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Clinical,
Histopathologic, and Molecular Markers of Prognosis: Toward a New Disease Risk
Stratification System for Medulloblastoma
Amar Gajjar, Roberto Hernan, Mehmet Kocak, Christine
Fuller, Youngsoo Lee, Peter J. McKinnon, Dana
Wallace, Ching Lau, Murali Chintagumpala, David
M. Ashley, Stewart J. Kellie, Larry Kun, Richard
J. Gilbertson
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.
Address reprint requests to Richard J. Gilbertson, MD, PhD, Department of
Developmental Neurobiology, St Jude Children's Research Hospital, 332 N
Lauderdale St, Memphis, TN 38105; e-mail: richard.gilbertson@stjude.org
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.
Supported
by Center of Research Excellence support grant no. CA 21765, American
Lebanese Syrian Associated Charities, and V Foundation for Cancer
Research, Cary, NC.
©
2004 American Society of Clinical Oncology
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