title: Adenoid cystic carcinoma of the lacrimal gland: MYB gene activation, genomic imbalances, and clinical characteristics.
abstract: OBJECTIVE
  To investigate genetic alterations in lacrimal gland adenoid cystic carcinomas (ACCs) with emphasis on the MYB-NFIB fusion oncogene and its downstream targets, MYB rearrangements, and copy number alterations in relation to clinical data and survival.
  
  
  METHODS
  Experimental study.
  
  
  METHODS
  Fourteen patients with primary lacrimal gland ACC were included. As a control, we also studied the expression of MYB-NFIB in 19 non-ACC lacrimal gland tumors.
  
  
  METHODS
  The expression and identity of MYB-NFIB fusion transcripts were studied using reverse transcriptase polymerase chain reaction (RT-PCR) and nucleotide sequence analyses. Quantitative polymerase chain reaction (PCR) and immunohistochemistry were used to evaluate the expression of MYB/MYB-NFIB target genes. High-resolution array-based comparative genomic hybridization (arrayCGH) and fluorescence in situ hybridization were used to study copy number alterations and MYB rearrangements.
  
  
  METHODS
  mRNA or protein expression of MYB-NFIB, MYB, and its down stream targets; copy number alterations; and genomic rearrangements.
  
  
  RESULTS
  The median age of the patients was 43 years (equal gender distribution), and the median time of survival was 8.6 years. The MYB-NFIB fusion was expressed in 7 of 14 ACCs. In contrast, all non-ACC tumors were fusion-negative. All 13 ACCs tested stained positive for the MYB protein, and for the MYB targets KIT and BCL2, 12 were positive for MYC and CCNE1, and 9 were positive for CCNB1. Rearrangements of MYB were detected in 8 of 13 cases, including 2 cases with gain of an apparently intact MYB gene. The arrayCGH analysis revealed recurrent copy number alterations with losses involving 6q23-q27, 12q12-q14.1, and 17p13.3-p12, and gains involving 19q12, 19q13.31-qter, 8q24.13-q24.21, 11q12.3-q14.1, and 6q23.3. Neither MYB-NFIB fusion nor any copy number alteration correlated with survival.
  
  
  CONCLUSIONS
  Lacrimal gland ACCs are frequently positive for the MYB-NFIB fusion, overexpress MYB and its downstream targets, and have genomic profiles characterized by losses involving 6q, 12q, and 17p, and gains involving 19q, 8q, and 11q. Our findings show that lacrimal gland ACCs are genetically and clinically similar to their salivary gland counterparts and that MYB-NFIB is a clinically useful diagnostic biomarker for ACC. Our data also suggest that MYB and its downstream targets are potential therapeutic targets for these tumors.
  
  
  BACKGROUND
  The author(s) have no proprietary or commercial interest in any materials discussed in this article.
authors.affiliation: Eye Pathology Section, Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Denmark; Sahlgrenska Cancer Center, Department of Pathology, University of Gothenburg, Sweden.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: von Holstein
authors.forename: André
authors.initials: A
authors.lastname: Fehr
authors.forename: Marta
authors.initials: M
authors.lastname: Persson
authors.forename: Marianne H
authors.initials: MH
authors.lastname: Therkildsen
authors.forename: Jan U
authors.initials: JU
authors.lastname: Prause
authors.forename: Steffen
authors.initials: S
authors.lastname: Heegaard
authors.forename: Göran
authors.initials: G
authors.lastname: Stenman
mesh_terms: D000328:Adult; D000368:Aged; D003528:Carcinoma, Adenoid Cystic / Q000235:genetics* / Q000378:metabolism; D005134:Eye Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020570:Genes, myb / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007766:Lacrimal Apparatus Diseases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: C545202:MYB-NFIB fusion protein, human; D015514:Oncogene Proteins, Fusion; D020598:Proto-Oncogene Proteins c-myb