High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma.
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.
Fredlund
Erik
E
Center for Molecular Pathology, Department of Laboratory Medicine, CREATE Health, University Hospital MAS, Lund University, SE-205 02 Malmö, Sweden. erik.fredlund@med.lu.se
Ringnér
Markus
M
Maris
John M
JM
Påhlman
Sven
S
D002454:Cell Differentiation; D005500:Follow-Up Studies; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D015398:Signal Transduction; D016896:Treatment Outcome; D015854:Up-Regulation
D016271:Proto-Oncogene Proteins c-myc
Nat Rev Neurosci. 2003 Oct;4(10):795-805
14523379
Genome Biol. 2007;8(5):R77
17498287
Eur J Cancer. 1995;31A(4):435-43
7576941
Oncogene. 2005 Nov 24;24(53):7902-12
16103881
J Natl Cancer Inst. 1984 Aug;73(2):405-16
6589432
Genes Dev. 2000 Jun 1;14(11):1390-9
10837031
Dev Biol. 2006 Oct 15;298(2):335-43
16928368
Oncogene. 2008 Feb 28;27(10):1478-88
17724465
Cancer Cell. 2005 Apr;7(4):337-50
15837623
Cancer. 2003 Aug 15;98(4):841-53
12910530
Cancer Cell. 2006 Nov;10(5):413-23
17097563
N Engl J Med. 1999 Jun 24;340(25):1954-61
10379019
J Natl Cancer Inst. 2006 Sep 6;98(17):1193-203
16954472
Proc Natl Acad Sci U S A. 2002 May 14;99(10):7021-6
12011461
Cancer Res. 2004 Oct 1;64(19):6883-91
15466177
Cancer Lett. 2005 Oct 18;228(1-2):5-11
15936139
Nature. 2006 Jan 19;439(7074):353-7
16273092
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7564-9
17452630
Am J Pathol. 1997 Jan;150(1):107-17
9006328
Cancer Lett. 2007 Oct 28;256(2):218-28
17643814
Lab Invest. 1996 Nov;75(5):659-75
8941212
Clin Cancer Res. 2007 Aug 15;13(16):4695-703
17652624
Cancer Lett. 2007 Jun 8;250(2):250-67
17126996
Genome Biol. 2003;4(10):R69
14519204
J Clin Oncol. 2000 Nov 1;18(21):3604-13
11054433
Nat Rev Cancer. 2003 Mar;3(3):203-16
12612655
Cancer. 1999 Jul 15;86(2):364-72
10421273
N Engl J Med. 2005 Nov 24;353(21):2243-53
16306521
J Pediatr Surg. 2004 Jan;39(1):63-8
14694373
Lancet. 2007 Jun 23;369(9579):2106-20
17586306
Semin Cancer Biol. 2007 Jun;17(3):248-56
16828305
Cancer Res. 2006 Mar 1;66(5):2826-33
16510605
J Clin Oncol. 2006 Nov 1;24(31):5070-8
17075126
Am J Pathol. 1927 May;3(3):203-216.7
19969740
Mol Cancer Ther. 2006 Oct;5(10):2444-9
17041087
Genome Biol. 2006;7(9):R84
16989664
Lab Invest. 2004 Apr;84(4):406-17
14767491
Lab Invest. 1998 Jan;78(1):29-45
9461120
Cancer Res. 2006 Jun 15;66(12):6050-62
16778177
Development. 1997 May;124(10):1953-62
9169842
Lab Invest. 1995 Jan;72(1):42-54
7837790
Oncogene. 1992 Jun;7(6):1241-7
1375720