, with 61% of the mutations resulting in frameshifts in, or around, exon 58, predicted to result in the loss of this conserved cysteine residue. The recurrence and clustering of deleterious mutations implicate UBR5 mutations as a critical pathogenic event in a subgroup of MCL.
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada V5Z 1L3.
authors: Barbara
authors: B
authors: Meissner
authors: Robert
authors: R
authors: Kridel
authors: Raymond S
authors: RS
authors: Lim
authors: Sanja
authors: S
authors: Rogic
authors: Kane
authors: K
authors: Tse
authors: David W
authors: DW
authors: Scott
authors: Richard
authors: R
authors: Moore
authors: Andy J
authors: AJ
authors: Mungall
authors: Marco A
authors: MA
authors: Marra
authors: Joseph M
authors: JM
authors: Connors
authors: Christian
authors: C
authors: Steidl
authors: Randy D
authors: RD
authors: Gascoyne
mesh_terms: D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D015331:Cohort Studies; D019938:Cyclin D1 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics; D016415:Sequence Alignment; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C117617:UBR5 protein, human; D044767:Ubiquitin-Protein Ligases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases