Transcript signatures that predict outcome and identify targetable pathways in MYCN-amplified neuroblastoma.
In the pediatric cancer neuroblastoma (NB), patients are stratified into low, intermediate or high-risk subsets based in part on MYCN amplification status. While MYCN amplification in general predicts unfavorable outcome, no clinical or genomic factors have been identified that predict outcome within these cohorts of high-risk patients. In particular, it is currently not possible at diagnosis to determine which high-risk neuroblastoma patients will ultimately fail upfront therapy.



We analyzed the prognostic potential of most published gene expression signatures for NB and developed a new prognostic signature to predict outcome for patients with MYCN amplification. Network and pathway analyses identified candidate therapeutic targets for this MYCN-amplified patient subset with poor outcome.



Most signatures have a high capacity to predict outcome of unselected NB patients. However, the majority of published signatures, as well as most randomly generated signatures, are highly confounded by MYCN amplification, and fail to predict outcome in subpopulations of high-risk patients with MYCN-amplified NB. We identify a MYCN module signature that predicts patient outcome for those with MYCN-amplified tumors, that also predicts potential tractable therapeutic signaling pathways and targets including the DNA repair enzyme Poly [ADP-ribose] polymerase 1 (PARP1).



Many prognostic signatures for NB are confounded by MYCN amplification and fail to predict outcome for the subset of high-risk patients with MYCN amplification. We report a MYCN module signature that is associated with distinct patient outcomes, and predicts candidate therapeutic targets in DNA repair pathways, including PARP1 in MYCN-amplified NB.
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada; James Birrell Laboratories, The Hospital for Sick Children, Toronto, Ontario, Canada.
Robin M
RM
Hallett
Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; James Birrell Laboratories, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Alex B K
AB
Seong
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada; James Birrell Laboratories, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
David R
DR
Kaplan
Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; James Birrell Laboratories, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Meredith S
MS
Irwin
D045744:Cell Line, Tumor; D015331:Cohort Studies; D005784:Gene Amplification / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics* / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011336:Probability; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics*; D016896:Treatment Outcome
C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D011065:Poly(ADP-ribose) Polymerases
Biomarkers; Confounding variables; Gene signatures; MYCN; Networks; Neuroblastoma