Zorbey Turkalp1, Jason Karamchandani2, Sunit Das3. 1. Division of Neurosurgery, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada2Faculty of Medicine, University of St Andrews, St Andrews, Scotland. 2. Department of Laboratory Medicine and Pathobiology, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada4Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada. 3. Division of Neurosurgery, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada3Department of Laboratory Medicine and Pathobiology, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada4Arthur and Sonia Labatt Brain Tumou.
Abstract
IMPORTANCE: Over the past 4 years, our understanding of gliomagenesis and the practice of neuro-oncology have been radically changed by the discovery of mutations involving the isocitrate dehydrogenase (IDH) enzymes. IDH mutation has been found to be an inciting event in gliomagenesis and to have a profound effect on the molecular and genetic route of oncogenic progression and on clinical outcome. OBJECTIVES: To review the role of IDH enzymes in normal physiology and describe aberrations in the IDH pathway that are associated with gliomagenesis, to review recent work examining the effect of IDH-targeted therapy in cancers harboring IDH mutation, and to determine how this work has expanded our understanding of the role of IDH in the development and progression of glioma. EVIDENCE REVIEW: A systematic review of the literature dating from 2008, when IDH mutation was discovered to be clinically significant in glioma, to 2013 was performed using the PubMed database. The following search terms were used: IDH, IDH1, IDH2, and isocitrate dehydrogenase, in conjunction with glioma or leukemia. The search was limited to articles published in English. Further hand searching was performed using a review of the pertinent references from the identified publications. All identified original articles were investigated for content and critiqued by Z.T. and S.D. FINDINGS: IDH mutation is an early event in gliomagenesis and has significant implications for glioma progression and tumor behavior. Early evidence suggests that IDH may be a therapeutic target in IDH-mutant gliomas. CONCLUSIONS AND RELEVANCE: IDH mutation is a central and defining event in the development and progression of glioma and may be a key target for future therapies for these types of neoplasms.
IMPORTANCE: Over the past 4 years, our understanding of gliomagenesis and the practice of neuro-oncology have been radically changed by the discovery of mutations involving the isocitrate dehydrogenase (IDH) enzymes. IDH mutation has been found to be an inciting event in gliomagenesis and to have a profound effect on the molecular and genetic route of oncogenic progression and on clinical outcome. OBJECTIVES: To review the role of IDH enzymes in normal physiology and describe aberrations in the IDH pathway that are associated with gliomagenesis, to review recent work examining the effect of IDH-targeted therapy in cancers harboring IDH mutation, and to determine how this work has expanded our understanding of the role of IDH in the development and progression of glioma. EVIDENCE REVIEW: A systematic review of the literature dating from 2008, when IDH mutation was discovered to be clinically significant in glioma, to 2013 was performed using the PubMed database. The following search terms were used: IDH, IDH1, IDH2, and isocitrate dehydrogenase, in conjunction with glioma or leukemia. The search was limited to articles published in English. Further hand searching was performed using a review of the pertinent references from the identified publications. All identified original articles were investigated for content and critiqued by Z.T. and S.D. FINDINGS:IDH mutation is an early event in gliomagenesis and has significant implications for glioma progression and tumor behavior. Early evidence suggests that IDH may be a therapeutic target in IDH-mutant gliomas. CONCLUSIONS AND RELEVANCE: IDH mutation is a central and defining event in the development and progression of glioma and may be a key target for future therapies for these types of neoplasms.
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