title: A Myc Activity Signature Predicts Poor Clinical Outcomes in Myc-Associated Cancers.
abstract: Myc transcriptional activity is frequently deregulated in human cancers, but a Myc-driven gene signature with prognostic ability across multiple tumor types remains lacking. Here, we selected 18 Myc-regulated genes from published studies of Myc family targets in epithelial ovarian cancer (EOC) and neuroblastoma. A Myc family activity score derived from the 18 genes was correlated toMYC/MYCN/MYCL1expression in a panel of 35 cancer cell lines. The prognostic ability of this signature was evaluated in neuroblastoma, medulloblastoma, diffuse large B-cell lymphoma (DLBCL), and EOC microarray gene expression datasets using Kaplan-Meier and multivariate Cox regression analyses and was further validated in 42 primary neuroblastomas using qPCR. Cell lines with highMYC, MYCN, and/orMYCL1gene expression exhibited elevated expression of the signature genes. Survival analysis showed that the signature was associated with poor outcome independently of well-defined prognostic factors in neuroblastoma, breast cancer, DLBCL, and medulloblastoma. In EOC, the 18-gene Myc activity signature was capable of identifying a group of patients with poor prognosis in a "high-MYCN" molecular subtype but not in the overall cohort. The predictive ability of this signature was reproduced using qPCR analysis of an independent cohort of neuroblastomas, including a subset of tumors withoutMYCNamplification. These data reveal an 18-gene Myc activity signature that is highly predictive of poor prognosis in diverse Myc-associated malignancies and suggest its potential clinical application in the identification of Myc-driven tumors that might respond to Myc-targeted therapies.Cancer Res; 77(4); 971-81. ©2016 AACR.
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Kensington, New South Wales, Australia.
authors.forename: MoonSun
authors.initials: M
authors.lastname: Jung
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Kensington, New South Wales, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Russell
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Kensington, New South Wales, Australia.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Joshy
authors.initials: J
authors.lastname: George
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Kensington, New South Wales, Australia.
authors.forename: Pei Yan
authors.initials: PY
authors.lastname: Liu
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Kensington, New South Wales, Australia.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Gynecological Oncology, Westmead Hospital and Centre for Cancer Research, The Westmead Millennium Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: DeFazio
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: David D L
authors.initials: DD
authors.lastname: Bowtell
authors.affiliation: Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne and Centre for Molecular Medicine Cologne, Cologne, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Oberthuer
authors.affiliation: Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School Division of Hematology/Oncology and Children's Oncology Group Statistics and Data Center, Boston, Massachusetts.
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Kensington, New South Wales, Australia.
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Fletcher
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Kensington, New South Wales, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Kensington, New South Wales, Australia.|University of New South Wales Centre for Childhood Cancer Research, University of New South Wales Australia, Kensington, New South Wales, Australia.
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Kensington, New South Wales, Australia. mhenderson@ccia.unsw.edu.au.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Henderson
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D006801:Humans; D008527:Medulloblastoma / Q000401:mortality; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics; D009369:Neoplasms / Q000401:mortality* / Q000628:therapy; D009375:Neoplasms, Glandular and Epithelial / Q000401:mortality; D009447:Neuroblastoma / Q000401:mortality; D010051:Ovarian Neoplasms / Q000401:mortality; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*
chemical_list: C489427:MYC protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D016271:Proto-Oncogene Proteins c-myc