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Prospective, high-throughput molecular profiling of human gliomas

  • Clinical Study - Patient Study
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Abstract

Gliomas consist of multiple histologic and molecular subtypes with different clinical phenotypes and responsiveness to treatment. However, enrollment criteria for clinical trials still largely do not take into account these underlying molecular differences. We have incorporated a high-throughput tumor genotyping program based on the ABI SNaPshot platform as well as other molecular diagnostic tests into the standard evaluation of glioma patients in order to assess whether prospective molecular profiling would allow rational patient selection onto clinical trials. From 218 gliomas we prospectively collected SNaPshot genotyping data on 68 mutated loci from 15 key cancer genes along with data from clinical assays for gene amplification (EGFR, PDGFRA, MET), 1p/19q co-deletion and MGMT promoter methylation. SNaPshot mutations and focal gene amplifications were detected in 38.5 and 47.1 % of glioblastomas, respectively. Genetic alterations in EGFR, IDH1 and PIK3CA closely matched frequencies reported in recent studies. In addition, we identified events that are rare in gliomas although are known driver mutations in other cancer types, such as mutations of AKT1, BRAF and KRAS. Patients with genetic alterations that activate signaling pathways were enrolled onto genetically selective clinical trials for malignant glioma as well as for other solid cancers. High-throughput molecular profiling incorporated into the routine clinical evaluation of glioma patients may enable the rational selection of patients for targeted therapy clinical trials and thereby improve the likelihood that such trials succeed.

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Acknowledgments

Preliminary data of this manuscript was presented at the 2011 American Association of Neurology Annual Meeting in Honolulu, Hawaii. Andrew S. Chi is supported by a Joan Ambriz American Brain Tumor Association Basic Research Fellowship and an Early Career research award from the Ben and Catherine Ivy Foundation. Ethical Standards: All results were obtained from the medical record of patients and collected in an IRB-approved patient database. Molecular testing was performed as part of routine medical care in CLIA-certified clinical laboratories. All molecular tests comply with the current laws of the USA.

Conflicts of interest

The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Yawkey 9E, 55 Fruit Street, Boston, MA, 02114, USA

    Andrew S. Chi, Tracy T. Batchelor & Daphne L. Wang

  2. Translational Research Laboratory, Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Dora Dias-Santagata, Darrell Borger, Leif Ellisen & A. John Iafrate

  3. Department of Pathology, Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Dora Dias-Santagata, David N. Louis & A. John Iafrate

  4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Charles D. Stiles

  5. Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA

    William T. Curry

  6. Center for Neuro-Oncology, Dana-Farber/Brigham and Women’s Cancer Center and Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA

    Patrick Y. Wen

  7. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute and Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Keith L. Ligon

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  1. Andrew S. Chi
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Correspondence to Andrew S. Chi.

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Chi, A.S., Batchelor, T.T., Dias-Santagata, D. et al. Prospective, high-throughput molecular profiling of human gliomas. J Neurooncol 110, 89–98 (2012). https://doi.org/10.1007/s11060-012-0938-9

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  • DOI: https://doi.org/10.1007/s11060-012-0938-9

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