TY - JOUR
T1 - Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples
AU - Northcott, Paul A.
AU - Shih, David J.H.
AU - Remke, Marc
AU - Cho, Yoon Jae
AU - Kool, Marcel
AU - Hawkins, Cynthia
AU - Eberhart, Charles G.
AU - Dubuc, Adrian
AU - Guettouche, Toumy
AU - Cardentey, Yoslayma
AU - Bouffet, Eric
AU - Pomeroy, Scott L.
AU - Marra, Marco
AU - Malkin, David
AU - Rutka, James T.
AU - Korshunov, Andrey
AU - Pfister, Stefan
AU - Taylor, Michael D.
N1 - Funding Information:
Acknowledgments M.D.T. is supported by a clinician-scientist award from the Canadian Institutes of Health Research. P.A.N. is supported by a Restracomp fellowship at the Hospital for Sick Children. Grant support is acknowledged from The Pediatric Brain Tumor Foundation, Genome Canada, Genome BC, Terry Fox Research Institute, Ontario Institute for Cancer Research, Pediatric Oncology Group Ontario, Funds from ‘The Family of Kathleen Lorette’ and the Clark H. Smith Brain Tumor Centre, Montreal Children’s Hospital Foundation, Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumor Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, B.R.A.I.N. Child. C.G.E is supported by an NIH R01 operating grant (NS055089). We thank Susan Archer for assistance with technical writing.
PY - 2012/4
Y1 - 2012/4
N2 - The diagnosis of medulloblastoma likely encompasses several distinct entities, with recent evidence for the existence of at least four unique molecular subgroups that exhibit distinct genetic, transcriptional, demographic, and clinical features. Assignment of molecular subgroup through routine profiling of high-quality RNA on expression microarrays is likely impractical in the clinical setting. The planning and execution of medulloblastoma clinical trials that stratify by subgroup, or which are targeted to a specific subgroup requires technologies that can be economically, rapidly, reliably, and reproducibly applied to formalin-fixed paraffin embedded (FFPE) specimens. In the current study, we have developed an assay that accurately measures the expression level of 22 medulloblastoma subgroup-specific signature genes (CodeSet) using nanoString nCounter Technology. Comparison of the nanoString assay with Affymetrix expression array data on a training series of 101 medulloblastomas of known subgroup demonstrated a high concordance (Pearson correlation r = 0.86). The assay was validated on a second set of 130 non-overlapping medulloblastomas of known subgroup, correctly assigning 98% (127/130) of tumors to the appropriate subgroup. Reproducibility was demonstrated by repeating the assay in three independent laboratories in Canada, the United States, and Switzerland. Finally, the nanoString assay could confidently predict subgroup in 88% of recent FFPE cases, of which 100% had accurate subgroup assignment. We present an assay based on nanoString technology that is capable of rapidly, reliably, and reproducibly assigning clinical FFPE medulloblastoma samples to their molecular subgroup, and which is highly suited for future medulloblastoma clinical trials.
AB - The diagnosis of medulloblastoma likely encompasses several distinct entities, with recent evidence for the existence of at least four unique molecular subgroups that exhibit distinct genetic, transcriptional, demographic, and clinical features. Assignment of molecular subgroup through routine profiling of high-quality RNA on expression microarrays is likely impractical in the clinical setting. The planning and execution of medulloblastoma clinical trials that stratify by subgroup, or which are targeted to a specific subgroup requires technologies that can be economically, rapidly, reliably, and reproducibly applied to formalin-fixed paraffin embedded (FFPE) specimens. In the current study, we have developed an assay that accurately measures the expression level of 22 medulloblastoma subgroup-specific signature genes (CodeSet) using nanoString nCounter Technology. Comparison of the nanoString assay with Affymetrix expression array data on a training series of 101 medulloblastomas of known subgroup demonstrated a high concordance (Pearson correlation r = 0.86). The assay was validated on a second set of 130 non-overlapping medulloblastomas of known subgroup, correctly assigning 98% (127/130) of tumors to the appropriate subgroup. Reproducibility was demonstrated by repeating the assay in three independent laboratories in Canada, the United States, and Switzerland. Finally, the nanoString assay could confidently predict subgroup in 88% of recent FFPE cases, of which 100% had accurate subgroup assignment. We present an assay based on nanoString technology that is capable of rapidly, reliably, and reproducibly assigning clinical FFPE medulloblastoma samples to their molecular subgroup, and which is highly suited for future medulloblastoma clinical trials.
KW - Clinical trials
KW - Medulloblastoma
KW - Molecular classification
KW - NanoString
UR - http://www.scopus.com/inward/record.url?scp=84862680481&partnerID=8YFLogxK
U2 - 10.1007/s00401-011-0899-7
DO - 10.1007/s00401-011-0899-7
M3 - Article
C2 - 22057785
AN - SCOPUS:84862680481
SN - 0001-6322
VL - 123
SP - 615
EP - 626
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 4
ER -