title: Integrated genomic analysis of the 8q24 amplification in endometrial cancers identifies ATAD2 as essential to MYC-dependent cancers.
abstract: Chromosome 8q24 is the most commonly amplified region across multiple cancer types, and the typical length of the amplification suggests that it may target additional genes to MYC. To explore the roles of the genes most frequently included in 8q24 amplifications, we analyzed the relation between copy number alterations and gene expression in three sets of endometrial cancers (N = 252); and in glioblastoma, ovarian, and breast cancers profiled by TCGA. Among the genes neighbouring MYC, expression of the bromodomain-containing gene ATAD2 was the most associated with amplification. Bromodomain-containing genes have been implicated as mediators of MYC transcriptional function, and indeed ATAD2 expression was more closely associated with expression of genes known to be upregulated by MYC than was MYC itself. Amplifications of 8q24, expression of genes downstream from MYC, and overexpression of ATAD2 predicted poor outcome and increased from primary to metastatic lesions. Knockdown of ATAD2 and MYC in seven endometrial and 21 breast cancer cell lines demonstrated that cell lines that were dependent on MYC also depended upon ATAD2. These same cell lines were also the most sensitive to the histone deacetylase (HDAC) inhibitor Trichostatin-A, consistent with prior studies identifying bromodomain-containing proteins as targets of inhibition by HDAC inhibitors. Our data indicate high ATAD2 expression is a marker of aggressive endometrial cancers, and suggest specific inhibitors of ATAD2 may have therapeutic utility in these and other MYC-dependent cancers.
authors: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway. Maria.Rader@uib.no
authors: Maria B
authors: MB
authors: Raeder
authors: Even
authors: E
authors: Birkeland
authors: Jone
authors: J
authors: Trovik
authors: Camilla
authors: C
authors: Krakstad
authors: Shyemaa
authors: S
authors: Shehata
authors: Steven
authors: S
authors: Schumacher
authors: Travis I
authors: TI
authors: Zack
authors: Antje
authors: A
authors: Krohn
authors: Henrica Mj
authors: HM
authors: Werner
authors: Susan E
authors: SE
authors: Moody
authors: Elisabeth
authors: E
authors: Wik
authors: Ingunn M
authors: IM
authors: Stefansson
authors: Frederik
authors: F
authors: Holst
authors: Anne M
authors: AM
authors: Oyan
authors: Pablo
authors: P
authors: Tamayo
authors: Jill P
authors: JP
authors: Mesirov
authors: Karl H
authors: KH
authors: Kalland
authors: Lars A
authors: LA
authors: Akslen
authors: Ronald
authors: R
authors: Simon
authors: Rameen
authors: R
authors: Beroukhim
authors: Helga B
authors: HB
authors: Salvesen
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D016259:Genes, myc / Q000235:genetics / Q000502:physiology*; D023281:Genomics / Q000379:methods*; D006801:Humans; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence
chemical_list: D004268:DNA-Binding Proteins; D000251:Adenosine Triphosphatases; C544857:ATAD2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities
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