High Myc Pathway Activity and Low Stage of Neuronal Differentiation Associate with Poor Outcome in Neuroblastoma

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2008 Sep 11

PMID 18780787

Citations 93

Authors

Erik Fredlund

Markus Ringner

John M Maris

Sven Pahlman

Affiliations

Soon will be listed here.

Abstract

The childhood cancer neuroblastoma arises in the developing sympathetic nervous system and is a genotypically and phenotypically heterogeneous disease. Prognostic markers of poor survival probability include amplification of the MYCN oncogene and an undifferentiated morphology. Whereas these features discriminate high- from low-risk patients with precision, identification of poor outcome low- and intermediate-risk patients is more challenging. In this study, we analyze two large neuroblastoma microarray datasets using a priori-defined gene expression signatures. We show that differential overexpression of Myc transcriptional targets and low expression of genes involved in sympathetic neuronal differentiation predicts relapse and death from disease. This was evident not only for high-risk patients but was also robust in identifying groups of poor prognosis patients who were otherwise judged to be at low- or intermediate-risk for adverse outcome. These data suggest that pathway-specific gene expression profiling might be useful in the clinic to adjust treatment strategies for children with neuroblastoma.

Citing Articles

Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial.

Hogarty M, Ziegler D, Franson A, Chi Y, Tsao-Wei D, Liu K Br J Cancer. 2024; 130(5):788-797.

PMID: 38200233 PMC: 10912730. DOI: 10.1038/s41416-023-02525-2.

Development and validation of a 21-gene prognostic signature in neuroblastoma.

Gupta M, Kannappan S, Jain M, Douglass D, Shah R, Bose P Sci Rep. 2023; 13(1):12526.

PMID: 37532697 PMC: 10397261. DOI: 10.1038/s41598-023-37714-9.

The deubiquitinase USP28 maintains the expression of the transcription factor MYCN and is essential in neuroblastoma cells.

Li J, Peng J, Wu L, Shen X, Zhen X, Zhang Y J Biol Chem. 2023; 299(7):104856.

PMID: 37230388 PMC: 10404617. DOI: 10.1016/j.jbc.2023.104856.

Diagnostic classification of childhood cancer using multiscale transcriptomics.

Comitani F, Nash J, Cohen-Gogo S, Chang A, Wen T, Maheshwari A Nat Med. 2023; 29(3):656-666.

PMID: 36932241 PMC: 10033451. DOI: 10.1038/s41591-023-02221-x.

Inhibition of PIM Kinases Promotes Neuroblastoma Cell Differentiation to a Neuronal Phenotype.

Julson J, Quinn C, Bownes L, Hutchins S, Stewart J, Aye J J Pediatr Surg. 2023; 58(6):1155-1163.

PMID: 36907773 PMC: 10198809. DOI: 10.1016/j.jpedsurg.2023.02.018.

References

Gammill L, Bronner-Fraser M . Neural crest specification: migrating into genomics. Nat Rev Neurosci. 2003; 4(10):795-805. DOI: 10.1038/nrn1219. View

Liu Y, Ringner M . Revealing signaling pathway deregulation by using gene expression signatures and regulatory motif analysis. Genome Biol. 2007; 8(5):R77. PMC: 1929148. DOI: 10.1186/gb-2007-8-5-r77. View

Hedborg F, Bjelfman C, Sparen P, Sandstedt B, Pahlman S . Biochemical evidence for a mature phenotype in morphologically poorly differentiated neuroblastomas with a favourable outcome. Eur J Cancer. 1995; 31A(4):435-43. DOI: 10.1016/0959-8049(95)00025-e. View

Schramm A, Schulte J, Klein-Hitpass L, Havers W, Sieverts H, Berwanger B . Prediction of clinical outcome and biological characterization of neuroblastoma by expression profiling. Oncogene. 2005; 24(53):7902-12. DOI: 10.1038/sj.onc.1208936. View

Shimada H, CHATTEN J, NEWTON Jr W, Sachs N, Hamoudi A, Chiba T . Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst. 1984; 73(2):405-16. DOI: 10.1093/jnci/73.2.405. View

Malynn B, de Alboran I, OHagan R, Bronson R, Davidson L, DePinho R . N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation. Genes Dev. 2000; 14(11):1390-9. PMC: 316670. View

Huber K . The sympathoadrenal cell lineage: specification, diversification, and new perspectives. Dev Biol. 2006; 298(2):335-43. DOI: 10.1016/j.ydbio.2006.07.010. View

Liu X, Mazanek P, Dam V, Wang Q, Zhao H, Guo R . Deregulated Wnt/beta-catenin program in high-risk neuroblastomas without MYCN amplification. Oncogene. 2007; 27(10):1478-88. DOI: 10.1038/sj.onc.1210769. View

Ohira M, Oba S, Nakamura Y, Isogai E, Kaneko S, Nakagawa A . Expression profiling using a tumor-specific cDNA microarray predicts the prognosis of intermediate risk neuroblastomas. Cancer Cell. 2005; 7(4):337-50. DOI: 10.1016/j.ccr.2005.03.019. View

10.

Raetz E, Kim M, Moos P, Carlson M, Bruggers C, Hooper D . Identification of genes that are regulated transcriptionally by Myc in childhood tumors. Cancer. 2003; 98(4):841-53. DOI: 10.1002/cncr.11584. View

11.

Holmquist-Mengelbier L, Fredlund E, Lofstedt T, Noguera R, Navarro S, Nilsson H . Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell. 2006; 10(5):413-23. DOI: 10.1016/j.ccr.2006.08.026. View

12.

Bown N, Cotterill S, Lastowska M, ONeill S, Pearson A, Plantaz D . Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med. 1999; 340(25):1954-61. DOI: 10.1056/NEJM199906243402504. View

13.

Asgharzadeh S, Pique-Regi R, Sposto R, Wang H, Yang Y, Shimada H . Prognostic significance of gene expression profiles of metastatic neuroblastomas lacking MYCN gene amplification. J Natl Cancer Inst. 2006; 98(17):1193-203. DOI: 10.1093/jnci/djj330. View

14.

Jogi A, Ora I, Nilsson H, Lindeheim A, Makino Y, Poellinger L . Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proc Natl Acad Sci U S A. 2002; 99(10):7021-6. PMC: 124521. DOI: 10.1073/pnas.102660199. View

15.

Wei J, Greer B, Westermann F, Steinberg S, Son C, Chen Q . Prediction of clinical outcome using gene expression profiling and artificial neural networks for patients with neuroblastoma. Cancer Res. 2004; 64(19):6883-91. PMC: 1298184. DOI: 10.1158/0008-5472.CAN-04-0695. View

16.

Ohira M, Oba S, Nakamura Y, Hirata T, Ishii S, Nakagawara A . A review of DNA microarray analysis of human neuroblastomas. Cancer Lett. 2005; 228(1-2):5-11. DOI: 10.1016/j.canlet.2005.01.054. View

17.

Bild A, Yao G, Chang J, Wang Q, Potti A, Chasse D . Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2005; 439(7074):353-7. DOI: 10.1038/nature04296. View

18.

Saal L, Johansson P, Holm K, Gruvberger-Saal S, She Q, Maurer M . Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci U S A. 2007; 104(18):7564-9. PMC: 1855070. DOI: 10.1073/pnas.0702507104. View

19.

Gestblom C, Hoehner J, Hedborg F, Sandstedt B, Pahlman S . In vivo spontaneous neuronal to neuroendocrine lineage conversion in a subset of neuroblastomas. Am J Pathol. 1997; 150(1):107-17. PMC: 1858509. View

20.

Koppen A, Ait-Aissa R, Hopman S, Koster J, Haneveld F, Versteeg R . Dickkopf-1 is down-regulated by MYCN and inhibits neuroblastoma cell proliferation. Cancer Lett. 2007; 256(2):218-28. DOI: 10.1016/j.canlet.2007.06.011. View