title: Novel MYBL1 Gene Rearrangements with Recurrent MYBL1-NFIB Fusions in Salivary Adenoid Cystic Carcinomas Lacking t(6;9) Translocations.
abstract: OBJECTIVE
  Adenoid cystic carcinoma (ACC) is an indolent salivary gland malignancy, characterized by t(6;9) translocations and MYB-NFIB gene fusions in approximately 50% of the tumors. The genetic alterations underlying t(6;9)-negative and t(6;9)-positive/MYB-NFIB fusion-negative ACC remain unknown. To uncover the genetic alterations in ACC lacking the canonical translocation and fusion transcript and identify new abnormalities in translocation positive tumors.
  
  
  METHODS
  We performed whole-genome sequencing in 21 salivary ACCs and conducted targeted molecular analyses in a validation set (81 patients). Microarray gene-expression data were also analyzed to explore the biologic differences between fusion positive and negative tumors.
  
  
  RESULTS
  We identified a novel MYBL1-NFIB gene fusion as a result of t(8;9) translocation and multiple rearrangements in the MYBL1 gene in 35% of the t(6;9)-negative ACCs. All MYBL1 alterations involved deletion of the C-terminal negative regulatory domain and were associated with high MYBL1 expression. Reciprocal MYB and MYBL1 expression was consistently found in ACCs. In addition, 5'-NFIB fusions that did not involve MYB/MYBL1 genes were identified in a subset of t(6;9)-positive/fusion-negative tumors. We also delineated distinct gene-expression profiles in ACCs associated with the length of the MYB or MYBL1 fusions, suggesting a biologic importance of the C-terminal part of these fusions.
  
  
  CONCLUSIONS
  Our study defines new molecular subclasses of ACC characterized by MYBL1 rearrangements and 5'-NFIB gene fusions.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Mitani
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Pulivarthi H
authors.initials: PH
authors.lastname: Rao
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Vishnupriya J
authors.initials: VJ
authors.lastname: Borra
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mark
authors.initials: M
authors.lastname: Zafereo
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Randal S
authors.initials: RS
authors.lastname: Weber
authors.affiliation: Department of Thoracic/Head and Neck Medicine Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Merrill
authors.initials: M
authors.lastname: Kies
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. anaggar@mdanderson.org ccaulin@mdanderson.org.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caulin
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. anaggar@mdanderson.org ccaulin@mdanderson.org.
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
mesh_terms: D003528:Carcinoma, Adenoid Cystic / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D056905:Chromosome Breakpoints; D002898:Chromosomes, Human, Pair 8; D002899:Chromosomes, Human, Pair 9; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023061:Gene Order; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D051839:NFI Transcription Factors / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015203:Reproducibility of Results; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: C088831:MYBL1 protein, human; D051839:NFI Transcription Factors; C110754:NFIB protein, human; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators