New research suggests that the most common form of malignant brain cancer in adults, glioblastoma multiforme (GBM), is probably not a single disease but a set of diseases, each with a distinct underlying molecular pathology. The study, published by Cell Press in the January issue of the journal Cancer Cell, provides a solid framework for investigation of future targeted therapies that may improve the near uniformly fatal prognosis of this devastating cancer.
"Previous work has established that gene expression profiling can be used to identify distinct subgroups of GBM," says senior study author, Dr. D. Neil Hayes from the Department of Internal Medicine at the University of North Carolina at Chapel Hill. "However, the exact number and clinical significance of these was unclear." Dr. Hayes and colleagues expanded on previous GBM classification studies and used expression profiling techniques to comprehensively analyze hundreds of GBM patient samples. The group was able to reliably identify four distinct molecular subtypes of GBM tumors.
The researchers then went on to perform a unique integrative analyses across multiple platforms to look for defining characteristics associated with each subtype. Their findings were quite striking, implying that there are distinct types of GBM and that each one is associated with a specific pathology. "We discovered a bundle of events that unequivocally occur almost exclusively within a subtype. In other words, these are some of the critical events that are either causative of subtype identity or closely associated with subtype pathophysiology," explains Dr. Hayes.
The researchers also report that the nature of these events indicate that the underlying pathology of each subtype may involve distinct cells of origin at a specific stage of differentiation. This is finding has potential clinical significance as determining the cells of origin of GBM is critical for establishing effective treatment regimens. Clearly, given this new information, it makes sense that some drug classes would be expected to work for some tumor subtypes and not other. In support of this conclusion, Dr. Hayes's group found that response to aggressive chemotherapy and radiation differed by subtype.
Taken together, the findings represent an important step towards more rational therapies for GBM. "It appears that the simple classification into these four subtypes carries a rich set of associations for which there is no existing diagnostic test," says Dr. Hayes "This comprehensive genomic and genetic-based classification of GBM should lay the groundwork from an improved molecular understanding of GBM pathway signaling that could ultimately result in personalized therapies for groups of patients with GBM."
The researchers include Roel G.W. Verhaak, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, Dana-Farber Cancer Institute, Boston, MA; Katherine A. Hoadley, University of North Carolina at Chapel Hill, Chapel Hill, NC; Elizabeth Purdom, University of California, Berkeley, CA; Victoria Wang, University of California, Berkeley, CA; Yuan Qi, University of North Carolina at Chapel Hill, Chapel Hill, NC; Matthew D. Wilkerson, University of North Carolina at Chapel Hill, Chapel Hill, NC; C. Ryan Miller, University of North Carolina at Chapel Hill, Chapel Hill, NC; Li Ding, Washington University School of Medicine, St. Louis, MO; Todd Golub, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, Dana-Farber Cancer Institute, Boston, MA; Jill P. Mesirov, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA Gabriele Alexe, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA Michael Lawrence, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, Dana-Farber Cancer Institute, Boston, MA; Michael O'Kelly, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, Dana-Farber Cancer Institute, Boston, MA; Pablo Tamayo, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA Barbara A. Weir, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, Dana-Farber Cancer Institute, Boston, MA; Stacey Gabriel, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA; Wendy Winckler, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, Dana-Farber Cancer Institute, Boston, MA; Supriya Gupta, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA; Lakshmi Jakkula, Lawrence Berkeley National Laboratory, Berkeley, CA; Heidi S. Feiler, Lawrence Berkeley National Laboratory, Berkeley, CA; J. Graeme Hodgson, University of California, San Francisco, CA; C. David James, University of California, San Francisco, CA; Jann N. Sarkaria, Mayo Clinic, Rochester, MN; Cameron Brennan, Memorial Sloan-Kettering Cancer Center, New York, NY ; Ari Kahn, SRA International, Fairfax, VA; Paul T. Spellman, Lawrence Berkeley National Laboratory, Berkeley, CA; Richard K. Wilson, Washington University School of Medicine, St. Louis, MO; Terence P. Speed, University of California, Berkeley, CA, Walter and Eliza Hall Institute, Parkville, Victoria, Australia; Joe W. Gray, Lawrence Berkeley National Laboratory, Berkeley, CA; Matthew Meyerson, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, Dana-Farber Cancer Institute, Boston, MA; Gad Getz, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA; Charles M. Perou, University of North Carolina at Chapel Hill, Chapel Hill, NC, University of California, Berkeley, CA; D. Neil Hayes, University of North Carolina at Chapel Hill, Chapel Hill, NC; and The Cancer Genome Atlas Research Network.