title: Loss, mutation and deregulation of L3MBTL4 in breast cancers.
abstract: BACKGROUND
  Many alterations are involved in mammary oncogenesis, including amplifications of oncogenes and losses of tumor suppressor genes (TSG). Losses may affect almost all chromosome arms and many TSGs remain to be identified.
  
  
  RESULTS
  We studied 307 primary breast tumors and 47 breast cancer cell lines by high resolution array comparative genomic hybridization (aCGH). We identified a region on 18p11.31 lost in about 20% of the tumors and 40% of the cell lines. The minimal common region of loss (Chr18:6,366,938-6,375,929 bp) targeted the L3MBTL4 gene. This gene was also targeted by breakage in one tumor and in two cell lines. We studied the exon sequence of L3MBTL4 in 180 primary tumor samples and 47 cell lines and found six missense and one nonsense heterozygous mutations. Compared with normal breast tissue, L3MBTL4 mRNA expression was downregulated in 73% of the tumors notably in luminal, ERBB2 and normal-like subtypes. Losses of the 18p11 region were associated with low L3MBTL4 expression level. Integrated analysis combining genome and gene expression profiles of the same tumors pointed to 14 other potential 18p TSG candidates. Downregulated expression of ZFP161, PPP4R1 and YES1 was correlated with luminal B molecular subtype. Low ZFP161 gene expression was associated with adverse clinical outcome.
  
  
  CONCLUSIONS
  We have identified L3MBTL4 as a potential TSG of chromosome arm 18p. The gene is targeted by deletion, breakage and mutations and its mRNA is downregulated in breast tumors. Additional 18p TSG candidates might explain the aggressive phenotype associated with the loss of 18p in breast tumors.
authors.affiliation: Marseille Cancer Research Center, Department of Molecular Oncology, UMR891 Inserm, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Lynda
authors.initials: L
authors.lastname: Addou-Klouche
authors.forename: José
authors.initials: J
authors.lastname: Adélaïde
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cervera
authors.forename: Anthony
authors.initials: A
authors.lastname: Ferrari
authors.forename: Ismahane
authors.initials: I
authors.lastname: Bekhouche
authors.forename: Fabrice
authors.initials: F
authors.lastname: Sircoulomb
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.forename: Patrice
authors.initials: P
authors.lastname: Viens
authors.forename: Soraya
authors.initials: S
authors.lastname: Moulessehoul
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: Max
authors.initials: M
authors.lastname: Chaffanet
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D017931:DNA Primers; D015536:Down-Regulation; D005260:Female; D006801:Humans; D009154:Mutation; D009693:Nucleic Acid Hybridization; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger