title: Recurrent mutations of MYD88 and TBL1XR1 in primary central nervous system lymphomas.
abstract: OBJECTIVE
  Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance.
  
  
  METHODS
  We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n = 29) and whole-exome sequencing (n = 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis.
  
  
  RESULTS
  All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P = 0.006 and P = 0.01) and CDKN2A homozygous deletion (P = 0.02 and P = 0.01) were significantly associated with shorter progression-free survival and overall survival.
  
  
  CONCLUSIONS
  Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-κB signaling pathway, which may be promising targets for future therapeutic strategies.
authors: Université Pierre et Marie Curie-Paris 6, Paris, France.
authors: Alberto
authors: A
authors: Gonzalez-Aguilar
authors: Ahmed
authors: A
authors: Idbaih
authors: Blandine
authors: B
authors: Boisselier
authors: Naïma
authors: N
authors: Habbita
authors: Marta
authors: M
authors: Rossetto
authors: Alice
authors: A
authors: Laurenge
authors: Aurélie
authors: A
authors: Bruno
authors: Anne
authors: A
authors: Jouvet
authors: Marc
authors: M
authors: Polivka
authors: Clovis
authors: C
authors: Adam
authors: Dominique
authors: D
authors: Figarella-Branger
authors: Catherine
authors: C
authors: Miquel
authors: Anne
authors: A
authors: Vital
authors: Hervé
authors: H
authors: Ghesquières
authors: Rémy
authors: R
authors: Gressin
authors: Vincent
authors: V
authors: Delwail
authors: Luc
authors: L
authors: Taillandier
authors: Olivier
authors: O
authors: Chinot
authors: Pierre
authors: P
authors: Soubeyran
authors: Emmanuel
authors: E
authors: Gyan
authors: Sylvain
authors: S
authors: Choquet
authors: Caroline
authors: C
authors: Houillier
authors: Carole
authors: C
authors: Soussain
authors: Marie-Laure
authors: ML
authors: Tanguy
authors: Yannick
authors: Y
authors: Marie
authors: Karima
authors: K
authors: Mokhtari
authors: Khê
authors: K
authors: Hoang-Xuan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016543:Central Nervous System Neoplasms / Q000235:genetics / Q000378:metabolism; D043171:Chromosomal Instability; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C473691:TBL1XR1 protein, human