title: Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma.
abstract: Adenoid cystic carcinomas (ACC) of the salivary glands are challenging to understand, treat, and cure. To better understand the genetic alterations underlying the pathogenesis of these tumors, we performed comprehensive genome analyses of 25 fresh-frozen tumors, including whole-genome sequencing and expression and pathway analyses. In addition to the well-described MYB-NFIB fusion that was found in 11 tumors (44%), we observed five different rearrangements involving the NFIB transcription factor gene in seven tumors (28%). Taken together, NFIB translocations occurred in 15 of 25 samples (60%, 95% CI, 41%-77%). In addition, mRNA expression analysis of 17 tumors revealed overexpression of NFIB in ACC tumors compared with normal tissues (P = 0.002). There was no difference in NFIB mRNA expression in tumors with NFIB fusions compared with those without. We also report somatic mutations of genes involved in the axonal guidance and Rho family signaling pathways. Finally, we confirm previously described alterations in genes related to chromatin regulation and Notch signaling. Our findings suggest a separate role for NFIB in ACC oncogenesis and highlight important signaling pathways for future functional characterization and potential therapeutic targeting.
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Eleni M
authors: EM
authors: Rettig
authors: Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: C Conover
authors: CC
authors: Talbot
authors: Personal Genome Diagnostics, Baltimore, Maryland.
authors: Mark
authors: M
authors: Sausen
authors: Personal Genome Diagnostics, Baltimore, Maryland.
authors: Sian
authors: S
authors: Jones
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Justin A
authors: JA
authors: Bishop
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Laura D
authors: LD
authors: Wood
authors: Johns Hopkins Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.
authors: Collin
authors: C
authors: Tokheim
authors: Johns Hopkins Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.
authors: Noushin
authors: N
authors: Niknafs
authors: Johns Hopkins Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland. Department of Oncology, John Hopkins University School of Medicine, Baltimore, Maryland.
authors: Rachel
authors: R
authors: Karchin
authors: Department of Oncology Biostatistics & Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Elana J
authors: EJ
authors: Fertig
authors: Department of Oncology, John Hopkins University School of Medicine, Baltimore, Maryland.
authors: Sarah J
authors: SJ
authors: Wheelan
authors: Department of Oncology, John Hopkins University School of Medicine, Baltimore, Maryland.
authors: Luigi
authors: L
authors: Marchionni
authors: Department of Oncology Biostatistics & Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Michael
authors: M
authors: Considine
authors: Shizhang
authors: S
authors: Ling
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Milton J. Dance Jr. Head and Neck Cancer Center, Greater Baltimore Medical Center, Baltimore, Maryland.
authors: Carole
authors: C
authors: Fakhry
authors: Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Nickolas
authors: N
authors: Papadopoulos
authors: Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Kenneth W
authors: KW
authors: Kinzler
authors: Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. nishant.agrawal@uchicago.edu nagrawal@jhmi.edu Patrick.Ha@ucsf.edu vogelbe@jhmi.edu.
authors: Bert
authors: B
authors: Vogelstein
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Milton J. Dance Jr. Head and Neck Cancer Center, Greater Baltimore Medical Center, Baltimore, Maryland. nishant.agrawal@uchicago.edu nagrawal@jhmi.edu Patrick.Ha@ucsf.edu vogelbe@jhmi.edu.
authors: Patrick K
authors: PK
authors: Ha
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Surgery, Section of Otolaryngology-Head and Neck Surgery, The University of Chicago, Chicago, Illinois States. nishant.agrawal@uchicago.edu nagrawal@jhmi.edu Patrick.Ha@ucsf.edu vogelbe@jhmi.edu.
authors: Nishant
authors: N
authors: Agrawal
mesh_terms: D063646:Carcinogenesis / Q000235:genetics; D003528:Carcinoma, Adenoid Cystic / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D015321:Gene Rearrangement; D006801:Humans; D051839:NFI Transcription Factors / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: C545202:MYB-NFIB fusion protein, human; D051839:NFI Transcription Factors; C110754:NFIB protein, human; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D051880:Receptors, Notch