An Integrated Genomic Analysis of Human Glioblastoma Multiforme

Abstract

Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs. †To whom correspondence should be addressed. E-mail: bertvog@gmail.com (B.V.); velculescu@jhmi.edu (V.E.V.); kinzlke@jhmi.edu (K.W.K.). * These authors contributed equally to this work. NIH Public Access Author ManuscriptScience. Author manuscript; available in PMC 2010 February 11. Published in final edited form as:Science. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMalignant gliomas are the most frequent and lethal cancers originating in the central nervous system. The most biologically aggressive subtype is glioblastoma multiforme (GBM) [World Health Organization (WHO) grade IV astrocytoma], a tumor associated with a dismal prognosis (1). The current standard of care for GBM patients-surgical resection followed by adjuvant radiation therapy and chemotherapy with the oral alkylating agent temozolomideproduces a median survival of only 15 months (2). Historically, GBMs have been categorized into two groups ("primary" and "secondary") on the basis of clinical presentation (3). Secondary GBMs are defined as cancers that have clinical, radiologic, or histopathologic evidence of malignant progression from a preexisting lower-grade tumor, whereas primary GBMs have no such history and present at diagnosis as advanced cancers (4). Clinical differences have been re ported between the two groups, with secondary GBMs occurring less frequently (~5% of GBMs) and predominantly in younger patients (median age ~45 years versus ~60 years for primary GBM) (5,6). The histopathologic findings of primary and secondary GBMs are indistinguishable, and the prognosis does not appear to be different after adjustment for age (5,6).Substantial research effort has focused on the identification of genetic alterations in GBMs that might help define subclasses of GBM patients with differing prognoses and/or response to specific therapies (7). Distinctions between the genetic lesions found in primary and secondary GBMs have been made, with TP53 mutations occurring more commonly in secondary GBMs and EGFR amplifications and ...

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

“…Yet, only few metabolic genes are presently known to be directly implicated in tumorigenesis. Those include mutations/loss of the genes encoding succinate dehydrogenase (SDH) complex subunits, which may cause paraganglioma (Frezza et al , 2011), the inactivation and loss of fumarate hydratase (FH), playing a casual role in hereditary leiomyomatosis and renal cell cancer (HLRCC) (Kiuru et al , 2002), and mutations in IDH1 and IDH2, which can lead to low‐grade gliomas and acute myeloid leukemia (AML) (Parsons et al , 2008; Dang et al , 2009; Mardis et al , 2009; Sciacovelli et al , 2016; Sykes et al , 2016). Overall, there is still much more to learn about the causal role of metabolic genes in cancer.…”

Long non‐coding RNAs in brain tumours: Focus on recent epigenetic findings in glioma

“…In GBM, genome‐wide sequencing has identified an enormous number of mutations in epigenetic regulatory genes, including histone deacetylase (HDAC) 2 and 9, histone demethylases and methyltransferases 84. Furthermore, globally altered expression levels of epigenetic modifiers have been linked to prognostic markers in glioma patients.…”

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

“…Interestingly, mutations only in IDH1 and IDH2 have thus far been linked to cancer. The presence of recurrent somatic point mutations in IDH1 was first identified in 12% of all adult glioblastoma tumors by high‐throughput DNA sequencing 51. Deep sequencing further revealed that mutated IDH1 and IDH2 occur in a high proportion (>70%) of low‐grade (grade II–III) astrocytomas and oligodendrogliomas and secondary glioblastoma 51, 52, 88, 89.…”

“…The presence of recurrent somatic point mutations in IDH1 was first identified in 12% of all adult glioblastoma tumors by high‐throughput DNA sequencing 51. Deep sequencing further revealed that mutated IDH1 and IDH2 occur in a high proportion (>70%) of low‐grade (grade II–III) astrocytomas and oligodendrogliomas and secondary glioblastoma 51, 52, 88, 89. Since these initial reports, mutations in IDH1 and IDH2 have also been found in other diverse cancers including 16–17% of patients with AML,53 20% of patients with angioimmunoblastic T‐cell lymphomas,90 and more rarely in cholangiocarcinomas,91 breast carcinomas,92 acute lymphoblastic leukemias,93 prostate cancer,93 osteosarcoma,94 and others 53, 91, 92, 93, 95, 96, 97.…”

“…It appears that the removal of the arginine, rather than the substitution of a specific residue, is the critical feature of this mutation, although the most frequent replacement observed is a histidine residue (R132H) 51, 52, 93, 98. Mutations in IDH2 in gliomas occur at a much lower frequency (0–6%) than IDH1 88 in the paralogous amino acid residue—R140—but also at R172.…”