Validation of a prognostic multi‐gene signature in high‐risk neuroblastoma using the high throughput digital NanoString nCounter™ system
Open accessAbstract
Microarray‐based molecular signatures have not been widely integrated into neuroblastoma diagnostic classification systems due to the complexities of the assay and requirement for high‐quality RNA. New digital technologies that accurately quantify gene expression using RNA isolated from formalin‐fixed paraffin embedded (FFPE) tissues are now available. In this study, we describe the first use of a high‐throughput digital system to assay the expression of genes in an “ultra‐high risk” microarray classifier in FFPE high‐risk neuroblastoma tumors. Customized probes corresponding to the 42 genes in a published multi‐gene neuroblastoma signature were hybridized to RNA isolated from 107 FFPE high‐risk neuroblastoma samples using the NanoString nCounter™ Analysis System. For classification of each patient, the Pearson's correlation coefficient was calculated between the standardized nCounter™ data and the molecular signature from the microarray data. We demonstrate that the nCounter™ 42‐gene panel sub‐stratified the high‐risk cohort into two subsets with statistically significantly different overall survival ( p = 0.0027) and event‐free survival ( p = 0.028). In contrast, none of the established prognostic risk markers (age, stage, tumor histology, MYCN status, and ploidy) were significantly associated with survival. We conclude that the nCounter™ System can reproducibly quantify expression levels of signature genes in FFPE tumor samples. Validation of this microarray signature in our high‐risk patient cohort using a completely different technology emphasizes the prognostic relevance of this classifier. Prospective studies testing the prognostic value of molecular signatures in high‐risk neuroblastoma patients using FFPE tumor samples and the nCounter™ System are warranted.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The best performing models were able to predict outcome of high-risk patients with a similar precision as previously published multigene signatures, and independently from current prognostic markers.
“In addition, we found that the best performing models were able to predict outcome of high-risk patients with a similar precision as previously published multigene signatures [18, 20, 33], and independently from current prognostic markers.”
From Comparison of RNA-seq and microarray-based models for clinical endpoint prediction (2015) · cites this paper as [33]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Nonparametric Estimation from Incomplete Observations
Kaplan, E. L., & Meier, P. (1992) · Springer series in statistics · doi:10.1007/978-1-4612-4380-9_25 · Cited by 45,232 · see citing works
A Direct Approach to False Discovery Rates
Storey, J. D. (2002) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/1467-9868.00346 · Cited by 5,603 · see citing works
Brodeur, G. M., Pritchard, J., Berthold, F., Carlsen, N., Castel, V., Castelberry, R. P., Bernardi, B. D., Evans, A. E., Favrot, M., & Hedborg, F. (1993) · Journal of Clinical Oncology · doi:10.1200/jco.1993.11.8.1466 · Cited by 2,287 · see citing works
Direct multiplexed measurement of gene expression with color-coded probe pairs
Geiss, G. K., Bumgarner, R. E., Birditt, B., Dahl, T., Dowidar, N., Dunaway, D. L., Fell, H. P., Ferree, S., George, R. D., Grogan, T., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1385 · Cited by 2,066 · see citing works
Maris, J. M., Hogarty, M. D., Bagatell, R., & Cohn, S. L. (2007) · The Lancet · doi:10.1016/s0140-6736(07)60983-0 · Cited by 2,029 · see citing works
Self-citationRecent Advances in Neuroblastoma
Maris, J. M. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0804577 · Cited by 1,991 · see citing works
Spiess, P. E., Lee, A. K., Leibovici, D., Wang, X., Do, K.-A., & Pisters, L. L. (2006) · Cancer · doi:10.1002/cncr.21979 · Cited by 1,930 · see citing works
The International Neuroblastoma Risk Group (INRG) Classification System: An INRG Task Force Report
Cohn, S. L., Pearson, A. D. J., London, W. B., Monclair, T. F., Ambros, P. F., Brodeur, G. M., Faldum, A., Hero, B., Iehara, T., Machin, D., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.16.6785 · Cited by 1,915 · see citing works
Self-citationMatthay, K. K., Reynolds, C. P., Seeger, R. C., Shimada, H., Adkins, E. S., Haas-Kogan, D., Gerbing, R. B., London, W. B., & Villablanca, J. G. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2007.13.8925 · Cited by 858 · see citing works
Self-citationRapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples
Northcott, P. A., Shih, D. J. H., Remke, M., Cho, Y., Kool, M., Hawkins, C. E., Eberhart, C. G., Dubuc, A. M., Guettouche, T., Cardentey, Y., et al. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0899-7 · Cited by 382 · see citing works
Digital Multiplexed Gene Expression Analysis Using the NanoString nCounter System
Kulkarni, M. M. (2011) · Current Protocols in Molecular Biology · doi:10.1002/0471142727.mb25b10s94 · Cited by 309 · see citing works
Kreissman, S. G., Seeger, R. C., Matthay, K. K., London, W. B., Sposto, R., Grupp, S. A., Haas-Kogan, D. A., LaQuaglia, M. P., Yu, A. L.-T., Diller, L., et al. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70309-7 · Cited by 304 · see citing works
Self-citationAsgharzadeh, S., Pique-Regi, R., Sposto, R., Wang, H., Yang, Y., Shimada, H., Matthay, K., Buckley, J., Ortega, A., & Seeger, R. C. (2006) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djj330 · Cited by 237 · see citing works
Self-citationWang, Q., Diskin, S. J., Rappaport, E. R., Attiyeh, E. F., Mossé, Y. P., Shue, D. S., Seiser, E., Jagannathan, J., Shusterman, S., Bansal, M., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4618 · Cited by 199 · see citing works
Self-citationVermeulen, J., De Preter, K., Naranjo, A., Vercruysse, L., Van Roy, N., Hellemans, J., Swerts, K., Bravo, S., Scaruffi, P., Tonini, G. P., et al. (2009) · The Lancet Oncology · doi:10.1016/s1470-2045(09)70154-8 · Cited by 192 · see citing works
Self-citationWei, J. S., Greer, B. T., Westermann, F., Steinberg, S. M., Son, C., Chen, Q., Whiteford, C. C., Bilke, S., Krasnoselsky, A. L., Cenacchi, N., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0695 · Cited by 183 · see citing works
Malkov, V. A., Serikawa, K. A., BALANTAC, N., Watters, J., Geiss, G. K., Mashadi-Hossein, A., & Fare, T. L. (2009) · BMC Research Notes · doi:10.1186/1756-0500-2-80 · Cited by 161 · see citing works
Payton, J. E., Grieselhuber, N. R., Chang, L., Murakami, M. A., Geiss, G. K., Link, D. C., Nagarajan, R., Watson, M. A., & Ley, T. J. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38248 · Cited by 135 · see citing works
Prognostic Impact of Gene Expression–Based Classification for Neuroblastoma
Oberthuer, A., Hero, B., Berthold, F., Juraeva, D., Faldum, A., Kahlert, Y., Asgharzadeh, S., Seeger, R., Scaruffi, P., Tonini, G. P., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.3367 · Cited by 135 · see citing works
Kletzel, M., Katzenstein, H. M., Haut, P. R., et al. (2002) · Journal of Clinical Oncology · doi:10.1200/jco.2002.06.060 · Cited by 128 · see citing works
Schramm, A. R., Schulte, J. H., Klein‐Hitpaß, L., Havers, W., Sieverts, H., Berwanger, B., Christiansen, H., Warnat, P., Brors, B., Eils, J., et al. (2005) · Oncogene · doi:10.1038/sj.onc.1208936 · Cited by 117 · see citing works
Preter, K. D., Vermeulen, J., Brors, B., Delattre, O., Eggert, A., Fischer, M., Janoueix‐Lerosey, I., Lavarino, C. E., Maris, J. M., Mora, J., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-2607 · Cited by 98 · see citing works
Accurate prediction of neuroblastoma outcome based on miRNA expression profiles
Schulte, J. H., Schowe, B., Mestdagh, P., Kaderali, L., Kalaghatgi, P., Schlierf, S., Vermeulen, J., Brockmeyer, B., Pajtler, K. W., Thor, T., et al. (2010) · International Journal of Cancer · doi:10.1002/ijc.25436 · Cited by 97 · see citing works
Involvement of Myc targets in c-myc and N-myc induced human tumors
Ben‐Yosef, T., Yanuka, O., Halle, D., et al. (1998) · Oncogene · doi:10.1038/sj.onc.1201939 · Cited by 83 · see citing works
Santana, V. M., Furman, W. L., Billups, C. A., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.02.097 · Cited by 80 · see citing works
Self-citationA Three-Gene Expression Signature Model for Risk Stratification of Patients with Neuroblastoma
García, I., Mayol, G., Ríos, J., Doménech, G., Cheung, N. V., Oberthuer, A., Fischer, M., Maris, J. M., Brodeur, G. M., Hero, B., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2483 · Cited by 63 · see citing works
Brem, H., & Lawson, H. C. (1999) · Cancer · doi:10.1002/(sici)1097-0142(19990715)86:2 · Cited by 38 · see citing works
Stricker, T. P., Henriksen, K., Tonsgard, J. H., et al. (2013) · Modern Pathology · doi:10.1038/modpathol.2012.242 · Cited by 34 · see citing works
Self-citationWagner, L. M., Billups, C. A., Furman, W. L., et al. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.01.002 · Cited by 33 · see citing works
Self-citationA 6-gene signature identifies four molecular subgroups of neuroblastoma
Abel, F., Dalevi, D., Nethander, M., Jörnsten, R. J., Preter, K. D., Vermeulen, J., Stallings, R., Kogner, P., Maris, J. M., & Nilsson, S. (2011) · Cancer Cell International · doi:10.1186/1475-2867-11-9 · Cited by 33 · see citing works
Furman, W. L., McGregor, L. M., McCarville, M. B., et al. (2011) · Investigational New Drugs · doi:10.1007/s10637-011-9724-3 · Cited by 30 · see citing works
Self-citationFernandez, P. C., Solenthaler, M., Spertini, O., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049010 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Comparison of RNA-seq and microarray-based models for clinical endpoint prediction
Zhang, W., Yu, Y., Hertwig, F., Thierry-Mieg, J., Zhang, W., Thierry-Mieg, D., Wang, J., Furlanello, C., Devanarayan, V., Cheng, J., et al. (2015) · Genome Biology · doi:10.1186/s13059-015-0694-1 · Cited by 393 · see citing works
- Authors
- Stricker, T. P., Morales La Madrid, A., Chlenski, A., Guerrero, L., Salwen, H. R., Gosiengfiao, Y., Perlman, E. J., Furman, W., Bahrami, A., Shohet, J. M., Zage, P. E., Hicks, M. J., Shimada, H., Suganuma, R., Park, J. R., So, S., London, W. B., Pytel, P., Maclean, K. H., & Cohn, S. L.
- Affiliations
- Vanderbilt University (US)
- University of Chicago (US)
- Northwestern University (US)
- St. Jude Children's Research Hospital (US)
- Baylor College of Medicine (US)
- Children's Hospital Los Angeles (US)
- Seattle Children's Hospital (US)
- Boston Children's Hospital (US)
- Nanostring Technologies (United States) (US)
- Corresponding author
- Cohn, Susan L.
- ORCID
- Venue
- Molecular Oncology
- Publisher
- Wiley
- Published
- 2014-01-31
- Volume
- 8
- Issue
- 3
- Pages
- 669-678
- ISSN
- 1574-7891 (ISSN-L)
- 1878-0261
- PMC
- PMC4004665
- OpenAlex
- W2013276712
- Cited by
- 36
- References
- 32
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 8 · 2015: 11 · 2014: 1
- FWCI
- 5.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Conquer Cancer Foundation (AML)
- St. Baldrick's Foundation (AML)
- Children's Neuroblastoma Cancer Foundation (SLC)
- Neuroblastoma Children's Cancer Society (SLC)
- Elise Anderson Foundation (SLC)
- The National Cancer Institute
- Topics
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- high-risk neuroblastoma, NanoString nCounter, digital gene expression profiling, formalin-fixed paraffin-embedded tissue, overall survival, event-free survival, MYCN, tumor ploidy, prognostic risk classification
- MeSH terms
- Humans, Infant, Neuroblastoma, Prognosis, Cohort Studies, Cluster Analysis, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
