title: Deregulation of MYCN, LIN28B and LET7 in a molecular subtype of aggressive high-grade serous ovarian cancers.
abstract: Molecular subtypes of serous ovarian cancer have been recently described. Using data from independent datasets including over 900 primary tumour samples, we show that deregulation of the Let-7 pathway is specifically associated with the C5 molecular subtype of serous ovarian cancer. DNA copy number and gene expression of HMGA2, alleles of Let-7, LIN28, LIN28B, MYC, MYCN, DICER1, and RNASEN were measured using microarray and quantitative reverse transcriptase PCR. Immunohistochemistry was performed on 127 samples using tissue microarrays and anti-HMGA2 antibodies. Fluorescence in situ hybridisation of bacterial artificial chromosomes hybridized to 239 ovarian tumours was used to measure translocation at the LIN28B locus. Short interfering RNA knockdown in ovarian cell lines was used to test the functionality of associations observed. Four molecular subtypes (C1, C2, C4, C5) of high-grade serous ovarian cancers were robustly represented in each dataset and showed similar pattern of patient survival. We found highly specific activation of a pathway involving MYCN, LIN28B, Let-7 and HMGA2 in the C5 molecular subtype defined by MYCN amplification and over-expression, over-expression of MYCN targets including the Let-7 repressor LIN28B, loss of Let-7 expression and HMGA2 amplification and over-expression. DICER1, a known Let-7 target, and RNASEN were over-expressed in C5 tumours. We saw no evidence of translocation at the LIN28B locus in C5 tumours. The reported interaction between LIN28B and Let-7 was recapitulated by siRNA knockdown in ovarian cancer cell lines. Our results associate deregulation of MYCN and downstream targets, including Let-7 and oncofetal genes, with serous ovarian cancer. We define for the first time how elements of an oncogenic pathway, involving multiple genes that contribute to stem cell renewal, is specifically altered in a molecular subtype of serous ovarian cancer. By defining the drivers of a molecular subtype of serous ovarian cancers we provide a novel strategy for targeted therapeutic intervention.
authors.affiliation: Division of Surgery and Cancer, Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Åslaug
authors.initials: Å
authors.lastname: Helland
authors.forename: Michael S
authors.initials: MS
authors.lastname: Anglesio
authors.forename: Joshy
authors.initials: J
authors.lastname: George
authors.forename: Prue A
authors.initials: PA
authors.lastname: Cowin
authors.forename: Cameron N
authors.initials: CN
authors.lastname: Johnstone
authors.forename: Colin M
authors.initials: CM
authors.lastname: House
authors.forename: Karen E
authors.initials: KE
authors.lastname: Sheppard
authors.forename: Dariush
authors.initials: D
authors.lastname: Etemadmoghadam
authors.forename: Nataliya
authors.initials: N
authors.lastname: Melnyk
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
authors.forename: Hilde
authors.initials: H
authors.lastname: Johnsen
authors.forename: Ruth
authors.initials: R
authors.lastname: Holm
authors.forename: Gunnar B
authors.initials: GB
authors.lastname: Kristensen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pearson
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: Anna
authors.initials: A
authors.lastname: deFazio
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: David D L
authors.initials: DD
authors.lastname: Bowtell
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D035683:MicroRNAs / Q000235:genetics*; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; C459801:MYCN protein, human; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human