Publications by authors named "Kimmo J Hatanpaa"

103 Publications

Distant Pituitary Adenoma Spread: A Systematic Review and Report of 2 Cases.

Oper Neurosurg (Hagerstown) 2022 Jan 14. Epub 2022 Jan 14.

Department of Neurological Surgery, University of Texas Southwestern Medical Center, Zale Lipshy Hospital, Dallas, Texas, USA.

Background: Distant spread of pituitary adenoma outside the sellar/suprasellar region is classified as pituitary carcinoma. Cerebrospinal fluid (CSF)-born spread of pituitary adenoma can occur after tumor cell spillage into the CSF space after surgery, irradiation, or apoplexy and is not necessarily related to intrinsic tumor biology.

Objective: To systematically review the literature and describe the clinical characteristics and treatment strategies of patients with pituitary carcinomas. We further present 2 cases from our institution.

Methods: A single-center retrospective review of patients with pituitary adenoma spread to distant intracranial locations between 2000 and 2020 was performed. Electronic databases were searched from their inception to May 25, 2021, and studies describing patients with pituitary spread to distant locations were included.

Results: Of 1210 pituitary adenoma cases reviewed, 2 (0.16%) showed tumor spread to distant locations. We found 134 additional cases (from 108 published articles) resulting in a total of 136 cases (61.9% were male). The time to tumor spread ranged between 0 and 516 months (median: 96 months). The follow-up duration ranged between 0 and 240 months (median: 11.5 months). All but 2 patients (98.5%) underwent surgical resection before adenoma spread. The 2 exceptions included a patient with evidence of an apoplectic event on autopsy and another patient with leptomeningeal pituitary spread but an unclear history of apoplexy. Elevated tumor markers were not linked to poor outcomes.

Conclusion: Distant spread of pituitary adenoma may occur after surgery, irradiation, or apoplexy. It is not necessarily associated with a malignant clinical course.
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http://dx.doi.org/10.1227/ONS.0000000000000089DOI Listing
January 2022

Establishment of patient-derived organoid models of lower grade glioma.

Neuro Oncol 2021 Nov 26. Epub 2021 Nov 26.

Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Background: Historically, creating patient-derived models of lower grade glioma (LGG) has been challenging, contributing to few experimental platforms that support laboratory-based investigations of this disease. Although organoid modeling approaches have recently been employed to create in vitro models of high grade glioma (HGG), it is unknown whether this approach can be successfully applied to LGG.

Methods: In this study, we developed an optimized protocol for the establishment of organoids from LGG primary tissue samples by utilizing physiologic (5%) oxygenation conditions and employed it to produce the first known suite of these models. To assess their fidelity, we surveyed key biological features of patient-derived organoids using metabolic, genomic, histologic, and lineage marker gene expression assays.

Results: Organoid models were created with a success rate of 91% (n = 20/22) from primary tumor samples across glioma histological subtypes and tumor grades (WHO Grades 1-4), and a success rate of 87% (13/15) for WHO Grade 1-3 tumors. Patient-derived organoids recapitulated stemness, proliferative, and tumor-stromal composition profiles of their respective parental tumor specimens. Cytoarchitectural, mutational, and metabolic traits of parental tumors were also conserved. Importantly, LGG organoids were maintained in vitro for weeks to months and reanimated after biobanking without loss of integrity.

Conclusions: We report an efficient method for producing faithful in vitro models of LGG. New experimental platforms generated through this approach are well positioned to support preclinical studies of this disease, particularly those related to tumor immunology, tumor-stroma interactions, identification of novel drug targets, and personalized assessments of treatment response profiles.
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http://dx.doi.org/10.1093/neuonc/noab273DOI Listing
November 2021

Alterations in the RB Pathway With Inactivation of RB1 Characterize Glioblastomas With a Primitive Neuronal Component.

J Neuropathol Exp Neurol 2021 Dec;80(12):1092-1098

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

A primitive neuronal component is a feature of some glioblastomas but defining molecular alterations of this histologic variant remains uncertain. We performed next-generation sequencing of 1500 tumor related genes on tissue from 9 patients with glioblastoma with a primitive component (G/PN) and analyzed 27 similar cases from the Cancer Genome Atlas (TCGA) dataset. Alterations in the RB pathway were identified in all of our patients' tumors and 81% of TCGA tumors with the retinoblastoma tumor suppressor gene (RB1) commonly affected. Although RB1 mutations were observed in some conventional glioblastomas, the allelic fractions of these mutations were significantly higher in tumors with a primitive neuronal component in both our and TCGA cohorts (median, 72% vs 25%, p < 0.001 and 80% vs 40%, p < 0.02, respectively). Further, in 78% of patients in our cohort, RB expression was lost by immunohistochemistry. Our findings indicate that alterations in the RB pathway are common in G/PNs and suggest that inactivation of RB1 may be a driving mechanism for the phenotype.
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http://dx.doi.org/10.1093/jnen/nlab109DOI Listing
December 2021

The efficacy of immunohistochemistry in the diagnosis of molecular genetic alterations in central nervous system gliomas: Next-generation sequencing of 212 mutations in 112 patients.

Clin Neuropathol 2021 Oct 21. Epub 2021 Oct 21.

Identification of molecular genetic alterations has become an important part of diagnosis and care of patients with brain tumors. Comparisons of immunohistochemistry (IHC) with DNA sequencing techniques have suggested that IHC is useful for identifying surrogates of mutations in gliomas; however, studies of the efficacy are relatively few. Our aim was to compare IHC in our neuropathology laboratory with a commercially available next-generation sequencing (NGS) platform, Tempus xT. We studied 212 immunohistochemically stained sections of gliomas to identify mutations of isocitrate dehydrogenase (IDH), p53, BRAF, the α-thalassemia/mental retardation syndrome X-linked protein (ATRX), and histone H3. Tempus xT NGS confirmed the IHC diagnosis of IDH1/R132H in 102 of 102 patients (100%), BRAF/V600E in 14 of 14 (100%) patients and H3/K27M in 10 of 10 (100%) patients. For p53, NGS confirmed the IHC diagnosis of mutation in 47 of 53 (87%) patients. For 6 patients, IHC was interpreted as wild-type while NGS indicated a mutation. NGS confirmed the IHC diagnosis of ATRX mutation in 29 of 31 (94%) patients. In 1 patient, IHC predicted a mutation that was not confirmed by NGS, and in another, IHC predicted wild-type, but NGS showed mutant. In 2 other patients, IHC diagnosis of ATRX mutation was equivocal; 1 was mutant and 1 was wild-type by NGS. Our single-center study suggests that IHC for IDH1/R132H, BRAF/V600E, and H3/K27M is highly reliable and may be used confidently in clinical practice. IHC for p53 and ATRX mutations is often reliable but possibly problematic, and genetic studies may be necessary to determine astrocytic or oligodendroglial differentiation.
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http://dx.doi.org/10.5414/NP301381DOI Listing
October 2021

Primary peripheral T-cell central nervous system lymphoma.

Surg Neurol Int 2021 13;12:465. Epub 2021 Sep 13.

Department of Neurological Surgery, The University of Texas Southwestern Medical Center, Dallas, Texas, United States.

Background: Primary peripheral T-cell central nervous system lymphoma (PCNSL) is a rare, aggressive tumor that arises in the craniospinal axis and has an increased risk in individuals who are immunocompromised. This lesion often mimics other benign and malignant processes on radiographic imaging, leading to misdiagnosis and delays in treatment. We present a case of a patient with a history of Sjögren's syndrome and progressive neurologic symptoms who underwent craniotomy for diagnosis.

Case Description: A 61-year-old woman with a history of Sjögren's syndrome, progressive aphasia, left facial droop, and right-sided paresthesias for 4 months presented for evaluation and management. An enhancing, infiltrative lesion in the left frontal lobe with underlying vasogenic edema was appreciated and suggestive of a primary or metastatic neoplasm. The patient underwent an open biopsy for further evaluation of the lesion. Extensive histopathologic evaluation revealed a diagnosis of T-cell PCNSL. The patient was started on induction methotrexate and temozolomide followed by consolidative radiotherapy.

Conclusion: Autoimmune conditions are a risk factor for T-cell PCNSL development. T-cell PCNSL has radiographic and gross histologic features that are consistent with a broad differential, including gliomas and inflammatory processes. Prompt diagnosis and extensive histopathological evaluation is essential to ensure appropriate treatment.
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http://dx.doi.org/10.25259/SNI_224_2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492444PMC
September 2021

Preoperative imaging of glioblastoma patients using hyperpolarized C pyruvate: Potential role in clinical decision making.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab092. Epub 2021 Jun 28.

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Background: Glioblastoma remains incurable despite treatment with surgery, radiation therapy, and cytotoxic chemotherapy, prompting the search for a metabolic pathway unique to glioblastoma cells.C MR spectroscopic imaging with hyperpolarized pyruvate can demonstrate alterations in pyruvate metabolism in these tumors.

Methods: Three patients with diagnostic MRI suggestive of a glioblastoma were scanned at 3 T 1-2 days prior to tumor resection using a C/H dual-frequency RF coil and a C/H-integrated MR protocol, which consists of a series of H MR sequences (T FLAIR, arterial spin labeling and contrast-enhanced [CE] T) and C spectroscopic imaging with hyperpolarized [1-C]pyruvate. Dynamic spiral chemical shift imaging was used for C data acquisition. Surgical navigation was used to correlate the locations of tissue samples submitted for histology with the changes seen on the diagnostic MR scans and the C spectroscopic images.

Results: Each tumor was histologically confirmed to be a WHO grade IV glioblastoma with isocitrate dehydrogenase wild type. Total hyperpolarized C signals detected near the tumor mass reflected altered tissue perfusion near the tumor. For each tumor, a hyperintense [1-C]lactate signal was detected both within CE and T-FLAIR regions on the H diagnostic images ( = .008). [C]bicarbonate signal was maintained or decreased in the lesion but the observation was not significant ( = .3).

Conclusions: Prior to surgical resection, C MR spectroscopic imaging with hyperpolarized pyruvate reveals increased lactate production in regions of histologically confirmed glioblastoma.
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http://dx.doi.org/10.1093/noajnl/vdab092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331053PMC
June 2021

Prognostic Value of Isolated TERT Promoter Mutation in Grade 2 and 3 IDH-Wildtype Astrocytomas.

J Neuropathol Exp Neurol 2021 09;80(9):885-886

Department of Pathology and Laboratory Medicine, University of Texas Health San Antonio, San Antonio, Texas, USA.

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http://dx.doi.org/10.1093/jnen/nlab067DOI Listing
September 2021

AIF3 splicing switch triggers neurodegeneration.

Mol Neurodegener 2021 04 14;16(1):25. Epub 2021 Apr 14.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

Background: Apoptosis-inducing factor (AIF), as a mitochondrial flavoprotein, plays a fundamental role in mitochondrial bioenergetics that is critical for cell survival and also mediates caspase-independent cell death once it is released from mitochondria and translocated to the nucleus under ischemic stroke or neurodegenerative diseases. Although alternative splicing regulation of AIF has been implicated, it remains unknown which AIF splicing isoform will be induced under pathological conditions and how it impacts mitochondrial functions and neurodegeneration in adult brain.

Methods: AIF splicing induction in brain was determined by multiple approaches including 5' RACE, Sanger sequencing, splicing-specific PCR assay and bottom-up proteomic analysis. The role of AIF splicing in mitochondria and neurodegeneration was determined by its biochemical properties, cell death analysis, morphological and functional alterations and animal behavior. Three animal models, including loss-of-function harlequin model, gain-of-function AIF3 knockin model and conditional inducible AIF splicing model established using either Cre-loxp recombination or CRISPR/Cas9 techniques, were applied to explore underlying mechanisms of AIF splicing-induced neurodegeneration.

Results: We identified a nature splicing AIF isoform lacking exons 2 and 3 named as AIF3. AIF3 was undetectable under physiological conditions but its expression was increased in mouse and human postmortem brain after stroke. AIF3 splicing in mouse brain caused enlarged ventricles and severe neurodegeneration in the forebrain regions. These AIF3 splicing mice died 2-4 months after birth. AIF3 splicing-triggered neurodegeneration involves both mitochondrial dysfunction and AIF3 nuclear translocation. We showed that AIF3 inhibited NADH oxidase activity, ATP production, oxygen consumption, and mitochondrial biogenesis. In addition, expression of AIF3 significantly increased chromatin condensation and nuclear shrinkage leading to neuronal cell death. However, loss-of-AIF alone in harlequin or gain-of-AIF3 alone in AIF3 knockin mice did not cause robust neurodegeneration as that observed in AIF3 splicing mice.

Conclusions: We identified AIF3 as a disease-inducible isoform and established AIF3 splicing mouse model. The molecular mechanism underlying AIF3 splicing-induced neurodegeneration involves mitochondrial dysfunction and AIF3 nuclear translocation resulting from the synergistic effect of loss-of-AIF and gain-of-AIF3. Our study provides a valuable tool to understand the role of AIF3 splicing in brain and a potential therapeutic target to prevent/delay the progress of neurodegenerative diseases.
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http://dx.doi.org/10.1186/s13024-021-00442-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048367PMC
April 2021

Molecular Characterization of "True" Low-Grade IDH-Wildtype Astrocytomas.

J Neuropathol Exp Neurol 2021 04;80(5):431-435

From the Department of Pathology and Laboratory Medicine and Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health San Antonio, San Antonio, Texas, USA.

Numerous recent studies have demonstrated that the vast majority of IDH-wildtype astrocytomas with WHO grade II/III histology have clinical outcomes equivalent to IDH-wildtype glioblastomas. This has called into question the existence of an IDH-wildtype lower-grade astrocytoma (LGA) category, and the cIMPACT-NOW study group has suggested 3 molecular features which, if present, warrant upgrading IDH-wildtype LGA to glioblastoma: EGFR amplification, 7+/10-, and TERT promoter mutation. Herein, we evaluate the clinical, histologic, and molecular features of IDH-wildtype low-grade astrocytomas, defined here as infiltrative adult astrocytoma lacking histologic features of glioblastoma (microvascular proliferation and/or necrosis), IDH1/2 mutation, and all 3 of the cIMPACT-NOW update 3 factors. Compared with their counterparts with cIMPACT-NOW features of glioblastoma (LGA-C+; n = 108), IDH-wildtype LGAs lacking these features (LGA-C0; n = 36) occur in significantly younger patients, are more frequently WHO grade II, have less total copy number variation distributed across the entire genome, less frequent homozygous deletion of CDKN2A, less frequent PTEN and PIK3CA alterations, and more frequent NF1 alterations. These results suggest that although rare, a "true" IDH-wildtype LGA category does exist, and has distinct clinical and molecular features consistent with relatively beneficial clinical outcomes in these patients.
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http://dx.doi.org/10.1093/jnen/nlab023DOI Listing
April 2021

Molecular Signatures of Chromosomal Instability Correlate With Copy Number Variation Patterns and Patient Outcome in IDH-Mutant and IDH-Wildtype Astrocytomas.

J Neuropathol Exp Neurol 2021 03;80(4):354-365

From the Department of Pathology and Laboratory Medicine; University of Texas Health San Antonio, San Antonio, Texas, USA.

Chromosomal instability due to mutations in genes guarding the stability of the genome is a well-known mechanism underlying tumorigenesis and malignant progression in numerous cancers. The effect of this process in gliomas is mostly unknown with relatively little research examining the effects of chromosomal instability on patient outcome and therapeutic efficacy, although studies have shown that overall/total copy number variation (CNV) is elevated in higher histologic grades and in cases with more rapid progression and shorter patient survival. Herein, we examine a 70-gene mRNA expression signature (CIN70), which has been previously shown to correlate tightly with chromosomal instability, in 2 independent cohorts of IDH-mutant astrocytomas (total n = 241), IDH-wildtype astrocytomas (n = 228), and oligodendrogliomas (n = 128). Our results show that CIN70 expression levels correlate with total CNV, as well as higher grade, progression-free survival, and overall survival in both IDH-mutant and IDH-wildtype astrocytomas. In oligodendrogliomas, these mRNA signatures correlate with total CNV but not consistently with clinical outcome. These data suggest that chromosomal instability is an underlying factor in aggressive behavior and progression of a subset of diffuse astrocytomas. In addition, chromosomal instability may in part explain the poor response of diffuse gliomas to treatment and may serve as a future therapeutic target.
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http://dx.doi.org/10.1093/jnen/nlab008DOI Listing
March 2021

Neurological infections in 2020: COVID-19 takes centre stage.

Lancet Neurol 2021 01;20(1):17-18

UT Southwestern Medical Center, University of Texas, Dallas, TX 75390, USA.

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http://dx.doi.org/10.1016/S1474-4422(20)30451-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833034PMC
January 2021

Spinal Cord Pilocytic Astrocytoma With FGFR1-TACC1 Fusion and Anaplastic Transformation.

J Neuropathol Exp Neurol 2021 02;80(3):283-285

UT Southwestern Medical Center, Department of Neurology and Neurotherapeutics, Dallas, Texas.

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http://dx.doi.org/10.1093/jnen/nlaa122DOI Listing
February 2021

Overcoming the Odds: Toward a Molecular Profile of Long-Term Survival in Glioblastoma.

J Neuropathol Exp Neurol 2020 10;79(10):1031-1037

University of Texas Southwestern Medical Center, Dallas, Texas; and Department of Pathology and Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, Texas.

For over a century, gliomas were characterized solely by histologic features. With the publication of the WHO Classification of Tumours of the Central Nervous System, Revised 4th Edition in 2016, integrated histologic and molecular diagnosis became the norm, providing improved tumor grading and prognosis with IDH1/2 (isocitrate dehydrogenase 1 and 2) mutation being the most significant prognostic feature in all grades of adult diffuse glioma. Since then, much work has been done to identify additional molecular prognostic features, but the bulk of the progress has been made in defining aggressive features in lower grade astrocytoma. Although there have been several large case series of glioblastomas with long-term survival (LTS; overall survival ≥36 months), less is known about the clinical and molecular features of these cases. Herein, we review 19 studies examining LTS glioblastoma patients from 2009 to 2020 that include variable molecular analysis, including 465 cases with survival of 36 months or more (total n = 2328). These studies suggest that while there is no definitive molecular signature of long survival, younger age, IDH mutation, and MGMT (methyl guanine methyl transferase) promoter hypermethylation are associated with longer overall survival, and in IDH-wildtype tumors, chromosome 19/20 co-gain and lack of EGFR amplification, chromosome 7 gain/10 loss, and TERT promoter mutation are associated with LTS.
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http://dx.doi.org/10.1093/jnen/nlaa102DOI Listing
October 2020

Phosphoprotein-based biomarkers as predictors for cancer therapy.

Proc Natl Acad Sci U S A 2020 08 20;117(31):18401-18411. Epub 2020 Jul 20.

Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233;

Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.
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http://dx.doi.org/10.1073/pnas.2010103117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414192PMC
August 2020

Molecular Correlates of Long Survival in IDH-Wildtype Glioblastoma Cohorts.

J Neuropathol Exp Neurol 2020 08;79(8):843-854

From the Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York.

IDH-wildtype glioblastoma is a relatively common malignant brain tumor in adults. These patients generally have dismal prognoses, although outliers with long survival have been noted in the literature. Recently, it has been reported that many histologically lower-grade IDH-wildtype astrocytomas have a similar clinical outcome to grade IV tumors, suggesting they may represent early or undersampled glioblastomas. cIMPACT-NOW 3 guidelines now recommend upgrading IDH-wildtype astrocytomas with certain molecular criteria (EGFR amplifications, chromosome 7 gain/10 loss, and/or TERT promoter mutations), establishing the concept of a "molecular grade IV" astrocytoma. In this report, we apply these cIMPACT-NOW 3 criteria to 2 independent glioblastoma cohorts, totaling 393 public database and institutional glioblastoma cases: 89 cases without any of the cIMPACT-NOW 3 criteria (GBM-C0) and 304 cases with one or more criteria (GBM-C1-3). In the GBM-C0 groups, there was a trend toward longer recurrence-free survival (median 12-17 vs 6-10 months), significantly longer overall survival (median 32-41 vs 15-18 months), younger age at initial diagnosis, and lower overall mutation burden compared to the GBM-C1-3 cohorts. These data suggest that while histologic features may not be ideal indicators of patient survival in IDH-wildtype astrocytomas, these 3 molecular features may also be important prognostic factors in IDH-wildtype glioblastoma.
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http://dx.doi.org/10.1093/jnen/nlaa059DOI Listing
August 2020

Occurrence of Glioma in Pregnant Patients: An Institutional Case Series and Review of the Literature.

Anticancer Res 2020 Jun;40(6):3453-3457

Department of Neurology & Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, U.S.A.

Background/aim: Gliomas present a uniquely challenging clinical situation in the context of pregnancy, with no standard recommendations. This case series aimed to describe the treatment regimen and outcomes of five pregnant patients with gliomas.

Patients And Methods: This is a retrospective study. A patient database from electronic medical records was evaluated to identify pregnant patients with gliomas treated at our institution between 2008-2018.

Results: Five study patients who were pregnant with gliomas were identified. Of these, 4 were diagnosed during pregnancy, while 1 was diagnosed prior to her pregnancy. One patient had grade 2 astrocytoma, 1 had grade 3 anaplastic astrocytoma, and 3 had grade 4 glioblastomas (GBM). All patients received surgery, and one patient received radiation therapy without concurrent chemotherapy during her pregnancy. All delivered healthy babies. Three of the 5 patients remain alive, and 2 of the 5 were progression-free at the last follow-up.

Conclusion: Treatment plans must be specifically tailored to the individual patient based on the glioma grade, the mother's desire to continue the pregnancy, and the risks of delaying treatment until after pregnancy. Additional studies need to be performed to definitively establish uniform guidelines for the treatment of pregnant patients with glioma.
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http://dx.doi.org/10.21873/anticanres.14331DOI Listing
June 2020

Regulation of branched-chain amino acid metabolism by hypoxia-inducible factor in glioblastoma.

Cell Mol Life Sci 2021 Jan 22;78(1):195-206. Epub 2020 Feb 22.

Department of Pathology, UT Southwestern Medical Center, Dallas, TX, 75390-9072, USA.

Hypoxia-inducible factors (HIFs) mediate metabolic reprogramming in response to hypoxia. However, the role of HIFs in branched-chain amino acid (BCAA) metabolism remains unknown. Here we show that hypoxia upregulates mRNA and protein levels of the BCAA transporter LAT1 and the BCAA metabolic enzyme BCAT1, but not their paralogs LAT2-4 and BCAT2, in human glioblastoma (GBM) cell lines as well as primary GBM cells. Hypoxia-induced LAT1 protein upregulation is mediated by both HIF-1 and HIF-2 in GBM cells. Although both HIF-1α and HIF-2α directly bind to the hypoxia response element at the first intron of the human BCAT1 gene, HIF-1α is exclusively responsible for hypoxia-induced BCAT1 expression in GBM cells. Knockout of HIF-1α and HIF-2α significantly reduces glutamate labeling from BCAAs in GBM cells under hypoxia, which provides functional evidence for HIF-mediated reprogramming of BCAA metabolism. Genetic or pharmacological inhibition of BCAT1 inhibits GBM cell growth under hypoxia. Together, these findings uncover a previously unrecognized HIF-dependent metabolic pathway that increases GBM cell growth under conditions of hypoxic stress.
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http://dx.doi.org/10.1007/s00018-020-03483-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112551PMC
January 2021

Glycine by MR spectroscopy is an imaging biomarker of glioma aggressiveness.

Neuro Oncol 2020 07;22(7):1018-1029

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.

Background: High-grade gliomas likely remodel the metabolic machinery to meet the increased demands for amino acids and nucleotides during rapid cell proliferation. Glycine, a non-essential amino acid and intermediate of nucleotide biosynthesis, may increase with proliferation. Non-invasive measurement of glycine by magnetic resonance spectroscopy (MRS) was evaluated as an imaging biomarker for assessment of tumor aggressiveness.

Methods: We measured glycine, 2-hydroxyglutarate (2HG), and other tumor-related metabolites in 35 glioma patients using an MRS sequence tailored for co-detection of glycine and 2HG in gadolinium-enhancing and non-enhancing tumor regions on 3T MRI. Glycine and 2HG concentrations as measured by MRS were correlated with tumor cell proliferation (MIB-1 labeling index), expression of mitochondrial serine hydroxymethyltransferase (SHMT2), and glycine decarboxylase (GLDC) enzymes, and patient overall survival.

Results: Elevated glycine was strongly associated with presence of gadolinium enhancement, indicating more rapidly proliferative disease. Glycine concentration was positively correlated with MIB-1, and levels higher than 2.5 mM showed significant association with shorter patient survival, irrespective of isocitrate dehydrogenase status. Concentration of 2HG did not correlate with MIB-1 index. A high glycine/2HG concentration ratio, >2.5, was strongly associated with shorter survival (P < 0.0001). GLDC and SHMT2 expression were detectable in all tumors with glycine concentration, demonstrating an inverse correlation with GLDC.

Conclusions: The data suggest that aggressive gliomas reprogram glycine-mediated one-carbon metabolism to meet the biosynthetic demands for rapid cell proliferation. MRS evaluation of glycine provides a non-invasive metabolic imaging biomarker that is predictive of tumor progression and clinical outcome.

Key Points: 1. Glycine and 2-hydroxyglutarate in glioma patients are precisely co-detected using MRS at 3T.2. Tumors with elevated glycine proliferate and progress rapidly.3. A high glycine/2HG ratio is predictive of shortened patient survival.
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http://dx.doi.org/10.1093/neuonc/noaa034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339885PMC
July 2020

Distinct Expression Patterns of Carbonic Anhydrase IX in Clear Cell, Microcystic, and Angiomatous Meningiomas.

J Neuropathol Exp Neurol 2019 12;78(12):1081-1088

Department of Pathology, UT Southwestern Medical Center, Dallas, Texas; Department of Pathology; Department of Neurological Surgery, University of Washington, Seattle, Washington; Department of Internal Medicine; Department of Neurology and Neurotherapeutics; and Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, Texas.

Clear cell, microcytic, and angiomatous meningiomas are 3 vasculature-rich variants with overlapping morphological features but different prognostic and treatment implications. Distinction between them is not always straightforward. We compared the expression patterns of the hypoxia marker carbonic anhydrase IX (CA-IX) in meningiomas with predominant clear cell (n = 15), microcystic (n = 9), or angiomatous (n = 11) morphologies, as well as 117 cases of other World Health Organization recognized histological meningioma variants. Immunostaining for SMARCE1 protein, whose loss-of-function has been associated with clear cell meningiomas, was performed on all clear cell meningiomas, and selected variants of meningiomas as controls. All clear cell meningiomas showed absence of CA-IX expression and loss of nuclear SMARCE1 expression. All microcystic and angiomatous meningiomas showed diffuse CA-IX immunoreactivity and retained nuclear SMARCE1 expression. In other meningioma variants, CA-IX was expressed in a hypoxia-restricted pattern and was highly associated with atypical features such as necrosis, small cell change, and focal clear cell change. In conclusion, CA-IX may serve as a useful diagnostic marker in differentiating clear cell, microcystic, and angiomatous meningiomas.
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http://dx.doi.org/10.1093/jnen/nlz091DOI Listing
December 2019

Tumoral Mimics of Subdural Hematomas: Case Report and Review of Diagnostic and Management Strategies in Primary B-Cell Lymphoma of the Subdural Space.

World Neurosurg 2020 Jan 25;133:49-54. Epub 2019 Sep 25.

Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Background: Subdural lymphomas are a rare subtype of primary central nervous system lymphomas that can radiographically mimic epidural blood and pose a diagnostic challenge. They can complicate treatment if not preemptively identified.

Methods: We present a case report of a subdural lymphoma that mimicked a compressive subdural hematoma, and we review the PubMed database for similar cases.

Results: A 77-year-old woman presented with a transient left facial droop and what appeared to be a subdural hematoma on computed tomography scan. The patient underwent surgery, during which grossly abnormal solid epicortical adherent tissue was noted instead of the expected appearance of a subdural hematoma. An intraoperative biopsy was suggestive of lymphoma, and the surgery was converted to a craniectomy. Pathology confirmed the diagnosis of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The patient underwent radiotherapy with no complications or recurrence. Magnetic resonance imaging demonstrated complete resolution of the mass at 3 months after treatment, at which time the patient underwent a synthetic cranioplasty. Seven case reports of primary dural lymphomas mimicking subdural blood were found, with variable pathologic subclassifications.

Conclusions: Although rare, a primary dural lymphoma can be mistaken for a subdural hematoma on computed tomography scan. The most common subtype is low-grade extranodal marginal zone lymphomas. It is important to keep these diseases in the differential diagnosis, especially when there is incongruence between imaging and the clinical picture, as earlier detection correlates to a stronger therapeutic response.
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http://dx.doi.org/10.1016/j.wneu.2019.09.091DOI Listing
January 2020

Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma.

Neuro Oncol 2019 12;21(12):1529-1539

Department of Neurology and Neurotherapeutics, Division of Hematology-Oncology, Dallas, Texas.

Background: Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM.

Methods: We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ.

Results: The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ.

Conclusion: EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs.
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http://dx.doi.org/10.1093/neuonc/noz127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917414PMC
December 2019

Establishing a prognostic threshold for total copy number variation within adult IDH-mutant grade II/III astrocytomas.

Acta Neuropathol Commun 2019 07 26;7(1):121. Epub 2019 Jul 26.

Department of Pathology, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA.

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http://dx.doi.org/10.1186/s40478-019-0778-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660955PMC
July 2019

Total copy number variation as a prognostic factor in adult astrocytoma subtypes.

Acta Neuropathol Commun 2019 06 10;7(1):92. Epub 2019 Jun 10.

Department of Pathology, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA.

Since the discovery that IDH1/2 mutations confer a significantly better prognosis in astrocytomas, much work has been done to identify other molecular signatures to help further stratify lower-grade astrocytomas and glioblastomas, with the goal of accurately predicting clinical outcome and identifying potentially targetable mutations. In the present study, we subclassify 135 astrocytomas (67 IDH-wildtype and 68 IDH-mutant) from The Cancer Genome Atlas dataset (TCGA) on the basis of grade, IDH-status, and the previously established prognostic factors, CDK4 amplification and CDKN2A/B deletion, within the IDH-mutant groups. We analyzed these groups for total copy number variation (CNV), total mutation burden, chromothripsis, specific mutations, and amplifications/deletions of specific genes/chromosomal regions. Herein, we demonstrate that across all of these tumor groups, total CNV level is a relatively consistent prognostic factor. We also identified a trend towards increased levels of chromothripsis in tumors with lower progression-free survival (PFS) and overall survival (OS) intervals. While no significant differences were identified in overall mutation load, we did identify a significantly higher number of cases with mutations in genes with functions related to maintaining genomic stability in groups with higher mean CNV and worse PFS and OS intervals, particularly in the IDH-mutant groups. Our data further support the case for total CNV level as a potential prognostic factor in astrocytomas, and suggest mutations in genes responsible for overall genomic instability as a possible underlying mechanism for some astrocytomas with poor clinical outcome.
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http://dx.doi.org/10.1186/s40478-019-0746-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556960PMC
June 2019

Genome-Wide Analysis of Glioblastoma Patients with Unexpectedly Long Survival.

J Neuropathol Exp Neurol 2019 06;78(6):501-507

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.

Glioblastoma (GBM), representing WHO grade IV astrocytoma, is a relatively common primary brain tumor in adults with an exceptionally dismal prognosis. With an incidence rate of over 10 000 cases in the United States annually, the median survival rate ranges from 10-15 months in IDH1/2-wildtype tumors and 24-31 months in IDH1/2-mutant tumors, with further variation depending on factors such as age, MGMT methylation status, and treatment regimen. We present a cohort of 4 patients, aged 37-60 at initial diagnosis, with IDH1-mutant GBMs that were associated with unusually long survival intervals after the initial diagnosis, currently ranging from 90 to 154 months (all still alive). We applied genome-wide profiling with a methylation array (Illumina EPIC Array 850k) and a next-generation sequencing panel to screen for genetic and epigenetic alterations in these tumors. All 4 tumors demonstrated methylation patterns and genomic alterations consistent with GBM. Three out of four cases showed focal amplification of the CCND2 gene or gain of the region on 12p that included CCND2, suggesting that this may be a favorable prognostic factor in GBM. As this study has a limited sample size, further evaluation of patients with similar favorable outcome is warranted to validate these findings.
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http://dx.doi.org/10.1093/jnen/nlz025DOI Listing
June 2019

Spinal Pleomorphic Xanthoastrocytoma With a QKI-RAF1 Fusion.

J Neuropathol Exp Neurol 2019 01;78(1):10-14

Department of Pathology.

Pleomorphic xanthoastrocytoma (PXA) is a slow-growing neoplasm that predominantly affects the pediatric and young adult population. This neoplasm has a good prognosis, with a median 10-year survival rate of 70%. The majority of tumors are supratentorial and arise in the temporal lobe, while spinal tumors are extremely rare, with only 8 reported cases. Molecular perturbations involving the MAPK/ERK signaling pathway have been described in PXAs. The most common mutation is BRAF V600E in 60%-80% of cases. Other mechanisms activating this pathway in the absence of this mutation are rare and include CRAF (RAF1) fusion genes. We report a PXA case in the cervical spinal cord of a 49-year-old man with slowly progressive coordination difficulties and extremity numbness. The tumor was negative for the V600E mutation, but 2 RNA sequencing platforms detected a QKI-RAF1 fusion (t(6; 3)(q26; p25)), which has not been previously reported in PXAs. This fusion is known to activate MAPK/ERK and PI3K/mTOR signaling. Although first- and second-generation RAF inhibitors are predicted to be ineffective, this fusion may be targetable by the novel RAF inhibitor LY3009120 and to some extent by the MEK inhibitor trametinib. Genetic analysis to screen for MAPK/ERK pathway mutations is warranted on PXAs negative for the V600E mutation.
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http://dx.doi.org/10.1093/jnen/nly112DOI Listing
January 2019

3D high-resolution imaging of 2-hydroxyglutarate in glioma patients using DRAG-EPSI at 3T in vivo.

Magn Reson Med 2019 02 14;81(2):795-802. Epub 2018 Sep 14.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.

Purpose: To develop 3D high-resolution imaging of 2-hydroxyglutarate (2HG) at 3T in vivo.

Methods: Echo-planar spectroscopic imaging with dual-readout alternated-gradients (DRAG-EPSI), which was recently reported for 2D imaging of 2HG at 7T, was tested for 3D imaging of 2HG at 3T. The frequency drifts and acoustic noise induced by DRAG-EPSI were investigated in comparison with conventional EPSI. Four patients with IDH-mutant gliomas were enrolled for 3D imaging of 2HG and other metabolites. A previously reported 2HG-tailored TE 97-ms PRESS sequence preceded the DRAG-EPSI readout gradients. Unsuppressed water, acquired with EPSI, was used as reference for multi-channel combination, eddy-current compensation, and metabolite quantification. Spectral fitting was conducted with the LCModel using in-house basis sets.

Results: With gradient strength of 4 mT/m and slew rate of 20 mT/m/ms, DRAG-EPSI produced frequency drifts smaller by 5.5-fold and acoustic noise lower by 25 dB compared to conventional EPSI. In a 19-min scan, 3D DRAG-EPSI provided images of 2HG with precision (CRLB <10%) at a resolution of 10 × 10 × 10 mm for a field of view of 240 × 180 × 80 mm . 2HG was estimated to be 5 mM in a pre-treatment patient. In 3 post-surgery patients, 2HG estimates were 3-6 mM, and the 2HG distribution was different from the water-T image pattern or highly concentrated in the post-contrast enhancing region.

Conclusion: Together with 2HG-optimized PRESS, DRAG-EPSI provides an effective tool for reliable 3D high-resolution imaging of 2HG at 3T in vivo.
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http://dx.doi.org/10.1002/mrm.27482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289635PMC
February 2019

Intradural Juvenile Xanthogranuloma with Involvement of Multiple Nerve Roots: A Case Report and Review of the Literature.

World Neurosurg 2018 Nov 7;119:189-196. Epub 2018 Aug 7.

Department of Neurological Surgery, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Background: Juvenile xanthogranuloma (JXG) is a rare, non-Langerhans cell histiocytic disorder that primarily presents as multiple cutaneous lesions in young males. Solitary lesions in the spinal column are an especially rare presentation of this disease, and central nervous system involvement can portend a poor prognosis. We report an unusual case of an adult woman with an unresectable JXG of the lumbar spine. A review of the reported cases of thoracolumbar JXG and the current data regarding diagnosis and treatment are presented.

Case Description: A 28-year-old woman presented with back pain and worsening lower extremity pain, numbness, and weakness. Magnetic resonance imaging demonstrated an enhancing lumbar mass. However, at surgery, no discrete mass was identified. Multiple roots were grossly enlarged, and electrical stimulation identified the L4 root with the most abnormal findings. Despite an attempt at debulking, most of the mass could not be safely removed. The patient experienced incomplete improvement of the symptoms postoperatively but elected to forgo chemotherapy. The 3-month follow-up imaging study showed active lumbar spinal disease, and imaging and follow-up examinations at 27 months revealed no changes. Her symptoms were satisfactorily controlled with conservative therapy.

Conclusions: JXG of the spine is a rare disease with nonspecific clinical and radiographic findings that can make it difficult to diagnose and dictates the use of immunohistochemical staining. If possible, total surgical resection will offer the best outcomes; however, other modalities such as chemotherapy can be viable alternatives or adjuvant modalities.
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http://dx.doi.org/10.1016/j.wneu.2018.07.273DOI Listing
November 2018

BRAF mutation leading to central nervous system rosai-dorfman disease.

Ann Neurol 2018 07 16;84(1):147-152. Epub 2018 Aug 16.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.

Rosai-Dorfman disease (RDD) is an uncommon histiocytic proliferative disorder that can present in nodal, extranodal, or, extremely rarely, in central nervous system (CNS)-restricted form. RDD is characterized histologically as a non-Langerhans cell histiocytosis composed of atypical CD68 /S-100 /CD1a macrophages demonstrating prominent emperipolesis and effacement of the surrounding tissue. Previously thought to represent a reactive process, recent studies have raised the possibility that RDD and other histiocytic lesions, including Erdheim-Chester and Langerhans cell histiocytosis, are clonal processes linked to somatic mutations in the mitogen-activated protein (MAP) kinase pathway. Herein, we present a fatal case of RDD isolated to the CNS and used a next-generation targeted gene panel and Sanger sequencing to uncover a pathogenic deletion in the β3-αC loop of the kinase domain in exon 12 of BRAF. This mutation, previously described in melanoma and Langerhans cell histiocytosis, represents the first BRAF mutation of this kind identified in RDD. These findings support the idea that RDD is a neoplastic condition and raise the possibility that inhibitors of the MAP kinase pathway may be effective in RDD. Ann Neurol 2018;83:147-152.
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http://dx.doi.org/10.1002/ana.25281DOI Listing
July 2018

Methylation of hypoxia-inducible factor (HIF)-1α by G9a/GLP inhibits HIF-1 transcriptional activity and cell migration.

Nucleic Acids Res 2018 07;46(13):6576-6591

Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.

Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator in response to hypoxia and its transcriptional activity is crucial for cancer cell mobility. Here we present evidence for a novel epigenetic mechanism that regulates HIF-1 transcriptional activity and HIF-1-dependent migration of glioblastoma cells. The lysine methyltransferases G9a and GLP directly bound to the α subunit of HIF-1 (HIF-1α) and catalyzed mono- and di-methylation of HIF-1α at lysine (K) 674 in vitro and in vivo. K674 methylation suppressed HIF-1 transcriptional activity and expression of its downstream target genes PTGS1, NDNF, SLC6A3, and Linc01132 in human glioblastoma U251MG cells. Inhibition of HIF-1 by K674 methylation is due to reduced HIF-1α transactivation domain function but not increased HIF-1α protein degradation or impaired binding of HIF-1 to hypoxia response elements. K674 methylation significantly decreased HIF-1-dependent migration of U251MG cells under hypoxia. Importantly, we found that G9a was downregulated by hypoxia in glioblastoma, which was inversely correlated with PTGS1 expression and survival of patients with glioblastoma. Therefore, our findings uncover a hypoxia-induced negative feedback mechanism that maintains high activity of HIF-1 and cell mobility in human glioblastoma.
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http://dx.doi.org/10.1093/nar/gky449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061882PMC
July 2018

Genetic and Epigenetic Features of Rapidly Progressing IDH-Mutant Astrocytomas.

J Neuropathol Exp Neurol 2018 07;77(7):542-548

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.

IDH-mutant astrocytomas are significantly less aggressive than their IDH-wildtype counterparts. We analyzed The Cancer Genome Atlas dataset (TCGA) and identified a small group of IDH-mutant, WHO grade II-III astrocytomas (n = 14) with an unexpectedly poor prognosis characterized by a rapid progression to glioblastoma and death within 3 years of the initial diagnosis. Compared with IDH-mutant tumors with the typical, extended progression-free survival in a control group of age-similar patients, the tumors in the rapidly progressing group were characterized by a markedly increased level of overall copy number alterations ([CNA]; p = 0.006). In contrast, the mutation load was similar, as was the methylation pattern, being consistent with IDH-mutant astrocytoma. Two of the gliomas (14%) in the rapidly progressing, IDH-mutant group but none of the other grade II-III gliomas in the TCGA (n = 283) had pathogenic mutations in genes (FANCB and APC) associated with maintaining chromosomal stability. These results suggest that chromosomal instability can negate the beneficial effect of IDH mutations in WHO II-III astrocytomas. The mechanism of the increased CNA is unknown but in some cases appears to be due to mutations in genes with a role in chromosomal stability. Increased CNA could serve as a biomarker for tumors at risk for rapid progression.
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http://dx.doi.org/10.1093/jnen/nly026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005148PMC
July 2018
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