Poster Presentation Advances in Neuroblastoma Research Congress 2016

An 18-gene Myc activity signature predicts poor clinical outcome in multiple Myc-associated cancer types (#163)

MoonSun Jung 1 , Amanda J. Russell 1 , Bing Liu 1 , Joshy George 2 , Pei Yan Liu 1 , Tao Liu 1 , Anna DeFazio 3 , David D.L. Bowtell 2 , André Oberthuer 4 , Wendy B. London 5 , Jamie I. Fletcher 1 , Michelle Haber 1 , Murray D. Norris 1 , Michelle J. Henderson 1
  1. Children's Cancer Institute Australia, Sydney, NSW, Australia
  2. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  3. Department of Gynaecological oncology and Westmead Institute for Cancer research, University of Sydney at the Westmead Millennium Institute, Sydney, NSW, Australia
  4. Children’s Hospital, Department of Pediatric Oncology and Hematology, University of Cologne and Centre for Molecular Medicine Cologne, Cologne, Germany
  5. Children’s Oncology Group Statistics and Data Center and Boston Children’s Hospital/Dana-Farber Cancer Institute, Boston, MA, USA

Background

Myc transcriptional activity is frequently deregulated in human cancers, but a Myc activity signature with predictive ability and clinical utility in multiple tumour types remains to be developed.

 

Methods

18 Myc-regulated genes were selected from published studies of Myc family targets based on analysis of gene expression and correlation with clinical outcome in epithelial ovarian cancer (EOC) and neuroblastoma. A Myc family activity score, derived from the expression of 18 genes using qPCR assays arrayed in Taqman low density format, was first correlated to MYC/MYCN/MYCL1 expression in a panel of 35 cancer cell lines. The prognostic utility of this signature was evaluated in neuroblastoma (n=649), medulloblastoma (n=130), diffuse large B-cell lymphoma (DLBCL; n=122) and EOC (n=540) microarray gene expression datasets using Kaplan-Meier and multivariate Cox regression analyses, and was further validated in 42 primary neuroblastomas using qPCR.

 

Results

Cell lines with high MYC, MYCN and/or MYCL1 gene expression exhibited elevated expression of the signature genes. Survival analysis showed that high signature score was significantly associated with poor outcome in the overall cohort (p<0.001) and a subset of tumours lacking MYCN amplification (p<0.001) in neuroblastoma. Moreover, high signature score was associated with poor prognosis 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 tumours without MYCN amplification.

 

Conclusion

An 18-gene Myc activity signature is highly predictive of clinical outcome in diverse Myc-associated malignancies, independent of Myc amplification. This suggests its potential clinical application in the identification of Myc-mediated tumours that might be treated with Myc-targeted therapies.