Distinct genetic alterations in pediatric glioblastomas

Byeon, Sun-Ju; Myung, Jae Kyung; Kim, Se Hoon; Kim, Seung Ki; Park, Shin Young

doi:10.1007/s00381-012-1773-1

Cited by 12 publications

(6 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While sequencing is considered the standard for detection of mutations, the sensitivity of this method is approximately 20% of mutant sequences in a wild-type background. 44 Brain tumor biopsy specimens universally contain contaminating nontumor tissues that add noise in Sanger sequencing. Immunohistochemistry is currently the preferred method for detection of IDH mutations in glioma.…”

Section: Methods For Detection Of Idh Mutationsmentioning

confidence: 99%

IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma

et al. 2013

View full text Add to dashboard Cite

Isocitrate dehydrogenase (IDH) enzymes have recently become a focal point for research aimed at understanding the biology of glioma. IDH1 and IDH2 are mutated in 50%-80% of astrocytomas, oligodendrogliomas, oligoastrocytomas, and secondary glioblastomas but are seldom mutated in primary glioblastomas. Gliomas with IDH1/2 mutations always harbor other molecular aberrations, such as TP53 mutation or 1p/19q loss. IDH1 and IDH2 mutations may serve as prognostic factors because patients with an IDH-mutated glioma survive significantly longer than those with an IDH-wild-type tumor. However, the molecular pathogenic role of IDH1/2 mutations in the development of gliomas is unclear. The production of 2-hydroxyglutarate and enhanced NADP+ levels in tumor cells with mutant IDH1/2 suggest mechanisms through which these mutations contribute to tumorigenesis. Elucidating the pathogenesis of IDH mutations will improve understanding of the molecular mechanisms of gliomagenesis and may lead to development of a new molecular classification system and novel therapies.

show abstract

Section: Methods For Detection Of Idh Mutationsmentioning

confidence: 99%

IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Overall, 80%-90% of adult grade II/III gliomas and secondary GBMs harbor mutations at either Arg132 of IDH1 or Arg172 of IDH2 (Table 1; Chang et al 2011). Conversely, <10% of primary GBMs and pediatric GBMs harbor IDH mutations, and no IDH mutations have been identified to date in brain tumors of nonglial subtypes (Balss et al 2008;Yan et al 2009;Capper et al 2010;Byeon et al 2012).…”

Section: Idh Mutations In Human Cancermentioning

confidence: 99%

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

2013

View full text Add to dashboard Cite

Mutations in metabolic enzymes, including isocitrate dehydrogenase 1 (IDH1) and IDH2, in cancer strongly implicate altered metabolism in tumorigenesis. IDH1 and IDH2 catalyze the interconversion of isocitrate and 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate and an essential cofactor for many enzymes, including JmjC domain-containing histone demethylases, TET 5-methylcytosine hydroxylases, and EglN prolyl-4-hydroxylases. Cancer-associated IDH mutations alter the enzymes such that they reduce 2OG to the structurally similarHere we review what is known about the molecular mechanisms of transformation by mutant IDH and discuss their implications for the development of targeted therapies to treat IDH mutant malignancies.Cellular metabolism has been hypothesized to play a central role in cancer since the observation made almost a century ago by Otto Warburg (Warburg 1956) that cancer cells preferentially generate energy by metabolizing glucose to lactate. Even in the presence of oxygen, cancer cells switch from generating ATP by the highly energy-efficient process of oxidative phosphorylation to the much less efficient process of glycolysis (Vander Heiden et al. 2009;Dang 2012). Why this switch occurs has long been a mystery, although the observation that normal cells use ''aerobic glycolysis'' during periods of increased proliferation supports the hypothesis that this metabolic switch is an important feature of rapidly dividing cells (Locasale and Cantley 2011;Lunt and Vander Heiden 2011). Recent work suggests that aerobic glycolysis facilitates cellular transformation by producing the high levels of glycolytic intermediates that proliferating cells need for the biosynthesis of lipids, amino acids, and nucleic acids. Moreover, metabolic reprogramming appears to be sufficient to mediate tumorigenesis in some systems (Lyssiotis and Cantley 2012;Sebastian et al. 2012). Nevertheless, whether altered cellular metabolism is a cause of cancer or merely an adaptive response of cancer cells in the face of accelerated cell proliferation is still a topic of some debate.The recent identification of cancer-associated mutations in three metabolic enzymes suggests that altered cellular metabolism can indeed be a cause of some cancers (Pollard et al. 2003;King et al. 2006;Raimundo et al. 2011). Two of these enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are bone fide tumor suppressors, and loss-of-function mutations in FH and SDH have been identified in various cancers, including renal cell carcinomas and paragangliomas. The third mutated enzyme, isocitrate dehydrogenase (IDH), is a more complicated case. Mutations in two isoforms of IDH, IDH1 and IDH2, are common in a diverse array of cancers, including gliomas and acute myelogenous leukemia (AML) (Dang et al. 2010). The mutant enzymes are not catalytically inactive. Rather, the cancer-associated mutations alter the catalytic activity of the enzymes such that they produce high levels of a metabolite, (R)-2-hydroxyglutarate [(R)-2HG], which is normally ...

show abstract

“…Whether rare IDH-mut pediatric diffuse gliomas represent an early occurrence of their adult counterparts has not yet been established. 61,66…”

Section: Idh-mut Is Uncommon In Pediatric Diffuse Gliomamentioning

confidence: 99%

Impending Impact of Molecular Pathology on Classifying Adult Diffuse Gliomas

Macaulay

2015

Cancer Control

View full text Add to dashboard Cite

The current practice of designating IDH-mut WHO grade 4 astrocytoma as secondary GBM will likely be discouraged, and primary or de novo GBM, which is always IDH-wt, may lose this qualification. Histologically, low- or intermediate-grade IDH-wt gliomas with molecular changes characteristic of GBM might justify the designation of GBM WHO grade 3. Mixed oligoastrocytoma is losing popularity as a diagnostic term because most cases will fall into either the FA or OD category. Distinguishing IDH-mut from IDH-wt tumors in clinical trials is likely to clarify sensitivity rates or tumor resistance among subgroups, thus suggesting opportunities for targeted therapy.

show abstract

Distinct genetic alterations in pediatric glioblastomas

Cited by 12 publications

References 24 publications

IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma

IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

Impending Impact of Molecular Pathology on Classifying Adult Diffuse Gliomas

Contact Info

Product

Resources

About