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Marked Genomic Differences Characterize Primary and Secondary Glioblastoma Subtypes and Identify Two Distinct Molecular and Clinical Secondary Glioblastoma Entities

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{at}dfci.harvard.edu.

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. (Cancer Res 2006; 66(23): 11502-13)

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