title: A unifying gene signature for adenoid cystic cancer identifies parallel MYB-dependent and MYB-independent therapeutic targets.
abstract: MYB activation is proposed to underlie development of adenoid cystic cancer (ACC), an aggressive salivary gland tumor with no effective systemic treatments. To discover druggable targets for ACC, we performed global mRNA/miRNA analyses of 12 ACC with matched normal tissues, and compared these data with 14 mucoepidermoid carcinomas (MEC) and 11 salivary adenocarcinomas (ADC). We detected a unique ACC gene signature of 1160 mRNAs and 22 miRNAs. MYB was the top-scoring gene (18-fold induction), however we observed the same signature in ACC without detectable MYB gene rearrangements. We also found 4 ACC tumors (1 among our 12 cases and 3 from public databases) with negligible MYB expression that retained the same ACC mRNA signature including over-expression of extracellular matrix (ECM) genes. Integration of this signature with somatic mutational analyses suggests that NOTCH1 and RUNX1 participate with MYB to activate ECM elements including the VCAN/HAPLN1 complex. We observed that forced MYB-NFIB expression in human salivary gland cells alters cell morphology and cell adhesion in vitro and depletion of VCAN blocked tumor cell growth of a short-term ACC tumor culture. In summary, we identified a unique ACC signature with parallel MYB-dependent and independent biomarkers and identified VCAN/HAPLN1 complexes as a potential target.
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, College of Medicine, University of Florida, Gainesville, FL, USA. Genetics & Genomics Graduate Program, Genetics Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Ruli
authors.initials: R
authors.lastname: Gao
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Cao
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Maria-Cecilia
authors.initials: MC
authors.lastname: Lopez
authors.affiliation: Genetics & Genomics Graduate Program, Genetics Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Zirong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Mitani
authors.affiliation: Department of Computational Biology and Bioinformatics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Anatomy & Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Zajac-Kaye
authors.affiliation: Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Lizi
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Rolf
authors.initials: R
authors.lastname: Renne
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Henry V
authors.initials: HV
authors.lastname: Baker
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Adel
authors.initials: A
authors.lastname: El-Naggar
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, College of Medicine, University of Florida, Gainesville, FL, USA. Genetics & Genomics Graduate Program, Genetics Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Kaye
mesh_terms: D000818:Animals; D003528:Carcinoma, Adenoid Cystic / Q000235:genetics* / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D015321:Gene Rearrangement; D020570:Genes, myb; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D051839:NFI Transcription Factors / Q000235:genetics; D020626:Oncogene Proteins v-myb / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051881:Receptor, Notch1 / Q000378:metabolism
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D035683:MicroRNAs; D051839:NFI Transcription Factors; C110754:NFIB protein, human; C497761:NOTCH1 protein, human; D020626:Oncogene Proteins v-myb; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C493728:RUNX1 protein, human; D051881:Receptor, Notch1