title: Clinically significant copy number alterations and complex rearrangements of MYB and NFIB in head and neck adenoid cystic carcinoma.
abstract: Adenoid cystic carcinoma (ACC) of the head and neck is a malignant tumor with poor long-term prognosis. Besides the recently identified MYB-NFIB fusion oncogene generated by a t(6;9) translocation, little is known about other genetic alterations in ACC. Using high-resolution, array-based comparative genomic hybridization, and massively paired-end sequencing, we explored genomic alterations in 40 frozen ACCs. Eighty-six percent of the tumors expressed MYB-NFIB fusion transcripts and 97% overexpressed MYB mRNA, indicating that MYB activation is a hallmark of ACC. Thirty-five recurrent copy number alterations (CNAs) were detected, including losses involving 12q, 6q, 9p, 11q, 14q, 1p, and 5q and gains involving 1q, 9p, and 22q. Grade III tumors had on average a significantly higher number of CNAs/tumor compared to Grade I and II tumors (P = 0.007). Losses of 1p, 6q, and 15q were associated with high-grade tumors, whereas losses of 14q were exclusively seen in Grade I tumors. The t(6;9) rearrangements were associated with a complex pattern of breakpoints, deletions, insertions, inversions, and for 9p also gains. Analyses of fusion-negative ACCs using high-resolution arrays and massively paired-end sequencing revealed that MYB may also be deregulated by other mechanisms in addition to gene fusion. Our studies also identified several down-regulated candidate tumor suppressor genes (CTNNBIP1, CASP9, PRDM2, and SFN) in 1p36.33-p35.3 that may be of clinical significance in high-grade tumors. Further, studies of these and other potential target genes may lead to the identification of novel driver genes in ACC.
authors.affiliation: Sahlgrenska Cancer Center, Department of Pathology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Marta
authors.initials: M
authors.lastname: Persson
authors.forename: Ywonne
authors.initials: Y
authors.lastname: Andrén
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Moskaluk
authors.forename: Henry F
authors.initials: HF
authors.lastname: Frierson
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Cooke
authors.forename: Philip Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Teresia
authors.initials: T
authors.lastname: Kling
authors.forename: Sven
authors.initials: S
authors.lastname: Nelander
authors.forename: Anders
authors.initials: A
authors.lastname: Nordkvist
authors.forename: Fredrik
authors.initials: F
authors.lastname: Persson
authors.forename: Göran
authors.initials: G
authors.lastname: Stenman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003528:Carcinoma, Adenoid Cystic / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D015321:Gene Rearrangement; D016147:Genes, Tumor Suppressor; D020570:Genes, myb; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D051839:NFI Transcription Factors / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051839:NFI Transcription Factors; C110754:NFIB protein, human; D015514:Oncogene Proteins, Fusion