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Etiology and Pathogenesis
> Tumor
Biology | Overall Management > Astrocytic
Tumors
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Cancer Research 66, 11502-11513, December 1, 2006. Published Online First
November 17, 2006;
doi: 10.1158/0008-5472.CAN-06-2072
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Abstract |
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Marked Genomic Differences
Characterize Primary and Secondary Glioblastoma Subtypes and Identify
Two Distinct Molecular and Clinical Secondary Glioblastoma Entities
Elizabeth A. Maher1,4,
Cameron Brennan10,
Patrick Y. Wen1,4,
Laura Durso1, Keith
L. Ligon5, Aaron
Richardson1, Deepak
Khatry2, Bin
Feng2, Raktim
Sinha2, David N.
Louis11, John
Quackenbush3,7, Peter
McL. Black8, Lynda
Chin2,4,6 and Ronald
A. DePinho2,4,9
1 Center for Neuro-Oncology,
2 Center for Applied Cancer Science, Belfer Institute for
Innovative Cancer Science, 3 Departments of Biostatistics
and Computational Biology and Cancer Biology, Dana-Farber Cancer
Institute; 4 Department of Medical Oncology, Dana-Farber
Cancer Institute and Harvard Medical School; Departments of 5
Pathology and 6 Dermatology, Brigham and Women's Hospital
and Harvard Medical School; 7 Department of Biostatistics,
Harvard School of Public Health; 8 Department of
Neurosurgery, Brigham and Women's Hospital; 9 Department of
Medicine and Genetics, Harvard Medical School, Boston, Massachusetts; 10
Neurosurgery Service, Memorial Sloan-Kettering Cancer Center, Weill-Cornell
Medical College, New York, New York; and 11 Department of
Pathology, Molecular Pathology Unit, CNY7, Massachusetts General
Hospital and Harvard Medical School, Charlestown, Massachusetts --
Requests for reprints: Ronald A. DePinho, Department of Medical
Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA
02115. Phone: 617-632-6085; Fax: 617-632-6069; E-mail: ron_depinho@dfci.harvard.edu.
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Glioblastoma is classified into two
subtypes on the basis of clinical history: "primary
glioblastoma" arising de novo without detectable
antecedent disease and "secondary glioblastoma" evolving
from a low-grade astrocytoma.
Despite their distinctive clinical courses,
they arrive at an indistinguishable clinical and pathologic end
point highlighted by widespread invasion and resistance to
therapy and, as such, are managed clinically as if they are one
disease entity.
Because the life history of a cancer cell
is often reflected in the pattern of genomic alterations, we
sought to determine whether primary and secondary glioblastomas
evolve through similar or different molecular pathogenetic
routes.
Clinically annotated primary and secondary
glioblastoma samples were subjected to high-resolution copy
number analysis using oligonucleotide-based array
comparative genomic hybridization.
Unsupervised classification using genomic
nonnegative matrix factorization methods identified three
distinct genomic subclasses.
Whereas one corresponded to clinically
defined primary glioblastomas, the remaining two stratified
secondary glioblastoma into two genetically distinct
cohorts.
Thus, this global genomic analysis showed
wide-scale differences between primary and secondary glioblastomas
that were previously unappreciated, and has shown for the
first time that secondary glioblastoma is heterogeneous in
its molecular pathogenesis.
Consistent with these findings, analysis
of regional recurrent copy number alterations revealed many
more events unique to these subclasses than shared.
The pathobiological
significance of these shared and subtype-specific copy
number alterations is reinforced by their frequent occurrence, resident
genes with clear links to cancer, recurrence in diverse cancer
types, and apparent association with clinical outcome.
We conclude that glioblastoma is composed
of at least three distinct molecular subtypes, including
novel subgroups of secondary glioblastoma, which may
benefit from different therapeutic strategies.
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© 2006 American Association for Cancer Research
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