Mutant ATRX: uncovering a new therapeutic target for glioma

Haase, Santiago; Garcia-Fabiani, María Belén; Carney, Stephen V.; Altshuler, David; Núñez, Felipe J.; Mendez, Flor; Nuñez, Fernando M.; Löwenstein, Pedro R.; Castro, Maria G.

doi:10.1080/14728222.2018.1487953

Cited by 121 publications

(105 citation statements)

References 132 publications

(165 reference statements)

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“…As reported, gliomas with different genotypes have different MRI appearances (43)(44)(45)(46). In our study we focused on 11 extracted radiomics features.…”

Section: Discussionmentioning

confidence: 95%

Radiomics Features Predict CIC Mutation Status in Lower Grade Glioma

et al. 2020

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MRI in combination with genomic markers are critical in the management of gliomas. Radiomics and radiogenomics analysis facilitate the quantitative assessment of tumor properties which can be used to model both molecular subtype and predict disease progression. In this work, we report on the Drosophila gene capicua (CIC) mutation biomarker effects alongside radiomics features on the predictive ability of CIC mutation status in lower-grade gliomas (LGG). Genomic data of lower grade glioma (LGG) patients from The Cancer Genome Atlas (TCGA) (n = 509) and corresponding MR images from TCIA (n = 120) were utilized. Following tumor segmentation, radiomics features were extracted from T1, T2, T2 Flair, and T1 contrast enhanced (CE) images. Lasso feature reduction was used to obtain the most important MR image features and then logistic regression used to predict CIC mutation status. In our study, CIC mutation rarely occurred in Astrocytoma but has a high probability of occurrence in Oligodendroglioma. The presence of CIC mutation was found to be associated with better survival of glioma patients (p < 1e−4, HR: 0.2445), even with co-occurrence of IDH mutation and 1p/19q co-deletion (p = 0.0362, HR: 0.3674). An eleven-feature model achieved glioma prediction accuracy of 94.2% (95% CI, 94.03-94.38%), a six-feature model achieved oligodendroglioma prediction accuracy of 92.3% (95% CI, 91.70-92.92%). MR imaging and its derived image of gliomas with CIC mutation appears more complex and non-uniform but are associated with lower malignancy. Our study identified CIC as a potential prognostic factor in glioma which has close associations with survival. MRI radiomic features could predict CIC mutation, and reflect less malignant manifestations such as milder necrosis and larger tumor volume in MRI and its derived images that could help clinical judgment.

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“…As reported, gliomas with different genotypes have different MRI appearances (43)(44)(45)(46). In our study we focused on 11 extracted radiomics features.…”

Section: Discussionmentioning

confidence: 95%

Radiomics Features Predict CIC Mutation Status in Lower Grade Glioma

et al. 2020

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“…Abnormal genomic events that alter telomere elongation are common in gliomas. Particularly, mutually exclusive mutations affect the TERT or the ATRX chromatin remodeler (ATRX) genes, a critical regulator of telomere homeostasis by chromatin remodeling [9].…”

Section: Discussionmentioning

confidence: 99%

New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma

Pierini

Nardelli

Fernandez

et al. 2020

acta neuropathol commun

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The catalytic activity of human Telomerase Reverse Transcriptase (TERT) compensates for the loss of telomere length, eroded during each cell cycle, to ensure a correct division of stem and germinal cells. In human tumors, ectopic TERT reactivation, most frequently due to hotspot mutations in the promoter region (TERTp), i.e. c.1-124 C > T, c.1-146 C > T, confers a proliferative advantage to neoplastic cells. In gliomas, TERTp mutations (TERTp mut) mainly occur in oligodendroglioma and glioblastoma. We screened, for TERTp hotspot mutations, 301 adult patients with gliomas and identified heterozygous mutations in 239 cases: 94% of oligodendroglioma, 85% of glioblastoma, and 37.5% of diffuse/anaplastic astrocytoma. Besides the recurrent c.1-124 C > T and c.1-146 C > T, two cases of glioblastoma harbored novel somatic TERTp variants, which consisted of a tandem duplications of 22 nucleotides, i.e. a TERTp c.1-100_1-79dup and TERTp c.1-110_1-89, both located downstream c.1-124 C > T and c.1-146 C > T. In silico analysis predicted the formation of 119 and 108 new transcription factor's recognition sites for TERTp c.1-100_1-79dup and TERTp c.1-110_1-89, respectively. TERTp duplications (TERTp dup) mainly affected the binding capacity of two transcription factors' families, i.e. the members of the E-twenty-six and the Specificity Protein/Krüppel-Like Factor groups. In fact, these new TERTpdup significantly enhanced the E-twenty-six transcription factors' binding capacity, which is also typically increased by the two c.1-124 C > T/c.1-146 C > T hotspot TERTp mut. On the other hand, they were distinguished by enhanced affinity for the Krüppel proteins. The luciferase assay confirmed that TERTp dup behaved as gain-of-function mutations causing a 2,3-2,5 fold increase of TERT transcription. The present study provides new insights into TERTp mutational spectrum occurring in central nervous system tumors, with the identification of new recurrent somatic gain-of-function mutations, occurring in 0.8% of glioblastoma IDH-wildtype.

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“…Identification of this recurrent mutation has led the World Health Organization (WHO) to reclassify this larger subset of DIPG into the new entity of "diffuse midline glioma, H3K27M mutant" (20). Other recurrent genomic alterations or amplifications are found in tumor protein p53 (TP53) (16,18), platelet-derived growth factor receptor alpha (PDGFRA) (14,21), and activin A receptor type I (ACVR1) (15,18,22,23), along with many more at lower frequencies more comprehensively described by Mackay et al (16), including ATRX (24). Although very little is known about how these mutations impact DIPG invasion, some data suggest that these intrinsic alterations can contribute to tumor cell migratory behavior (Figure 1).…”

Section: Tumor Cell-intrinsic Molecular Alterations Can Contribute Tomentioning

confidence: 99%

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

et al. 2020

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Diffuse Intrinsic Pontine Glioma (DIPG) is a rare, highly aggressive pediatric brain tumor that originates in the pons. DIPG is untreatable and universally fatal, with a median life expectancy of less than a year. Resection is not an option, due to the anatomical location of the tumor, radiotherapy has limited effect and no chemotherapeutic or targeted treatment approach has proven to be successful. This poor prognosis is partly attributed to the tumor's highly infiltrative diffuse and invasive spread. Thus, targeting the invasive behavior of DIPG has the potential to be of therapeutic value. In order to target DIPG invasion successfully, detailed mechanistic knowledge on the underlying drivers is required. Here, we review both DIPG tumor cell's intrinsic molecular processes and extrinsic environmental factors contributing to DIPG invasion. Importantly, DIPG represents a heterogenous disease and through advances in whole-genome sequencing, different subtypes of disease based on underlying driver mutations are now being recognized. Recent evidence also demonstrates intra-tumor heterogeneity in terms of invasiveness and implies that highly infiltrative tumor subclones can enhance the migratory behavior of neighboring cells. This might partially be mediated by "tumor microtubes," long membranous extensions through which tumor cells connect and communicate, as well as through the secretion of extracellular vesicles. Some of the described processes involved in invasion are already being targeted in clinical trials. However, more research into the mechanisms of DIPG invasion is urgently needed and might result in the development of an effective therapy for children suffering from this devastating disease. We discuss the implications of newly discovered invasive mechanisms for therapeutic targeting and the challenges therapy development face in light of disease in the developing brain.

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Mutant ATRX: uncovering a new therapeutic target for glioma

Cited by 121 publications

References 132 publications

Radiomics Features Predict CIC Mutation Status in Lower Grade Glioma

Radiomics Features Predict CIC Mutation Status in Lower Grade Glioma

New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

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