Gene Summary

Gene:ATRX; ATRX chromatin remodeler
Aliases: JMS, XH2, XNP, MRX52, RAD54, RAD54L, ZNF-HX
Summary:The protein encoded by this gene contains an ATPase/helicase domain, and thus it belongs to the SWI/SNF family of chromatin remodeling proteins. This protein is found to undergo cell cycle-dependent phosphorylation, which regulates its nuclear matrix and chromatin association, and suggests its involvement in the gene regulation at interphase and chromosomal segregation in mitosis. Mutations in this gene are associated with X-linked syndromes exhibiting cognitive disabilities as well as alpha-thalassemia (ATRX) syndrome. These mutations have been shown to cause diverse changes in the pattern of DNA methylation, which may provide a link between chromatin remodeling, DNA methylation, and gene expression in developmental processes. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2017]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcriptional regulator ATRX
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
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Cancer Overview

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Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: ATRX (cancer-related)

Buentzel J, Yao S, Elakad O, et al.
Expression and prognostic impact of alpha thalassemia/mental retardation X-linked and death domain-associated protein in human lung cancer.
Medicine (Baltimore). 2019; 98(31):e16712 [PubMed] Related Publications
Molecular characterization of lung cancer specimens after radical surgery offers additional prognostic information and may help to guide adjuvant therapeutic procedures. The transcriptional regulators alpha thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) have recently been described in different cancer entities as a useful prognostic biomarker. This study was initiated to explore their protein expression patterns and prognostic value in patients with operable lung cancer disease.The protein abundance (in the following text also named protein expression) of ATRX and DAXX were analyzed by immunohistochemistry in 194 samples of squamous cell lung carcinoma (SQCLC), 111 samples of pulmonary adenocarcinoma (AC) and 40 samples of small cell lung cancer (SCLC). The protein levels of ATRX and DAXX were correlated with clinicopathological characteristics and patient outcome.ATRX showed strong protein expression in 16.2% of AC, 11.9% of SQCLC, and 42.5% of SCLC. DAXX was highly expressed in 54.9% of AC, 76.2% of SQCLC, and 82.5% of SCLC. Immunostaining of both ATRX and DAXX were seen in 14.4% of AC, 11.3% of SQCLC, and 42.5% of SCLC. High protein expression of ATRX was a favorable prognostic marker for patients with AC (hazard ratio 0.38, P = .02). Sub-group analyses showed a significant correlation between ATRX and the clinical stage of SQCLC and SCLC. Histological grading and ATRX were also significantly associated in cases of SQCLC.The presence of ATRX and DAXX are correlated with lung cancer histology. Strong ATRX protein expression is associated with a significantly longer overall survival in patients with AC.

Malzkorn B, Reifenberger G
Integrated diagnostics of diffuse astrocytic and oligodendroglial tumors.
Pathologe. 2019; 40(Suppl 1):9-17 [PubMed] Related Publications
BACKGROUND: Diffuse astrocytic and oligodendroglial gliomas are the most common neuroepithelial tumors. Their classification is based on the integration of histological and molecular findings according to the classification of tumors of the central nervous system published by the World Health Organization (WHO) in 2016.
OBJECTIVES: This review describes the different entities and variants of diffuse gliomas and summarizes the current diagnostic criteria for these tumors.
MATERIALS AND METHODS: Based on the 2016 WHO classification and selected other publications, the histomolecular diagnostics of diffuse gliomas is presented and illustrated.
RESULTS: Diffuse gliomas are divided into isocitrate dehydrogenase (IDH)-mutant or IDH-wildtype gliomas by detection of mutations in the IDH1 or IDH2 genes. Among the IDH-mutant gliomas, oligodendroglial tumors are characterized by combined losses of chromosome arms 1p and 19q. Loss of nuclear expression of the ATRX protein is a marker of IDH- mutant astrocytic gliomas. Glioblastoma, IDH-wildtype, is the most common diffuse glioma. Diffuse and anaplastic astrocytic gliomas without IDH mutation should be further evaluated for molecular features of glioblastoma, IDH-wildtype. Diffuse gliomas in the thalamus, brainstem, or spinal cord carrying a histone 3 (H3)-K27M mutation are classified as diffuse midline gliomas, H3-K27M-mutant. By determining the IDH and 1p/19q status, oligoastrocytomas can be stratified into either astrocytic or oligodendroglial gliomas. Gliomatosis cerebri is no longer regarded as a distinct glioma entity.
CONCLUSIONS: Diffuse gliomas can today be classified accurately and reproducibly by means of histological, immunohistochemical, and molecular analyses.

Oppel F, Tao T, Shi H, et al.
Loss of atrx cooperates with p53-deficiency to promote the development of sarcomas and other malignancies.
PLoS Genet. 2019; 15(4):e1008039 [PubMed] Free Access to Full Article Related Publications
The SWI/SNF-family chromatin remodeling protein ATRX is a tumor suppressor in sarcomas, gliomas and other malignancies. Its loss of function facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells, while it also affects Polycomb repressive complex 2 (PRC2) silencing of its target genes. To further define the role of inactivating ATRX mutations in carcinogenesis, we knocked out atrx in our previously reported p53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas. Complete inactivation of atrx using CRISPR/Cas9 was lethal in developing fish and resulted in an alpha-thalassemia-like phenotype including reduced alpha-globin expression. In p53/nf1-deficient zebrafish neither peripheral nerve sheath tumors nor gliomas showed accelerated onset in atrx+/- fish, but these fish developed various tumors that were not observed in their atrx+/+ siblings, including epithelioid sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma and rare types of carcinoma. These cancer types are included in the AACR Genie database of human tumors associated with mutant ATRX, indicating that our zebrafish model reliably mimics a role for ATRX-loss in the early pathogenesis of these human cancer types. RNA-seq of p53/nf1- and p53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied ALT-mediated lengthening of the telomeres in atrx-mutant samples. Moreover, inactivating mutations in atrx disturbed PRC2-target gene silencing, indicating a connection between ATRX loss and PRC2 dysfunction in cancer development.

Ahmed KI, Govardhan HB, Roy M, et al.
Cell-free circulating tumor DNA in patients with high-grade glioma as diagnostic biomarker - A guide to future directive.
Indian J Cancer. 2019 Jan-Mar; 56(1):65-69 [PubMed] Related Publications
BACKGROUND: Owing to the aggressive nature of high-grade gliomas (HGGs), its early diagnosis holds the key to a favorable prognosis. Currently, tissue biopsy is the gold standard to verify HGG's initial diagnosis and can be challenging due to its invasive nature. In this study, our objective was a noninvasive panel for timely detection of HGG and its progression using cell-free circulating tumor DNA (cfTDNA).
MATERIALS AND METHODS: Twenty-seven patients with HGG were tested with a 50-gene tumor panel. cfTDNA isolated from serum was checked for single-nucleotide variations (SNVs) or copy number alterations using targeted next-generation sequencing, with further validation of results by checking respective formalin-fixed paraffin-embedded tumor tissues for the same genetic alterations.
RESULTS: About 88.8% of the patients were detected with HGG-associated cfTDNA. Around 25% patients were detected with one, 25% patients had three, 25% patients had four, and 12.5% patients each had five and six genetic alterations. About 12 of 50 genes were detected in the serum samples. The SNVs detected included TP53 in 87.5% of patients; PIK3CA and EGFR in 50% of patients; PTEN in 37.5%; KIT and VHL in each 25% of patients; and RB1, NF2, MET, ATRX, CDK2A, and CTNNB1 each in 8.3%-16.6%. On combining EGFR, KIT, PTEN, PIK3CA, TP53, and VHL genes (Govardhan Diagnostic Genetic Module for high-grade glioma), at least one of the genetic alterations was found in 100% of patients.
Conclusion: These findings illustrate that cfTDNA is easily demonstrable and can be used as a surrogate to tissue biopsy in brain tumor.

Rao S, Kanuri NN, Nimbalkar V, et al.
High frequency of H3K27M immunopositivity in adult thalamic glioblastoma.
Neuropathology. 2019; 39(2):78-84 [PubMed] Related Publications
Adult thalamic glioblastomas (GBM) are uncommon tumors with limited available molecular data. One of the reported molecular alterations in these tumors is the H3K27M mutation. It has been documented that H3K27M mutation is found in a high proportion of pediatric thalamic gliomas. In this study, we have analyzed the molecular alterations exclusive to adult thalamic GBM. This is a 6 years retrospective study of adult thalamic GBM patients who underwent surgical decompression of the tumor. Clinical data were obtained from the case records. Immunohistochemistry (IHC) was performed on the tumors using antibodies directed against the gene products of R132H mutant isocitrate dehydrogenase 1 (IDH1), alpha-thalassemia/mental retardation X-linked (ATRX), p53, H3K27M, H3K27me3, and V600E mutant BRAF. Molecular analyses were carried out to detect other IDH1 and IDH2 mutations, O

Sonoda Y, Yokoo H, Tanaka S, et al.
Practical procedures for the integrated diagnosis of astrocytic and oligodendroglial tumors.
Brain Tumor Pathol. 2019; 36(2):56-62 [PubMed] Related Publications
The publication of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 WHO CNS) represented a major change in the classification of brain tumors. However, many pathologists in Japan cannot diagnose astrocytic or oligodendroglial tumors according to the 2016 WHO CNS due to financial or technical problems. Therefore, the Japan Society of Brain Tumor Pathology established a committee for molecular diagnosis to facilitate the integrated diagnosis of astrocytic and oligodendroglial tumors in Japan. We created three levels of diagnoses: Level 1 was defined as simple histopathological diagnosis using hematoxylin and eosin staining and routine cell lineage-based immunostaining. Level 2 was defined as immunohistochemical diagnosis using immunohistochemical examinations using R132H mutation-specific IDH1, ATRX, and/or p53 antibodies. Level 3 was defined as molecular diagnosis, such as diagnosis based on 1p/19q status or the mutation status of the IDH1 and IDH2 genes. In principle, astrocytic and oligodendroglial tumors should be diagnosed based on the 2016 WHO CNS and/or cIMPACT-NOW criteria; however, the findings obtained through our diagnostic flowchart can be added to the histological diagnosis in parentheses. This classification system would be helpful for pathologists with limited resources.

Wang Y, Yang J, Wild AT, et al.
G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma.
Nat Commun. 2019; 10(1):943 [PubMed] Free Access to Full Article Related Publications
Mutational inactivation of ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in large subsets of malignant glioma. Yet the pathogenic consequences of ATRX deficiency remain unclear, as do tractable mechanisms for its therapeutic targeting. Here we report that ATRX loss in isogenic glioma model systems induces replication stress and DNA damage by way of G-quadruplex (G4) DNA secondary structure. Moreover, these effects are associated with the acquisition of disease-relevant copy number alterations over time. We then demonstrate, both in vitro and in vivo, that ATRX deficiency selectively enhances DNA damage and cell death following chemical G4 stabilization. Finally, we show that G4 stabilization synergizes with other DNA-damaging therapies, including ionizing radiation, in the ATRX-deficient context. Our findings reveal novel pathogenic mechanisms driven by ATRX deficiency in glioma, while also pointing to tangible strategies for drug development.

Tanori M, Pannicelli A, Pasquali E, et al.
Cancer risk from low dose radiation in Ptch1
DNA Repair (Amst). 2019; 74:70-79 [PubMed] Related Publications
DSBs are harmful lesions produced through endogenous metabolism or by exogenous agents such as ionizing radiation, that can trigger genomic rearrangements. We have recently shown that exposure to 2 Gy of X-rays has opposite effects on the induction of Shh-dependent MB in NHEJ- and HR-deficient Ptch1

Kim J, Kim JH, Kang HG, et al.
Integrated molecular characterization of adult soft tissue sarcoma for therapeutic targets.
BMC Med Genet. 2018; 19(Suppl 1):216 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Several studies have investigated the molecular drivers and therapeutic targets in adult soft tissue sarcomas. However, such studies are limited by the genomic heterogeneity and rarity of sarcomas, particularly in those with complex and unbalanced karyotypes. Additional biomarkers are needed across sarcoma types to improve therapeutic strategies. To investigate the molecular characteristics of complex karyotype sarcomas (CKSs) for therapeutic targets, we performed genomic profiling.
RESULTS: The mutational landscape showed that TP53, ATRX, and PTEN genes were highly mutated. CKS samples were categorized into three groups based on copy number variations that were associated with CDK4 and RB1 signatures. Integrated analysis of genomic and transcriptomic data revealed several pathways related to PDGFR, which could be a strategic target for anti-sarcoma therapy.
CONCLUSIONS: This study provides a detailed molecular classification of CKSs and proposes several therapeutic targets. Targeted or combinational therapies for treating CKS should be considered before chemotherapy.

D'Angelo F, Ceccarelli M, Tala, et al.
The molecular landscape of glioma in patients with Neurofibromatosis 1.
Nat Med. 2019; 25(1):176-187 [PubMed] Related Publications
Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.

Synhaeve NE, van den Bent MJ, French PJ, et al.
Clinical evaluation of a dedicated next generation sequencing panel for routine glioma diagnostics.
Acta Neuropathol Commun. 2018; 6(1):126 [PubMed] Free Access to Full Article Related Publications
Since 2013 next-generation sequencing (NGS) targeting genes mutated in diffuse gliomas is part of routine diagnostics in our institute. In the present report, we evaluate the use of this custom tailored NGS platform on 434 samples. The NGS panel assesses mutations in ATRX, CIC, EGFR, FUBP1, NOTCH1, PTEN; H3F3A, IDH1/2, PIK3CA, and BRAF, amplifications in EGFR or MDM2 and copy number alterations (CNA) of chromosome 1p, 7, 10 and 19q. TERT promoter mutations were assessed separately when indicated. Of the 433 samples of individual tumors with NGS data available, 176 cases were diagnosed as grade 2 or 3 glioma (40.6) and in 201 patients a glioblastoma (46.4%). Of the remaining 56 patients, 22 had inconclusive histology. In 378 cases (87.1%) a diagnosis solely based on glioma-targeted NGS could be established and resulted in a different diagnosis in ~ 1/4 of the cases. In 17 out of 22 cases without a conclusive histological diagnosis NGS resulted in a molecular diagnosis.The current study on a large cohort of patients confirms the diagnostic strength of the platform we developed, with a clear separation of glioma subgroups with different outcomes. It demonstrates the diagnostic value and the efficiency of glioma-targeted NGS for routine glioma diagnostics allowing with a single assay a glioma diagnosis in the large majority of cases. It allows in one run the molecular assessments required for the WHO classification of diffuse gliomas, including the recent recommendations to assess copy number alterations of chromosome 7 and 10, and of the TERT promoter region in IDHwt lower grade glioma.

Williams EA, Miller JJ, Tummala SS, et al.
TERT promoter wild-type glioblastomas show distinct clinical features and frequent PI3K pathway mutations.
Acta Neuropathol Commun. 2018; 6(1):106 [PubMed] Free Access to Full Article Related Publications
TERT promoter (TERTp) mutations are found in the majority of World Health Organization (WHO) grade IV adult IDH wild-type glioblastoma (IDH-wt GBM). Here, we characterized the subset of IDH-wt GBMs that do not have TERTp mutations. In a cohort of 121 adult grade IV gliomas, we identified 109 IDH-wt GBMs, after excluding 11 IDH-mutant cases and one H3F3A -mutant case. Within the IDH-wt cases, 16 cases (14.7%) were TERTp wild-type (TERTp-wt). None of the 16 had BRAF V600E or H3F3A G34 hotspot mutations. When compared to TERTp mutants, patients with TERTp-wt GBMs, were significantly younger at first diagnosis (53.2 years vs. 60.7 years, p = 0.0096), and were more frequently found to have cerebellar location (p = 0.0027). Notably, 9 of 16 (56%) of TERTp-wt GBMs contained a PIK3CA or PIK3R1 mutation, while only 16/93 (17%) of TERTp-mutant GBMs harbored these alterations (p = 0.0018). As expected, 8/16 (50%) of TERTp-wt GBMs harbored mutations in the BAF complex gene family (ATRX, SMARCA4, SMARCB1, and ARID1A), compared with only 8/93 (9%) of TERTp-mutant GBMs (p = 0.0003). Mutations in BAF complex and PI3K pathway genes co-occurred more frequently in TERTp-wt GBMs (p = 0.0002), an association that has been observed in other cancers, suggesting a functional interaction indicative of a distinct pathway of gliomagenesis. Overall, our finding highlights heterogeneity within WHO-defined IDH wild-type GBMs and enrichment of the TERTp-wt subset for BAF/PI3K-altered tumors, potentially comprising a distinct clinical subtype of gliomas.

Chan CS, Laddha SV, Lewis PW, et al.
ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup.
Nat Commun. 2018; 9(1):4158 [PubMed] Free Access to Full Article Related Publications
The commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. We genotyped 64 PanNETs and found 58% carry ATRX, DAXX, and MEN1 mutations (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis to reveal two distinct subgroups with one consisting entirely of A-D-M mutant PanNETs. Two genes differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha-cells (FDR q-value < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.

Vizcaino MA, Palsgrove DN, Yuan M, et al.
Granular cell astrocytoma: an aggressive IDH-wildtype diffuse glioma with molecular genetic features of primary glioblastoma.
Brain Pathol. 2019; 29(2):193-204 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Granular cell astrocytoma (GCA) is a rare adult infiltrating glioma subtype. We studied a series of 39 GCAs. Median age of presentation was 57.8 years and most cases developed in the frontal or temporal lobes. Tumors included grade II (n = 14), grade III (n = 11), and grade IV (n = 14) by WHO criteria. Granular cell morphology was diffuse in 31 (79%) cases and partial in eight (21%). Immunohistochemistry showed frequent positivity for GFAP (28 of 31), OLIG2 (16 of 16), and CD68 (27 of 30), but HAM56, CD163, and IBA-1 histiocytic markers were all negative (22 of 22). IDH1(R132H) was negative in all the cases tested (16 of 16), while ATRX expression was retained (12 of 12). Cytogenetics demonstrated monosomy 10 (6 of 6) cases, +7 in 4 (of 6), -13q in 4 of 6, and -14 in 4 of 6. Next-generation sequencing demonstrated mutations in PTEN/PIK3 genes in 6/13 (46%), NF1 in 3 of 10 (30%), TP53 in 3 of 13 (23%), PALB2 in 3 of 10 (30%), STAG2 in 3 of 10 (30%), EGFR mutation/amplification in 3 of 13 (23%), and AR in 2 of 10 (20%). CDKN2A/B deletion was identified in 5 of 13 (30%) cases (homozygous deletion in 4). The TERT C228T mutation was identified in 9 of 13 (69%). No mutations were encountered in IDH1, IDH2, CIC, FUBP1, H3F3A, BRAF or ATRX genes. The mean overall survival was 11.3 months. Patients >60 years old at diagnosis had a worse survival than patients <60 years (P = 0.001). There were no statistically significant differences in survival by WHO grade, extent of granular cell change, sex or MIB-1 (P > 0.05). GCA is a variant of IDH-wildtype diffuse glioma with aggressive behavior irrespective of grade and extent of granular cell morphology, and with molecular genetic features corresponding to primary glioblastoma.

Ding Y, Wang C, Li X, et al.
Novel clinicopathological and molecular characterization of metanephric adenoma: a study of 28 cases.
Diagn Pathol. 2018; 13(1):54 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
BACKGROUND: Metanephric adenoma is a rare, benign renal neoplasm with occasional misdiagnosis. However, its molecular characterization is not fully understood.
METHODS: In this study, we use the hybrid capture-based Next-Generation Sequencing to sequence a panel of 295 well-established oncogene or tumor suppressor genes in 28 cases of MA patients in China. Novel clinicopathological markers associated with the mitogen-activated protein kinase (MAPK) pathway in metanephric adenoma were detected by immunohistochemistry.
RESULTS: It was found that except for BRAF (22/28) mutations (c.1799 T > A, p.V600E), NF1 (6/28), NOTCH1 (5/28), SPEN (5/28), AKT2 (4/28), APC (4/28), ATRX (3/28), and ETV4 (3/28) mutations could also be detected. Meanwhile, a novel and rare gene fusion of STARD9-BRAF, CUX1-BRAF, and LOC100507389-BRAF was detected in one MA patient. In addition, although MEK phosphorylation was normally activated, the phosphorylation level of ERK was low in metanephric adenoma cases. Highly expressed p16 and DUSP6 may have contributed to these results, which maintained MA as a benign renal tumor.
CONCLUSIONS: This study provides novel molecular and pathological markers for metanephric adenoma, which could improve its diagnosis and increase the understanding of its pathologic mechanism.

Phillips JJ, Gong H, Chen K, et al.
The genetic landscape of anaplastic pleomorphic xanthoastrocytoma.
Brain Pathol. 2019; 29(1):85-96 [PubMed] Related Publications
Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of 23 PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n = 2) or promoter hotspot mutation (n = 5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.

Koba H, Kimura H, Nishikawa S, et al.
Next-generation sequencing analysis identifies genomic alterations in pathological morphologies: A case of pulmonary carcinosarcoma harboring EGFR mutations.
Lung Cancer. 2018; 122:146-150 [PubMed] Related Publications
OBJECTIVES: Pulmonary carcinosarcoma is a rare lung malignancy and little analysis has been performed to identify associated genomic alterations. We used next-generation sequencing (NGS) to analyze a pulmonary carcinosarcoma harboring an epidermal growth factor receptor (EGFR) mutation.
MATERIALS AND METHODS: The lung carcinosarcoma used for this study contained components of adenocarcinoma and chondrosarcoma and originated from a 73-year-old female. Both components carried deletion mutations in exon 19 of EGFR and both had equally strong EGFR protein expression. This study analyzed the biological and genetic characteristics of both components, using NGS and immunohistochemical (IHC) staining.
RESULTS AND CONCLUSION: IHC staining revealed that both total EGFR and deletion mutation specific EGFR proteins were equally expressed in both components. Intriguingly, identification of genomic alterations with NGS found five identical alterations in four genes (EGFR, CBLB, TP53, and MEN1) that were shared by the two components, and that each component had a large number of individual alterations. Additionally, we focused on an alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutation which was only present in the sarcoma component. ATRX protein expression was also only detected in the sarcoma component. This is the first report of the exhaustive genomic alterations in a pulmonary carcinosarcoma harboring an EGFR mutation. The results show that our case had the same EGFR status in both components. The EGFR mutation is the driver mutation in both components. In our case, we found that TP53 may be a common alteration and ATRX may be a specific alteration in the sarcoma component.

Saglam O, Naqvi SMH, Zhang Y, et al.
Female genitourinary tract melanoma: mutation analysis with clinicopathologic correlation: a single-institution experience.
Melanoma Res. 2018; 28(6):586-591 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Female genitourinary tract melanoma (FGTM) is a rare and often-fatal form of mucosal melanoma. We describe our institutional experience with 55 cases of FGTM, 16 of which were evaluated with next-generation sequencing targeting 151 cancer-associated genes. Tumors tended to be thicker than conventional melanoma at presentation (median: 3.2 mm), were frequently ulcerated (50%), and characterized by incomplete initial resections. Regional lymph nodes showed tumor involvement at presentation in 28% of cases. With a median follow-up of 23.6 months, the median recurrence free survival was 14.5 months and the median overall survival was 29.6 months. Genomic analysis revealed mutually exclusive mutations in TP53 and KIT in 25%, while 19% of cases showed BRAF mutation. NRAS mutation was found in 13% of cases. Mutation in ATRX, previously undescribed in mucosal melanoma, was seen in three (10%) of 16 patients. Only invasive melanoma cases were included in statistical analyses. Patients with three or more mutations had marginally worse overall survival rates than those with two or less (P=0.07). Further studies are required for potential adjuvant treatment modalities to improve survival outcomes of FGTM.

Ogura K, Hosoda F, Arai Y, et al.
Integrated genetic and epigenetic analysis of myxofibrosarcoma.
Nat Commun. 2018; 9(1):2765 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Myxofibrosarcoma (MFS) is a common adult soft tissue sarcoma characterized by an infiltrative growth pattern and a high local recurrence rate. Here we report the genetic and epigenetic landscape of MFS based on the results of whole-exome sequencing (N = 41), RNA sequencing (N = 29), and methylation analysis (N = 41), using 41 MFSs as a discovery set, and subsequent targeted sequencing of 140 genes in the entire cohort of 99 MFSs and 17 MFSs' data from TCGA. Fourteen driver genes are identified, including potentially actionable therapeutic targets seen in 37% of cases. There are frequent alterations in p53 signaling (51%) and cell cycle checkpoint genes (43%). Other conceivably actionable driver genes including ATRX, JAK1, NF1, NTRK1, and novel oncogenic BRAF fusion gene are identified. Methylation patterns cluster into three subtypes associated with unique combinations of driver mutations, clinical outcomes, and immune cell compositions. Our results provide a valuable genomic resource to enable the design of precision medicine for MFS.

Wang AC, Jones DTW, Abecassis IJ, et al.
Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations.
Mol Cancer Res. 2018; 16(10):1491-1498 [PubMed] Related Publications
Desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA) are extremely rare tumors that typically arise in infancy; however, these entities have not been well characterized in terms of genetic alterations or clinical outcomes. Here, through a multi-institutional collaboration, the largest cohort of DIG/DIA to date is examined using advanced laboratory and data processing techniques. Targeted DNA exome sequencing and DNA methylation profiling were performed on tumor specimens obtained from different patients (

D'Amico RS, Zanazzi G, Wu P, et al.
Pineal region glioblastomas display features of diffuse midline and non-midline gliomas.
J Neurooncol. 2018; 140(1):63-73 [PubMed] Related Publications
INTRODUCTION: Pineal region glioblastomas (GBM) are very rare, with approximately 46 cases described in the literature. The epidemiology, pathogenesis, and treatment of these lesions are poorly characterized.
METHODS: We identified all cases of pineal region GBM treated surgically at our institution between 1990 and 2017. Demographic and clinical follow-up data were extracted from the medical records for all cases. Pathology was reviewed and classified according to 2016 World Health Organization (WHO) criteria. Specific attention was given to the frequency of histone H3 K27M mutations in these midline gliomas.
RESULTS: Eight patients (seven men, one woman) with pineal region GBM, WHO grade IV, were identified. The most common presenting symptoms were headache (75%), vision changes (75%), and gait imbalance/ataxia (50%). Median age at diagnosis was 48.5 years (range 36-74 years). Radical subtotal resection, via a supracerebellar infratentorial approach, was achieved in 75% of patients. Review of the surgical pathology revealed seven primary GBMs (including one giant cell GBM) and one pineal region GBM that developed three years after resection of a pineal parenchymal tumor of intermediate differentiation. No cases demonstrated evidence of IDH-1 R132H mutation (N = 6) or 1p/19q co-deletion (N = 3). One case tested positive for the histone H3 K27M-mutation. Targeted exome sequencing of 467 cancer-related genes revealed nonsense mutations in ATRX and NF1. Adjuvant radiation and chemotherapy was employed in 87.5% and 75.0% of patients, respectively. Median overall survival (OS) was 15 months (range 2-24 months) from GBM diagnosis.
CONCLUSIONS: This study expands the clinical and pathologic spectrum of pineal region GBM, and provides the first report of the genetic landscape of these tumors.

Demicco EG, Wani K, Ingram D, et al.
TERT promoter mutations in solitary fibrous tumour.
Histopathology. 2018; 73(5):843-851 [PubMed] Related Publications
AIMS: TERT promoter mutations have been reported in 22% of solitary fibrous tumours (SFT) and have been associated with poor outcomes. We performed testing for TERT hot-spot mutations in a large series of SFT in order to confirm this finding and explore clinicopathological correlates of mutation status.
METHODS AND RESULTS: PCR for TERT hot-spot mutations C250T and C228T was performed on DNA extracted from 216 SFT and mutation status correlated with clinicopathological factors, including predicted risk for metastasis using a previously published model. Testing was successful in 189 tumours from 172 patients, and mutations were present in 29%. The presence of TERT promoter mutation was associated with larger primary tumour size, necrosis and older patient age. TERT promoter mutations were most common in high-risk tumours (nine of 20, 45%), and were present in 11 of 26 (42%) moderate-risk tumours and 14 of 67 (21%) low-risk tumours (P = 0.004). Overall, TERT mutations were associated with shorter time to first metastasis (P = 0.04), but had no impact on overall survival. TERT promoter mutation status was found not to provide additional prognostic information in low- and high-risk SFT, but did identify a group of patients with intermediate risk SFT who had an increased risk of metastasis.
CONCLUSIONS: TERT promoter mutations were more frequent in SFT with higher risk of metastasis, but TERT promoter mutation status was not a reliable predictor of clinical outcome by itself. However, mutations in the TERT promoter may be useful in further stratifying patients with intermediate risk tumours.

Dutta B, Park JE, Qing ITY, et al.
Soy-Derived Phytochemical Genistein Modifies Chromatome Topology to Restrict Cancer Cell Proliferation.
Proteomics. 2018; 18(16):e1700474 [PubMed] Related Publications
Epidemiological data indicate that human cancer risk is significantly reduced by the consumption of soy-based foods containing the "phytoestrogen" genistein, which can signal via host cell estrogen receptors. While additional chemoprotective effects of genistein induced by epigenetic factors have also been reported, the key molecules and mechanisms involved are poorly defined. We therefore investigated genistein effects on chromatin-bound proteins in the estrogen receptor-deficient cell line MDA-MB-231 which is insensitive to phytoestrogen signaling. After exposure to low-dose genistein for >1 month, MDA-MB-231 cells exhibited stable epigenetic alterations that are analyzed via partial MNase digestion and TMT-based quantitative proteomics. 3177 chromatin-bound proteins are identified with high confidence, including 882 molecules that displayed altered binding topology after cell conditioning with genistein. Prolonged phytochemical exposure conferred heritable changes in the binding topology of key epigenetic regulators including ATRX, SUV39H1/H2, and HP1BP3 that are preserved in untreated progeny, resulting in sustained downregulation of proliferation genes and reduced cell growth. These data indicate that soy derivative genistein exerts complex estrogen receptor-independent effects on the epigenome likely to influence tumorigenesis by restricting cell growth.

Wang R, Li Y, Chen Y, et al.
Inhibition of RAD54B suppresses proliferation and promotes apoptosis in hepatoma cells.
Oncol Rep. 2018; 40(3):1233-1242 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
RAD54 homolog B is a central motor protein of homologous recombination (HR), which plays an important role in the development and evolution of human cancer. Recent studies have indicated that RAD54B is aberrantly expressed in a variety of cancers and exhibits numerous biological functions, including participating in the repair of DNA double strand breaks. However, the expression and function of RAD54B in liver cancer have not yet been reported. The aim of the present study was to investigate the expression of RAD54B and elucidate its role in liver cancer cell lines by inhibiting RAD54B using a lentivirus-mediated shRNA interference system. We also assessed the effect of RAD54B on cell proliferation, colony formation, cell cycle distribution and cell apoptosis in BEL-7404 and SMMC-7721 cell lines using shRAD54B or shCtrl transfection. Furthermore, we analyzed the relationship between the expression of RAD54B protein, as measured by immunohistochemical staining, and the prognosis of patients with hepatoma. We found that RAD54B was highly expressed in liver cancer cell lines compared with the normal hepatic cell line LO2. Similarly, positive expression of RAD54B, which is associated with poor prognosis, was also observed in 52/83 samples of liver cancer tissue. Additionally, RAD54B downregulation significantly inhibited cell proliferation and colony formation, while also inducing G1/S cell cycle arrest and apoptosis in BEL-7404 and SMMC-7721 cells. These results indicated that RAD54B has oncogenic properties, and may be a potential treatment target for liver cancer patients.

Tang L, Deng L, Bai HX, et al.
Reduced expression of DNA repair genes and chemosensitivity in 1p19q codeleted lower-grade gliomas.
J Neurooncol. 2018; 139(3):563-571 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Lower-grade gliomas (LGGs, defined as WHO grades II and III) with 1p19q codeletion have increased chemosensitivity when compared to LGGs without 1p19q codeletion, but the mechanism is currently unknown.
METHODS: RNAseq data from 515 LGG patients in the Cancer Genome Atlas (TCGA) were analyzed to compare the effect of expression of the 9 DNA repair genes located on chromosome arms 1p and 19q on progression free survival (PFS) and overall survival (OS) between patients who received chemotherapy and those who did not. Chemosensitivity of cells with DNA repair genes knocked down was tested using MTS cell proliferation assay in HS683 cell line and U251 cell line.
RESULTS: The expression of 9 DNA repair genes on 1p and 19q was significantly lower in 1p19q-codeleted tumors (n = 175) than in tumors without the codeletion (n = 337) (p < 0.001). In LGG patients who received chemotherapy, lower expression of LIG1, POLD1, PNKP, RAD54L and MUTYH was associated with longer PFS and OS. This difference between chemotherapy and non-chemotherapy groups in the association of gene expression with survival was not observed in non-DNA repair genes located on chromosome arms 1p and 19q. MTS assays showed that knockdown of DNA repair genes LIG1, POLD1, PNKP, RAD54L and MUTYH significantly inhibited recovery in response to temozolomide when compared with control group (p < 0.001).
CONCLUSIONS: Our results suggest that reduced expression of DNA repair genes on chromosome arms 1p and 19q may account for the increased chemosensitivity of LGGs with 1p19q codeletion.

Haase S, Garcia-Fabiani MB, Carney S, et al.
Mutant ATRX: uncovering a new therapeutic target for glioma.
Expert Opin Ther Targets. 2018; 22(7):599-613 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
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.

Zhang J, Jiang J, Luo Y, et al.
Molecular evaluation of a sporadic paraganglioma with concurrent IDH1 and ATRX mutations.
Endocrine. 2018; 61(2):216-223 [PubMed] Related Publications
PURPOSE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors of neural crest origin. Germline or somatic mutations of numerous genes have been implicated in the pathogenesis of PPGLs, including the isocitrate dehydrogenase 1 (IDH1) gene and alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene. Although concurrent IDH1 and ATRX mutations are frequently seen in gliomas, they have never been reported together in PPGLs. The aim of this study was to characterize one paraganglioma with concurrent IDH1 and ATRX mutations identified by whole exome sequencing.
METHODS: Leukocyte and tumor DNA were used for whole exome sequencing and Sanger sequencing. 2-hydroxyglurarate level and the global DNA methylation status in the tumor were measured. ATRX's cDNA transcripts were analyzed. Tyrosine hydroxylase (TH), HIF1α and ATRX staining, as well as telomere-specific FISH was also performed.
RESULTS: The presence of a somatic IDH1 (c.394C>T, p.R132C) mutation and a concurrent somatic ATRX splicing mutation (c.4318-2A>G) in the current case was confirmed. Dramatic accumulation of 2-hydroxyglutarate was detected in the paraganglioma without the global DNA hypermethylation, and pseudohypoxia was also activated. Importantly, immunohistochemistry revealed negative TH staining in the tumor and the first exon region of TH gene was hypermethylated resulting in normal plasma metanephrines. The splicing ATRX mutation resulted in two transcripts, causing frameshifts. Immunohistochemistry revealed scarce ATRX staining in the tumor. Alternative lengthening of telomeres (ALT) was detected by FISH.
CONCLUSIONS: This case represents the first concurrence of IDH1 and ATRX mutations in PPGLs. Although relatively rare, a somatic R132C mutation of IDH1 might play a role in a small subset of sporadic PPGLs.

Tauziède-Espariat A, Saffroy R, Pagès M, et al.
Cerebellar high-grade gliomas do not present the same molecular alterations as supratentorial high-grade gliomas and may show histone H3 gene mutations.
Clin Neuropathol. 2018 Sep/Oct; 37(5):209-216 [PubMed] Related Publications
Numerous molecular alterations have been described in supratentorial high-grade gliomas (1p19q co-deletion, IDH1/2, histone H3, hTERT promotor mutations, loss of ATRX) which have led to a new histomolecular classification of diffuse gliomas. We aimed at describing these alterations in a series of 19 adults with pure cerebellar high-grade gliomas. Systematic immunohistochemical analyses, including that of IDH1R132H, ATRX, p53, PTEN, EGFR, p16, FGFR3, BRAFV600E, mismatch repair proteins, H3K27me3, H3K36me3, and H3K27M; molecular analyses of IDH1/2, hTERT, BRAF, H3F3A, and HIST1H3B mutation hotspots; and EGFR, PTEN FISH were retrospectively performed in a multicentric study. We histopathologically identified 14 glioblastomas, 4 grade III astrocytomas and 1 gliosarcoma. Two cases showed a H3F3A K27M mutation. Only one case harbored a classical profile of glioblastoma with hTERT mutation, EGFR gain and 10q loss. The most frequent alteration was the absence of p16 immunoexpression. We report a histomolecular analysis of pure cerebellar high grade gliomas. The histomolecular profile appears to be different from that of supratentorial gliomas, with no IDH1/2 gene mutations and only 1 case with a classic profile of de novo glioblastoma. In 2 cases, we identified H3F3A K27M mutation, classically described in pediatric midline gliomas.

Diplas BH, He X, Brosnan-Cashman JA, et al.
The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma.
Nat Commun. 2018; 9(1):2087 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH). These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX-mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, about 20% of glioblastomas lack alterations in TERTp and IDH. These tumors, designated TERTp

Lee SC
Diffuse Gliomas for Nonneuropathologists: The New Integrated Molecular Diagnostics.
Arch Pathol Lab Med. 2018; 142(7):804-814 [PubMed] Related Publications
Diffuse gliomas comprise the bulk of "brain cancer" in adults. The recent update to the 4th edition of the World Health Organization's classification of tumors of the central nervous system reflects an unprecedented change in the landscape of the diagnosis and management of diffuse gliomas that will affect all those involved in the management and care of patients. Of the recently discovered gene alterations, mutations in the Krebs cycle enzymes isocitrate dehydrogenases (IDHs) 1 and 2 have fundamentally changed the way the gliomas are understood and classified. Incorporating information on a few genetic parameters (IDH, ATRX and/or p53, and chromosome 1p19q codeletion), a relatively straightforward diagnostic algorithm has been generated with robust and reproducible results that correlate with patients' survival far better than relying on conventional histology alone. Evidence also supports the conclusion that the vast majority of diffuse gliomas without IDH mutations (IDH-wild-type astrocytomas) behave like IDH-wild-type glioblastomas ("molecular GBM"). Together, these changes reflect a big shift in the practice of diagnostic neuropathology in which tumor risk stratification aligns better with molecular information than histology/grading. The purpose of this review is to provide the readers with a brief synopsis of the changes in the 2016 World Health Organization update with an emphasis on diffuse gliomas and to summarize key gene abnormalities on which these classifications are based. Practical points involved in day-to-day diagnostic workup are also discussed, along with a comparison of the various diagnostic tests, including immunohistochemistry, with an emphasis on targeted next-generation sequencing panel technology as a future universal approach.

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