Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma
Open accessAbstract
Purpose: To assess the feasibility of performing central molecular analyses of fresh medulloblastomas obtained from multiple institutions and using these data to identify prognostic markers for contemporaneously treated patients. Materials and Methods: Ninety-seven samples of medulloblastoma were collected. Tumor content in samples was judged by frozen section review. Tumor ERBB2 protein and MYCC, MYCN, and TRKC mRNA levels were measured blind to clinical details using Western blotting and real-time polymerase chain reaction, respectively. Histopathologic and clinical review of each case was also performed. All data were subjected to independent statistical analysis. Results: Sample acquisition and analysis times ranged from 3 to 6 days. Eighty-six samples contained sufficient tumor for analysis, including 38 classic, 30 nodular desmoplastic, and 18 large-cell anaplastic (LCA) medulloblastomas. Protein and mRNA were extracted from 81 and 49 tumors, respectively. ERBB2 was detected in 40% (n = 32 of 81) of tumors, most frequently in LCA disease (P = .005), and was independently associated with a poor prognosis (P = .031). A combination of clinical characteristics and ERBB2 expression provided a highly accurate means of discriminating disease risk. One hundred percent (n = 26) of children with clinical average-risk, ERBB2-negative disease were alive at 5 years, with a median follow-up of 5.6 years, compared with only 54% for children with average-risk, ERBB2-positive tumors (n = 13; P = .0001). TRKC, MYCC, and MYCN expression and histopathologic subtype were not associated with prognosis in this study. Conclusion: Central and rapid molecular analysis of frozen medulloblastomas collected from multiple institutions is feasible. ERBB2 expression and clinical risk factors together constitute a highly accurate disease risk stratification tool.
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.
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
Regression Models and Life-Tables
Cox, D. R. (1972) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1972.tb00899.x · Cited by 39,793 · see citing works
Nonparametric Estimation from Incomplete Observations
Kaplan, E. L., & Meier, P. (1958) · Journal of the American Statistical Association · doi:10.1080/01621459.1958.10501452 · Cited by 39,158 · see citing works
Regression Models and Life-Tables
Cox, D. R. (1992) · Springer Series in Statistics · doi:10.1007/978-1-4612-4380-9_37 · Cited by 26,297 · see citing works
Statistical Aspects of the Analysis of Data From Retrospective Studies of Disease
(1959) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/22.4.719 · Cited by 14,689 · see citing works
Untangling the ErbB signalling network
Yarden, Y., & Sliwkowski, M. X. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35052073 · Cited by 6,974 · see citing works
Asymptotically Efficient Rank Invariant Test Procedures
Peto, R., & Peto, J. (1972) · Journal of the Royal Statistical Society. Series A (General) · doi:10.2307/2344317 · Cited by 3,393 · see citing works
Neuroblastoma: biological insights into a clinical enigma
Brodeur, G. M. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1014 · Cited by 2,161 · see citing works
The WHO Classification of Tumors of the Nervous System
Kleihues, P., Louis, D. N., Scheithauer, B. W., RORKE, L. B., Reifenberger, G., Burger, P. C., & Cavenee, W. K. (2002) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/61.3.215 · Cited by 1,963 · see citing works
Muller, W., Sinn, E., Pattengale, P., Wallace, R., & Leder, P. (1988) · Cell · doi:10.1016/0092-8674(88)90184-5 · Cited by 1,246 · see citing works
Guy, C. T., Webster, M. A., Schaller, M. D., Parsons, T. J., Cardiff, R. D., & Muller, W. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.22.10578 · Cited by 1,193 · see citing works
c-MYC: more than just a matter of life and death
Pelengaris, S., Khan, M., & Evan, G. I. (2002) · Nature reviews. Cancer · doi:10.1038/nrc904 · Cited by 1,172 · see citing works
Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous systemPreprint
Bibel, M., & Barde, Y. (2000) · Genes & Development · doi:10.1101/gad.841400 · Cited by 1,054 · see citing works
erb B-2 Is a Potent Oncogene When Overexpressed in NIH/3T3 Cells
Fiore, P. P. D., Pierce, J. H., Kraus, M. H., Segatto, O., King, C. R., & Aaronson, S. A. (1987) · Science · doi:10.1126/science.2885917 · Cited by 1,011 · see citing works
Zeltzer, P. M., Boyett, J. M., Finlay, J. L., Albright, A. L., RORKE, L. B., Milstein, J. M., Allen, J. C., Stevens, K. R., Stanley, P., Li, H., et al. (1999) · Journal of Clinical Oncology · doi:10.1200/jco.1999.17.3.832 · Cited by 750 · see citing works
Packer, R. J., Goldwein, J. L., Nicholson, H. S., Vezina, L. G., Allen, J. C., Ris, M. D., Muraszko, K. M., RORKE, L. B., Wara, W. M., Cohen, B. H., et al. (1999) · Journal of Clinical Oncology · doi:10.1200/jco.1999.17.7.2127 · Cited by 616 · see citing works
Ris, M. D., Packer, R. J., Goldwein, J. L., Jones-Wallace, D., & Boyett, J. M. (2001) · Journal of Clinical Oncology · doi:10.1200/jco.2001.19.15.3470 · Cited by 529 · see citing works
Kortmann, R., Kühl, J., Timmermann, B., Mittler, U., Urban, C., Budach, V., Richter, E., Willich, N. A., Flentje, M., Berthold, F., et al. (2000) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/s0360-3016(99)00369-7 · Cited by 423 · see citing works
Palmer, S. L., Goloubeva, O. G., Reddick, W. E., Glass, J. O., Gajjar, A. J., Kun, L. E., Merchant, T. E., & Mulhern, R. K. (2001) · Journal of Clinical Oncology · doi:10.1200/jco.2001.19.8.2302 · Cited by 400 · see citing works
Self-citationTaylor, R. E., Bailey, C. C., Robinson, K., et al. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.05.116 · Cited by 354 · see citing works
Whole-brain irradiation and decline in intelligence: the influence of dose and age on IQ score.
Silber, J. H., Radcliffe, J., Peckham, V. C., Perilongo, G., Kishnani, P. S., Fridman, M., Goldwein, J. W., & Meadows, A. T. (1992) · Journal of Clinical Oncology · doi:10.1200/jco.1992.10.9.1390 · Cited by 341 · see citing works
Histopathologic grading of medulloblastomas
Eberhart, C. G., Kepner, J. L., Goldthwaite, P. T., Kun, L. E., Duffner, P. K., Friedman, H. S., Strother, D. R., & Burger, P. C. (2002) · Cancer · doi:10.1002/cncr.10189 · Cited by 314 · see citing works
Self-citationMulhern, R. K., Palmer, S. L., Reddick, W. E., Glass, J. O., Kun, L. E., Taylor, J. S., Langston, J., & Gajjar, A. J. (2001) · Journal of Clinical Oncology · doi:10.1200/jco.2001.19.2.472 · Cited by 304 · see citing works
Self-citationGrill, J., Renaux, V. K., Bulteau, C., et al. (1999) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/s0360-3016(99)00177-7 · Cited by 290 · see citing works
Bargmann, C. I., & Weinberg, R. A. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.15.5394 · Cited by 229 · see citing works
TrkC Expression Predicts Good Clinical Outcome in Primitive Neuroectodermal Brain Tumors
Grotzer, M. A., Janss, A. J., Fung, K., et al. (2000) · Journal of Clinical Oncology · doi:10.1200/jco.2000.18.5.1027 · Cited by 225 · see citing works
Walter, A. W., Mulhern, R. K., Gajjar, A. J., Heideman, R. L., Reardon, D. A., Sanford, R. A., Xiong, X., & Kun, L. E. (1999) · Journal of Clinical Oncology · doi:10.1200/jco.1999.17.12.3720 · Cited by 225 · see citing works
Self-citationClassifying the medulloblastoma: insights from morphology and molecular genetics
Ellison, D. W. (2002) · Neuropathology and Applied Neurobiology · doi:10.1046/j.1365-2990.2002.00419.x · Cited by 217 · see citing works
Transformation of NIH 3T3 Cells by HER3 or HER4 Receptors Requires the Presence of HER1 or HER2
Zhang, K., Sun, J., Liu, N., Wen, D., Chang, D., Thomason, A., & Yoshinaga, S. K. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.7.3884 · Cited by 207 · see citing works
“Large Cell/Anaplastic” Medulloblastomas: A Pediatric Oncology Group Study
Brown, H. G., Kepner, J. L., Perlman, E. J., Friedman, H. S., Strother, D. R., Duffner, P. K., Kun, L. E., Goldthwaite, P. T., & Burger, P. C. (2000) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/59.10.857 · Cited by 198 · see citing works
Self-citationGilbertson, R. J., Bentley, L., Hernán, R., Junttila, T. T., Frank, A., Haapasalo, H. K., Connelly, M., Wetmore, C., Curran, T., Elenius, K., et al. (2002) · PubMed · doi:10.25405/ncl.34665585 · Cited by 184 · see citing works
Self-citationGrotzer, M. A., Hogarty, M. D., Janss, A. J., et al. (2001) · PubMed · Cited by 171 · see citing works
ERBB2 up-regulates S100A4 and several other prometastatic genes in medulloblastoma.
Hernán, R., Fasheh, R., Calabrese, C. R., Frank, A. J., Maclean, K. H., Allard, D., Barraclough, R., & Gilbertson, R. J. (2003) · PubMed · Cited by 170 · see citing works
Self-citationClinical and molecular stratification of disease risk in medulloblastoma
Gilbertson, R. J., Wickramasinghe, C. D., Hernán, R., et al. (2001) · British Journal of Cancer · doi:10.1054/bjoc.2001.1987 · Cited by 169 · see citing works
Self-citationStrother, D. R., Ashley, D. M., Kellie, S. J., et al. (2001) · Journal of Clinical Oncology · doi:10.1200/jco.2001.19.10.2696 · Cited by 160 · see citing works
Self-citationLong-Term Survivors of Childhood Cancer: The Late Effects of Therapy
Schwartz, C. L. (1999) · The Oncologist · doi:10.1634/theoncologist.4-1-45 · Cited by 157 · see citing works
Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas.
Kim, J. Y. H., Sutton, M. E., Lu, D. J., Cho, T. A., Goumnerova, L. C., Goritchenko, L., Kaufman, J. R., Lam, K., Billett, A. L., Tarbell, N. J., et al. (1999) · PubMed · Cited by 139 · see citing works
Eberhart, C. G., Kratz, J. E., Schuster, A. E., et al. (2002) · Brain Pathology · doi:10.1111/j.1750-3639.2002.tb00420.x · Cited by 128 · see citing works
What's new in neuro-oncology? Recent advances in medulloblastoma
Ellison, D. W., Clifford, S. C., Gajjar, A. J., et al. (2003) · European Journal of Paediatric Neurology · doi:10.1016/s1090-3798(03)00014-x · Cited by 104 · see citing works
Self-citationLong-term neuro-endocrine sequelae after treatment for childhood medulloblastoma
Heikens, J., Michiels, E. M. C., Behrendt, H., Endert, E., Bakker, P. J. M., & Fliers, E. (1998) · European Journal of Cancer · doi:10.1016/s0959-8049(98)00212-3 · Cited by 97 · see citing works
Palmer, S. L., Reddick, W. E., Glass, J. O., et al. (2002) · PubMed · Cited by 80 · see citing works
Transformation of NIH 3T3 Cells by Overexpression of the Normal Coding Sequence of the Rat neu Gene
Marco, E. D., Pierce, J. H., Knicley, C. L., et al. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.6.3247-3252.1990 · Cited by 74 · see citing works
Childhood medulloblastoma: progress and future challenges
Packer, R. J. (1999) · Brain and Development · doi:10.1016/s0387-7604(98)00085-0 · Cited by 65 · see citing works
Gilbertson, R., Hernan, R., Pietsch, T., Pinto, L., Scotting, P., Allibone, R., Ellison, D., Perry, R., Pearson, A., & Lunec, J. (2001) · Genes Chromosomes and Cancer · doi:10.1002/gcc.1146 · Cited by 60 · see citing works
Perry, A. (2002) · Advances in Anatomic Pathology · doi:10.1097/00125480-200211000-00003 · Cited by 52 · see citing works
Paediatric embryonic brain tumours
Gilbertson, R. J. (2002) · European Journal of Cancer · doi:10.1016/s0959-8049(01)00315-x · Cited by 52 · see citing works
Self-citationTransformation of NIH 3T3 cells by overexpression of the normal coding sequence of the rat neu gene.
Marco, E. D., Pierce, J., Knicley, C. L., et al. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.6.3247 · Cited by 52 · see citing works
Recent advances in the treatment and understanding of childhood acute lymphoblastic leukaemia
Rubnitz, J. E., & Pui, C. (2003) · Cancer Treatment Reviews · doi:10.1016/s0305-7372(02)00106-8 · Cited by 50 · see citing works
Manne, U., Weiss, H. L., & Grizzle, W. E. (2000) · International Journal of Cancer · doi:10.1002/1097-0215(20000920)89:5 · Cited by 46 · see citing works
Prognostic factors in medulloblastoma
Gilbertson, R. J. (1992) · The Lancet · doi:10.1016/0140-6736(92)91797-c · Cited by 18 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Gajjar, A., Robinson, G. W., Smith, K. S., Lin, T., Merchant, T. E., Chintagumpala, M., Mahajan, A., Su, J., Bouffet, E., Bartels, U., et al. (2021) · Journal of Clinical Oncology · doi:10.1200/jco.20.01372 · Cited by 241 · see citing works
Self-citationGangwani, K., Lu, C., Dhanda, S. K., Sioson, E., Zaldívar Peraza, A., Matt, G. Y., Paul, R., Wang, J., Reilly, C., Acić, A., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-24-4976 · Cited by 1 · see citing works
“In G4 tumors, poor prognosis has been associated with early age at diagnosis (infancy) and metastatic disease (12, 13).”
- Authors
- Gajjar, A., Hernan, R., Kocak, M., Fuller, C., Lee, Y., McKinnon, P. J., Wallace, D., Lau, C., Chintagumpala, M., Ashley, D. M., Kellie, S. J., Kun, L., & Gilbertson, R. J.
- Affiliations
- The University of Sydney (AU)
- From the St Jude Children's Research Hospital, Memphis TN; Texas Children's Hospital, Houston TX; Royal Children's Hospital, Melbourne; and The Children's Hospital at Westmead and University of Sydney, Sydney, Australia
- Corresponding author
- Gilbertson, Richard J.
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2004-03-15
- Volume
- 22
- Issue
- 6
- Pages
- 984-993
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2170501066
- Cited by
- 279
- References
- 50
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 7 · 2022: 2 · 2021: 9 · 2020: 7 · 2019: 2 · 2018: 6 · 2017: 8 · 2016: 9 · 2015: 7 · 2014: 4 · 2013: 12 · 2012: 20
- FWCI
- 13.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- American Lebanese Syrian Associated Charities (CA 21765)
- National Cancer Institute (CA21765, P30CA021765)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Keywords
- medulloblastoma, ERBB2, prognostic factors, disease risk stratification, MYCN, TrkC, pediatric brain tumors
- MeSH terms
- Adolescent, Australia, Cerebellar Neoplasms, Child, Child, Preschool, Feasibility Studies, Female, Humans, Infant, Male, Medulloblastoma, Pathology, Clinical, Predictive Value of Tests, Prognosis, Risk Factors, Specimen Handling, Biomarkers, Tumor, United States, Proportional Hazards Models, Survival Analysis, Risk Assessment, Disease-Free Survival, Erb-b2 Receptor Tyrosine Kinases
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
