ATRX mutations and glioblastoma: Impaired DNA damage repair, alternative lengthening of telomeres, and genetic instability

OBJECTIVE5-aminolevulinic acid (5-ALA)–induced protoporphyrin IX (PpIX) fluorescence is an effective surgical adjunct for the intraoperative identification of tumor tissue during resection of high-grade gliomas. The use of 5-ALA-induced PpIX fluorescence in glioblastoma (GBM) has been shown to double the extent of gross-total resection and 6-month progression-free survival. The heterogeneity of 5-ALA-induced PpIX fluorescence observed during surgery presents a technical and diagnostic challenge when utilizing this tool intraoperatively. While some regions show bright fluorescence after 5-ALA administration, other regions do not, despite that both regions of the tumor may be histopathologically indistinguishable. The authors examined the biological basis of this heterogeneity using computational methods.METHODSThe authors collected both fluorescent and nonfluorescent GBM specimens from a total of 14 patients undergoing surgery and examined their gene expression profiles.RESULTSIn this study, the authors found that the gene expression patterns characterizing fluorescent and nonfluorescent GBM surgical specimens were profoundly different and were associated with distinct cellular functions and different biological pathways. Nonfluorescent tumor tissue tended to resemble the neural subtype of GBM; meanwhile, fluorescent tumor tissue did not exhibit a prominent pattern corresponding to known subtypes of GBM. Consistent with this observation, neural GBM samples from The Cancer Genome Atlas database exhibited a significantly lower fluorescence score than nonneural GBM samples as determined by a fluorescence gene signature developed by the authors.CONCLUSIONSThese results provide a greater understanding regarding the biological basis of differential fluorescence observed intraoperatively and can provide a basis to identify novel strategies to maximize the effectiveness of fluorescence agents.

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“…2). 6,17,23 These observations further reveal the distinctions between fluorescent and nonfluorescent GBM tissues.…”

Section: The Gene Expression Profiles Of Nonfluorescent Gbm Specimensmentioning

confidence: 59%

Characterizing the heterogeneity in 5-aminolevulinic acid–induced fluorescence in glioblastoma

Bonnin

Havrda

Lee

et al. 2020

Journal of Neurosurgery

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“…Methylation of the promoter of this gene is found in 35%-45% of HGG and is associated with a better response to chemotherapy by alkylating agent temozolomide (TMZ) and better overall survival [6]. About a third of paediatric GBM patients have mutations in TP53 and ATRX (Alpha thalassemia/mental retardation syndrome X-linked) genes [7]. In addition, mutations in the promoter of TERT, a gene that encodes the catalytic subunit of telomerase, are observed in a significant subset of GBM [8].…”

Section: Introductionmentioning

confidence: 99%

Using Light for Therapy of Glioblastoma Multiforme (GBM)

et al. 2020

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Glioblastoma multiforme (GBM) is the most malignant form of primary brain tumour with extremely poor prognosis. The current standard of care for newly diagnosed GBM includes maximal surgical resection followed by radiotherapy and adjuvant chemotherapy. The introduction of this protocol has improved overall survival, however recurrence is essentially inevitable. The key reason for that is that the surgical treatment fails to eradicate GBM cells completely, and adjacent parenchyma remains infiltrated by scattered GBM cells which become the source of recurrence. This stimulates interest to any supplementary methods which could help to destroy residual GBM cells and fight the infiltration. Photodynamic therapy (PDT) relies on photo-toxic effects induced by specific molecules (photosensitisers) upon absorption of photons from a light source. Such toxic effects are not specific to a particular molecular fingerprint of GBM, but rather depend on selective accumulation of the photosensitiser inside tumour cells or, perhaps their greater sensitivity to the effects, triggered by light. This gives hope that it might be possible to preferentially damage infiltrating GBM cells within the areas which cannot be surgically removed and further improve the chances of survival if an efficient photosensitiser and hardware for light delivery into the brain tissue are developed. So far, clinical trials with PDT were performed with one specific type of photosensitiser, protoporphyrin IX, which tends to accumulate in the cytoplasm of the GBM cells. In this review we discuss the idea that other types of molecules which build up in mitochondria could be explored as photosensitisers and used for PDT of these aggressive brain tumours.

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“…There is a correlation between ATRX mutations and Alternative Lengthening of Telomeres (ALT), a non-telomerase-dependent telomere lengthening mechanism [4, 5, 6, 7, 8]. ATRX loss in gliomas has been demonstrated to promote ALT.…”

Section: Introductionmentioning

confidence: 99%

“…ATRX mutation was found to be associated with increased mutation rate at the single-nucleotide variant level. ATRX deficiency has been shown to impair non-homologous end joining (NHEJ), which may explain increased cellular sensitivity to DNA-damaging agents that induce double-strand DNA breaks [4]. These results are in concordance with a recent report in which authors developed an in utero electroporation-based method to model diffuse intrinsic pontine glioma (DIPG) with p53 knock down alone or p53 + Atrx knock downs in combination, to study the molecular mechanisms of H3.3K27M mutation on these genetic backgrounds.…”

Section: Introductionmentioning

confidence: 99%

Mutant ATRX: uncovering a new therapeutic target for glioma

Haase

Garcia-Fabiani

Carney

et al. 2018

Expert Opinion on Therapeutic Targets

Self Cite

113

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Introduction ATRX is a chromatin remodeling protein whose main function is the deposition of the histone variant H3.3. ATRX mutations are widely distributed in glioma, and correlate with alternative lengthening of telomeres (ALT) development, but they also affect other cellular functions related to epigenetic regulation. Areas covered We discuss the main molecular characteristics of ATRX, from its various functions in normal development to the effects of its loss in ATRX syndrome patients and animal models. We focus on the salient consequences of ATRX mutations in cancer, from a clinical to a molecular point of view, focusing on both adult and pediatric glioma. Finally, we will discuss the therapeutic opportunities future research perspectives. Expert opinion ATRX is a major component of various essential cellular pathways, exceeding its functions as a histone chaperone (e.g., DNA replication and repair, chromatin higher-order structure regulation, gene transcriptional regulation, etc.). However, it is unclear how the loss of these functions in ATRX-null cancer cells affects cancer development and progression. We anticipate new treatments and clinical approaches will emerge for glioma and other cancer types as mechanistic and molecular studies on ATRX are only just beginning to reveal the many critical functions of this protein in cancer.

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ATRX mutations and glioblastoma: Impaired DNA damage repair, alternative lengthening of telomeres, and genetic instability

Cited by 44 publications

References 10 publications

Characterizing the heterogeneity in 5-aminolevulinic acid–induced fluorescence in glioblastoma

Characterizing the heterogeneity in 5-aminolevulinic acid–induced fluorescence in glioblastoma

Using Light for Therapy of Glioblastoma Multiforme (GBM)

Mutant ATRX: uncovering a new therapeutic target for glioma

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