DAXX

Gene Summary

Gene:DAXX; death domain associated protein
Aliases: DAP6, EAP1, BING2
Location:6p21.32
Summary:This gene encodes a multifunctional protein that resides in multiple locations in the nucleus and in the cytoplasm. It interacts with a wide variety of proteins, such as apoptosis antigen Fas, centromere protein C, and transcription factor erythroblastosis virus E26 oncogene homolog 1. In the nucleus, the encoded protein functions as a potent transcription repressor that binds to sumoylated transcription factors. Its repression can be relieved by the sequestration of this protein into promyelocytic leukemia nuclear bodies or nucleoli. This protein also associates with centromeres in G2 phase. In the cytoplasm, the encoded protein may function to regulate apoptosis. The subcellular localization and function of this protein are modulated by post-translational modifications, including sumoylation, phosphorylation and polyubiquitination. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:death domain-associated protein 6
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: DAXX (cancer-related)

Backman S, Norlén O, Eriksson B, et al.
Detection of Somatic Mutations in Gastroenteropancreatic Neuroendocrine Tumors Using Targeted Deep Sequencing.
Anticancer Res. 2017; 37(2):705-712 [PubMed] Related Publications
Mutations affecting the mechanistic target of rapamycin (MTOR) signalling pathway are frequent in human cancer and have been identified in up to 15% of pancreatic neuroendocrine tumours (NETs). Grade A evidence supports the efficacy of MTOR inhibition with everolimus in pancreatic NETs. Although a significant proportion of patients experience disease stabilization, only a minority will show objective tumour responses. It has been proposed that genomic mutations resulting in activation of MTOR signalling could be used to predict sensitivity to everolimus.
PATIENTS AND METHODS: Patients with NETs that underwent treatment with everolimus at our Institution were identified and those with available tumour tissue were selected for further analysis. Targeted next-generation sequencing (NGS) was used to re-sequence 22 genes that were selected on the basis of documented involvement in the MTOR signalling pathway or in the tumourigenesis of gastroenterpancreatic NETs. Radiological responses were documented using Response Evaluation Criteria in Solid Tumours.
RESULTS: Six patients were identified, one had a partial response and four had stable disease. Sequencing of tumour tissue resulted in a median sequence depth of 667.1 (range=404-1301) with 1-fold coverage of 95.9-96.5% and 10-fold coverage of 87.6-92.2%. A total of 494 genetic variants were discovered, four of which were identified as pathogenic. All pathogenic variants were validated using Sanger sequencing and were found exclusively in menin 1 (MEN1) and death domain associated protein (DAXX) genes. No mutations in the MTOR pathway-related genes were observed.
CONCLUSION: Targeted NGS is a feasible method with high diagnostic yield for genetic characterization of pancreatic NETs. A potential association between mutations in NETs and response to everolimus should be investigated by future studies.

Kawashima M, Kojima M, Ueda Y, et al.
Telomere biology including TERT rearrangements in neuroblastoma: a useful indicator for surgical treatments.
J Pediatr Surg. 2016; 51(12):2080-2085 [PubMed] Related Publications
PURPOSE: Our telomere biology study of neuroblastomas (NBLs) has revealed that unfavorable NBLs acquired telomere stabilization by telomerase activation or ALT (alternative lengthening of telomeres). Recently, genomic rearrangements in a region proximal to the telomerase reverse transcriptase (TERT) gene have been discovered in NBLs. In this study, TERT rearrangements were examined in NBLs along with their relationship to other aspects of telomere biology.
METHODS: In 121 NBLs, including 67 cases detected by mass-screening whose telomere length, telomerase activity, ALT with ATRX/DAXX alterations, and MYCN amplification were already known, TERT rearrangements were examined using GeneChip SNP arrays.
RESULTS: The 11 ATRX/DAXX mutated ALT cases and 29 cases with high telomerase activity showed poor prognosis. MYCN amplification and TERT rearrangements were independently detected in 16 and 13 cases, respectively, and these alterations were significantly correlated with high telomerase activity. In 81 infant cases, MYCN amplification, TERT rearrangements and ATRX mutations were detected in 3, 4, and 3 cases, respectively. Among them, 6 cases showed progression or recurrences.
CONCLUSIONS: Telomere stabilization in NBLs is acquired by telomerase activation through MYCN amplification, TERT rearrangements or by ALT. Since these tumors usually show progression and recurrence, complete resection should be considered, even in infant cases.
LEVEL OF EVIDENCE: Prognosis study, level III.

Nasirden A, Saito T, Fukumura Y, et al.
In Japanese patients with papillary thyroid carcinoma, TERT promoter mutation is associated with poor prognosis, in contrast to BRAF (V600E) mutation.
Virchows Arch. 2016; 469(6):687-696 [PubMed] Related Publications
The prognostic value of BRAF (V600E) and TERT promoter mutation in papillary thyroid carcinoma (PTC) is controversial. We examined alterations in BRAF (V600E) and TERT promoter by PCR-direct sequencing in PTC of 144 Japanese patients. Alternative lengthening of telomeres was examined as another mechanism of telomere maintenance by immunohistochemical staining for ATRX and DAXX. Of the clinicopathological characteristics, regional lymph node metastasis, extra-thyroid extension, multifocality/intrathyroidal spread, and advanced stage (III/V) were associated with shorter disease-free survival rate (DFSR). TERT promoter mutation was found in eight patients (6 %), and this was significantly associated with total thyroidectomy, multifocality/intrathyroidal spread, lymph node metastasis and advanced stage. The BRAF (V600E) mutation was found in 53 patients (38.2 %) but was not associated with any clinicopathological factors. TERT mutations were not correlated with BRAF (V600E) mutation status. TERT mutation-positive tumors (TERT+) showed lower DFSR than BRAF (V600E) -mutation-positive tumors (BRAF (V600E) +), and TERT+/BRAF (V600E) + tumors showed lower DFSR than BRAF (V600E) + tumors. No cases showed loss of ATRX/DAXX expression by immunohistochemistry. TERT promoter mutations showed a lower prevalence in our series and appeared to be associated with aggressive behavior. In PTCs, telomerase activation by TERT promoter mutation might be more important than alternative lengthening of telomeres.

Jafri MA, Ansari SA, Alqahtani MH, Shay JW
Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies.
Genome Med. 2016; 8(1):69 [PubMed] Free Access to Full Article Related Publications
Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized.

Zhang D, Li Y, Wang R, et al.
Inhibition of REST Suppresses Proliferation and Migration in Glioblastoma Cells.
Int J Mol Sci. 2016; 17(5) [PubMed] Free Access to Full Article Related Publications
Glioblastoma (GBM) is the most common primary brain tumor, with poor prognosis and a lack of effective therapeutic options. The aberrant expression of transcription factor REST (repressor element 1-silencing transcription factor) had been reported in different kinds of tumors. However, the function of REST and its mechanisms in GBM remain elusive. Here, REST expression was inhibited by siRNA silencing in U-87 and U-251 GBM cells. Then CCK-8 assay showed significantly decreased cell proliferation, and the inhibition of migration was verified by scratch wound healing assay and transwell assay. Using cell cycle analysis and Annexin V/PI straining assay, G1 phase cell cycle arrest was found to be a reason for the suppression of cell proliferation and migration upon REST silencing, while apoptosis was not affected by REST silencing. Further, the detection of REST-downstream genes involved in cytostasis and migration inhibition demonstrated that CCND1 and CCNE1 were reduced; CDK5R1, BBC3, EGR1, SLC25A4, PDCD7, MAPK11, MAPK12, FADD and DAXX were enhanced, among which BBC3 and DAXX were direct targets of REST, as verified by ChIP (chromatin immunoprecipitation) and Western blotting. These data suggested that REST is a master regulator that maintains GBM cells proliferation and migration, partly through regulating cell cycle by repressing downstream genes, which might represent a potential target for GBM therapy.

Mäkinen N, Aavikko M, Heikkinen T, et al.
Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12.
PLoS Genet. 2016; 12(2):e1005850 [PubMed] Free Access to Full Article Related Publications
Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether, 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%), alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%), and mediator complex subunit 12 (MED12; 4/19; 21%). Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52%) showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT), and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX), another gene previously associated with ALT, and the tumor showed ALT positivity. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.

Neychev V, Sadowski SM, Zhu J, et al.
Neuroendocrine Tumor of the Pancreas as a Manifestation of Cowden Syndrome: A Case Report.
J Clin Endocrinol Metab. 2016; 101(2):353-8 [PubMed] Related Publications
CONTEXT: Germline mutations in the phosphatase and tensin homolog (PTEN) tumor suppressor gene are found in the majority of patients with Cowden syndrome (CS), who have an increased risk of breast, thyroid, and endometrial cancer. According to our current understanding of genetic changes in the PTEN gene and the resultant phenotypic features of CS, pancreatic neuroendocrine tumors (NETs) are not considered part of the clinical spectrum of CS.
CASE DESCRIPTION: We report a unique case of an advanced NET of the pancreas in a patient with CS. The germline DNA sequencing confirmed the clinical diagnosis of CS and revealed a PTEN mutation c.697C→T (p.R233*) causing a premature stop codon in exon 7. The tumor DNA sequencing showed no loss of heterozygosity or any copy number changes and no other deleterious genetic alterations, including those commonly mutated in sporadic pancreatic NETs: MEN1, ATRX, DAXX, TP53, and genes involved in the mammalian target of rapamycin pathway. In addition, the high-throughput transcriptome analyzed by RNA-seq did not reveal any missed genetic alterations, aberrant splicing variants, gene fusions, or gene expression alterations. The immunohistochemical staining of the tumor for PTEN revealed an abnormal, uniformly strong cytoplasmic staining of tumor cells with virtually absent nuclear staining.
CONCLUSION: The results from genetic testing and histopathological techniques used to confirm CS diagnosis and characterize this unusual tumor tempted us to believe that in this case, the pancreatic NET was not a sporadic malignancy that occurred by coincidence, but rather represented a new entity in the spectrum of malignancies associated with CS.

Watson LA, Goldberg H, Bérubé NG
Emerging roles of ATRX in cancer.
Epigenomics. 2015; 7(8):1365-78 [PubMed] Related Publications
ATRX was identified over 20 years ago as the gene responsible for a rare developmental disorder characterized by α-thalassemia and intellectual disability. Similarities to the sucrose nonfermentable SNF2 type chromatin remodelers initially suggested a role in transcriptional regulation. However, over the last years, our knowledge of the epigenetic activities of ATRX has expanded steadily. Recent exciting discoveries have propelled ATRX into the limelight of chromatin and telomere biology, development and cancer research. This review summarizes recent breakthroughs in understanding ATRX function in heterochromatin structure, genome stability and its frequent dysregulation in a variety of cancers.

Liau JY, Lee JC, Tsai JH, et al.
Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas.
Mod Pathol. 2015; 28(12):1545-54 [PubMed] Related Publications
According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere-maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomeres-positive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (P<0.001). We conclude that alternative lengthening of telomeres is a frequent telomere-maintenance mechanism in cytogenetically complex sarcomas. Loss of ATRX is highly associated with this feature.

Yoshida M, Ogawa R, Yoshida H, et al.
TERT promoter mutations are frequent and show association with MED12 mutations in phyllodes tumors of the breast.
Br J Cancer. 2015; 113(8):1244-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Phyllodes tumors are rare fibroepithelial neoplasms of the breast, which carry the potential risk of local recurrence and metastasis. Phyllodes tumors share several histological features with fibroadenomas, and no widely accepted markers for distinguishing these lesions have been identified.
METHODS: We analyzed molecular abnormalities related to telomere elongation in tumors, including TERT promoter mutations, as well as loss of expression of ATRX and DAXX, in a total of 104 phyllodes tumors and fibroadenomas.
RESULTS: Sequencing analyses showed that TERT promoter mutations were frequent in phyllodes tumors (30/46, 65%), but rare in fibroadenomas (4/58, 7%). Among phyllodes tumors, the mutations were more frequent in borderline tumors (13/15, 87%), but were also common in benign (9/18, 50%) and malignant tumors (8/13, 62%). Remarkably, all but one TERT promoter-mutated tumor also contained MED12 mutations, indicating that these mutations are strongly associated (P=8.4 × 10(-6)). Expression of ATRX and DAXX, as evaluated by immunohistochemistry, was retained in all tumors.
CONCLUSIONS: Our observations suggest a critical role of TERT promoter mutations, in cooperation with MED12 mutations, in the development of phyllodes tumors. Because TERT promoter mutations are rare among fibroadenomas, their detection may be of potential use in discriminating between phyllodes tumors and fibroadenomas.

Liu G, Wu D, Liang X, et al.
Mechanisms and in vitro effects of cepharanthine hydrochloride: Classification analysis of the drug-induced differentially-expressed genes of human nasopharyngeal carcinoma cells.
Oncol Rep. 2015; 34(4):2002-10 [PubMed] Related Publications
Nasopharyngeal carcinoma (NPC) is the most commonly diagnosed head and neck malignancy and is prevalent worldwide. Previous studies have demonstrated the antitumor properties of cepharanthine hydrochloride (CH) in several human cancer cells. However, the action of CH in NPC cells has yet to be determined. In the present study, we investigated the effects of CH in human NPC cell lines including CNE-1 and CNE-2 on cell growth and apoptosis in vitro. Using MTT and ATP-tumor chemosensitivity assays it was found that CH inhibited cell viability. Additionally, flow cytometric and analysis electron microscopy revealed the inhibition of cell cycle progression and reduction of apoptosis, respectively, in human NPC cell lines including CNE-1 and CNE-2 in vitro. To identify the potential action mechanisms of CH, the cDNA microarray analysis results were confirmed by quantitative PCR analysis using a number of genes, including CDKN1A/P21, NR4A1/TR3 and DAXX. In total, 138 upregulated and 63 downregulated genes in CNE-2 cells were treated with CH. According to their biological function, the genes were classified as: i) cell cycle-related genes; ii) DNA repair‑related genes; iii) apoptosis-related genes and iv) nuclear factor-κB (NF-κB) transcription factors signal pathways. The results of the present study showed that CH is a potential therapeutic agent against human NPC, and provide rational explanations and a scientific basis for the study of the development of CH in the treatment of NPC.

Vavougios GD, Solenov EI, Hatzoglou C, et al.
Computational genomic analysis of PARK7 interactome reveals high BBS1 gene expression as a prognostic factor favoring survival in malignant pleural mesothelioma.
Am J Physiol Lung Cell Mol Physiol. 2015; 309(7):L677-86 [PubMed] Related Publications
The aim of our study was to assess the differential gene expression of Parkinson protein 7 (PARK7) interactome in malignant pleural mesothelioma (MPM) using data mining techniques to identify novel candidate genes that may play a role in the pathogenicity of MPM. We constructed the PARK7 interactome using the ConsensusPathDB database. We then interrogated the Oncomine Cancer Microarray database using the Gordon Mesothelioma Study, for differential gene expression of the PARK7 interactome. In ConsensusPathDB, 38 protein interactors of PARK7 were identified. In the Gordon Mesothelioma Study, 34 of them were assessed out of which SUMO1, UBC3, KIAA0101, HDAC2, DAXX, RBBP4, BBS1, NONO, RBBP7, HTRA2, and STUB1 were significantly overexpressed whereas TRAF6 and MTA2 were significantly underexpressed in MPM patients (network 2). Furthermore, Kaplan-Meier analysis revealed that MPM patients with high BBS1 expression had a median overall survival of 16.5 vs. 8.7 mo of those that had low expression. For validation purposes, we performed a meta-analysis in Oncomine database in five sarcoma datasets. Eight network 2 genes (KIAA0101, HDAC2, SUMO1, RBBP4, NONO, RBBP7, HTRA2, and MTA2) were significantly differentially expressed in an array of 18 different sarcoma types. Finally, Gene Ontology annotation enrichment analysis revealed significant roles of the PARK7 interactome in NuRD, CHD, and SWI/SNF protein complexes. In conclusion, we identified 13 novel genes differentially expressed in MPM, never reported before. Among them, BBS1 emerged as a novel predictor of overall survival in MPM. Finally, we identified that PARK7 interactome is involved in novel pathways pertinent in MPM disease.

Liau JY, Tsai JH, Yang CY, et al.
Alternative lengthening of telomeres phenotype in malignant vascular tumors is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas.
Hum Pathol. 2015; 46(9):1360-6 [PubMed] Related Publications
Alternative lengthening of telomeres (ALT) is a mechanism using homologous recombination to maintain telomere length and sustain limitless replicability of cancer cells. Recently, ALT has been found to be associated with inactivation of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. In this study, 119 tumors (88 angiosarcomas, 11 epithelioid hemangioendotheliomas, and 20 Kaposi sarcomas) were analyzed to determine the ALT status, its relationship to loss of ATRX/DAXX expression, and the clinicopathological features. In addition, the mutation status in the telomerase reverse transcriptase gene (TERT) promoter was also studied. Loss of ATRX expression was observed in 21% (16/77) of the primary angiosarcomas and 9% (1/11) of epithelioid hemangioendotheliomas. DAXX expression was intact in all but 2 ATRX-deficient angiosarcomas. Telomere-specific fluorescence in situ hybridization assay showed 28% (17/61) of the primary angiosarcomas were ALT positive. Remarkably, ALT was highly associated with loss of ATRX expression: all but 2 ALT-positive angiosarcomas were ATRX deficient. Notably, hepatic angiosarcomas were frequently ATRX deficient (8/13) and/or ALT positive (8/12). None of the secondary angiosarcomas were ATRX/DAXX deficient or ALT positive. The only ATRX-deficient epithelioid hemangioendothelioma was positive for ALT. Forty-seven angiosarcomas were tested for TERT promoter mutation. Despite the fact that angiosarcoma occurs most commonly in sun-damaged skin, mutation was detected in only 1 radiation-associated angiosarcoma (2%). We conclude that ALT is an important telomere maintenance mechanism in primary angiosarcomas. This feature is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas.

Boora GK, Kanwar R, Kulkarni AA, et al.
Exome-level comparison of primary well-differentiated neuroendocrine tumors and their cell lines.
Cancer Genet. 2015 Jul-Aug; 208(7-8):374-81 [PubMed] Related Publications
Neuroendocrine cancer cell lines are used to investigate therapeutic targets in neuroendocrine tumors (NET) and have been instrumental in the design of clinical trials targeting the PI3K/AKT/mTOR pathways, VEGF inhibitors, and somatostatin analogues. It remains unknown, however, whether the genomic makeup of NET cell lines reflect that of primary NET since comprehensive unbiased genome sequencing has not been performed on the cell lines. Four bronchopulmonary NET (BP-NET)-NCI-H720, NCI-H727, NCI-H835, and UMC11-and two pancreatic neuroendocrine tumors (panNET)-BON-1 and QGP1-were cultured. DNA was isolated, and exome sequencing was done. GATK and EXCAVATOR were used for bioinformatic analysis. We detected a total of 1,764 nonsynonymous single nucleotide variants at a rate of 8 per Mb in BP-NET and 4.3 per Mb in panNET cell lines, including 52 mutated COSMIC cancer genes in these cell lines, such as TP53, BRCA1, RB1, TSC2, NOTCH1, EP300, GNAS, KDR, STK11, and APC but not ATRX, DAXX, nor MEN1. Our data suggest that mutation rate, the pattern of copy number variations, and the mutational spectra in the BP-NET cell lines are more similar to the changes observed in small cell lung cancer than those found in primary BP-NET. Likewise, mutation rate and pattern including the absence of mutations in ATRX/DAXX, MEN1, and YY1 in the panNET cell lines BON1 and QGP1 suggest that these cell lines do not have the genetic signatures of a primary panNET. These results suggest that results from experiments with BP-NET and panNET cell lines need to be interpreted with caution.

Kim HS, Lee HS, Nam KH, et al.
Telomere length abnormalities and telomerase RNA component expression in gastroenteropancreatic neuroendocrine tumors.
Anticancer Res. 2015; 35(6):3501-10 [PubMed] Related Publications
Telomere lengths in normal human cells are tightly regulated within a narrow range. Telomere length abnormalities are prevalent genetic alterations in malignant transformation. We studied telomere length abnormalities, telomerase RNA component (TERC) expression, alpha-thalassemia X-linked mental retardation (ATRX) expression, and death domain-associated protein (DAXX) expression in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We used tissue microarrays to perform telomere fluorescent in situ hybridization (FISH) and TERC in situ hybridization in 327 formalin-fixed paraffin-embedded tissues of GEP-NETs. Telomere length abnormalities were detected in 35% of 253 informative cases by using telomere FISH. Ten cases had altered lengthening of telomeres (ALT), an ALT-positive phenotype (4%), and 79 cases had telomere shortening (31%). The ALT-positive phenotype was significantly associated with tumors of pancreatic origin (7/10) and loss of ATRX or DAXX protein (8/10). Telomere shortening was significantly associated with low TERC expression. In the survival analysis, loss of ATRX or DAXX protein was associated with a decreased overall survival. Multivariate regression analysis showed that lymph node metastasis and high TERC expression were independent prognostic factors of reduced overall survival (OS) for patients with GEP-NETs. Our results showed that telomere lengthening (the ALT-positive phenotype) and telomere shortening accompanied by low TERC levels are two types of clinically significant telomere abnormalities in GEP-NETs.

Appin CL, Brat DJ
Biomarker-driven diagnosis of diffuse gliomas.
Mol Aspects Med. 2015; 45:87-96 [PubMed] Related Publications
The diffuse gliomas are primary central nervous system tumors that arise most frequently in the cerebral hemispheres of adults. They are currently classified as astrocytomas, oligodendrogliomas or oligoastrocytomas and range in grade from II to IV. Glioblastoma (GBM), grade IV, is the highest grade and most common form. The diagnosis of diffuse gliomas has historically been based primarily on histopathologic features, yet these tumors have a wide range of biological behaviors that are only partially explained by morphology. Biomarkers have now become an established component of the neuropathologic diagnosis of gliomas, since molecular alterations aid in classification, prognostication and prediction of therapeutic response. Isocitrate dehydrogenase (IDH) mutations are frequent in grades II and III infiltrating gliomas of adults, as well as secondary GBMs, and are a major discriminate of biologic class. IDH mutant infiltrating astrocytomas (grades II and III), as well as secondary GBMs, are characterized by TP53 and ATRX mutations. Oligodendrogliomas are also IDH mutant, but instead are characterized by 1p/19q co-deletion and mutations of CIC, FUBP1, Notch1 and the TERT promoter. Primary GBMs typically lack IDH mutations and demonstrate EGFR, PTEN, TP53, PDGFRA, NF1 and CDKN2A/B alterations and TERT promoter mutations. Pediatric gliomas differ in their spectrum of disease from those in adults; high grade gliomas occurring in children frequently have mutations in H3F3A, ATRX and DAXX, but not IDH. Circumscribed, low grade gliomas, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma and ganglioglioma, need to be distinguished from diffuse gliomas in the pediatric population. These gliomas often harbor mutations or activating gene rearrangements in BRAF.

Puto LA, Brognard J, Hunter T
Transcriptional Repressor DAXX Promotes Prostate Cancer Tumorigenicity via Suppression of Autophagy.
J Biol Chem. 2015; 290(25):15406-20 [PubMed] Free Access to Full Article Related Publications
The DAXX transcriptional repressor was originally associated with apoptotic cell death. However, recent evidence that DAXX represses several tumor suppressor genes, including the DAPK1 and DAPK3 protein kinases, and is up-regulated in many cancers argues that a pro-survival role may predominate in a cancer context. Here, we report that DAXX has potent growth-enhancing effects on primary prostatic malignancy through inhibition of autophagy. Through stable gene knockdown and mouse subcutaneous xenograft studies, we demonstrate that DAXX promotes tumorigenicity of human ALVA-31 and PC3 prostate cancer (PCa) cells in vivo. Importantly, DAXX represses expression of essential autophagy modulators DAPK3 and ULK1 in vivo, revealing autophagy suppression as a mechanism through which DAXX promotes PCa tumorigenicity. Furthermore, DAXX knockdown increases autophagic flux in cultured PCa cells. Finally, interrogation of the Oncomine(TM) database suggests that DAXX overexpression is associated with malignant transformation in several human cancers, including prostate and pancreatic cancers. Thus, DAXX may represent a new cancer biomarker for the detection of aggressive disease, whose tissue-specific down-regulation can serve as an improved therapeutic modality. Our results establish DAXX as a pro-survival protein in PCa and reveal that, in the early stages of tumorigenesis, autophagy suppresses prostate tumor formation.

Wimmer P, Berscheminski J, Blanchette P, et al.
PML isoforms IV and V contribute to adenovirus-mediated oncogenic transformation by functionally inhibiting the tumor-suppressor p53.
Oncogene. 2016; 35(1):69-82 [PubMed] Related Publications
Although modulation of the cellular tumor-suppressor p53 is considered to have the major role in E1A/E1B-55K-mediated tumorigenesis, other promyelocytic leukemia nuclear body (PML-NB)/PML oncogenic domain (POD)-associated factors including SUMO, Mre11, Daxx, as well as the integrity of these nuclear bodies contribute to the transformation process. However, the biochemical consequences and oncogenic alterations of PML-associated E1B-55K by SUMO-dependent PML-IV and PML-V interaction have so far remained elusive. We performed mutational analysis to define a PML interaction motif within the E1B-55K polypeptide. Our results showed that E1B-55K/PML binding is not required for p53, Mre11 and Daxx interaction. We also observed that E1B-55K lacking subnuclear PML localization because of either PML-IV or PML-V-binding deficiency was no longer capable of mediating E1B-55K-dependent SUMOylation of p53, inhibition of p53-mediated transactivation or efficiently transforming primary rodent cells. These results together with the observation that E1B-55K-dependent SUMOylation of p53 is required for efficient cell transformation, provides evidence for the idea that the SUMO ligase activity of the E1B-55K viral oncoprotein is intimately linked to its growth-promoting oncogenic activities.

Capurso G, Archibugi L, Delle Fave G
Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors.
J Hepatobiliary Pancreat Sci. 2015; 22(8):594-601 [PubMed] Related Publications
Over the past few years, knowledge regarding the molecular pathology of sporadic pancreatic neuroendocrine tumors (PNETs) has increased substantially, and a number of targeted agents have been tested in clinical trials in this tumor type. For some of these agents there is a strong biological rationale. Among them, the mammalian target of rapamycin inhibitor Everolimus and the antiangiogenic agent Sunitinib have both been approved for the treatment of PNETs. However, there is lack of knowledge regarding biomarkers able to predict their efficacy, and mechanisms of resistance. Other angiogenesis inhibitors, such as Pazopanib, inhibitors of Src, Hedgehog or of PI3K might all be useful in association or sequence with approved agents. On the other hand, the clinical significance, and potential for treatment of the most common mutations occurring in sporadic PNETs, in the MEN-1 gene and in ATRX and DAXX, remains uncertain. The present paper reviews the main molecular changes occurring in PNETs and how they might be linked with treatment options.

Kurihara S, Hiyama E, Onitake Y, et al.
Clinical features of ATRX or DAXX mutated neuroblastoma.
J Pediatr Surg. 2014; 49(12):1835-8 [PubMed] Related Publications
PURPOSE: Previously, we reported that alternative lengthening of telomere (ALT) may be a biomarker for chemo-sensitivity and late recurrence in neuroblastoma (NBL). In this study, alterations of ATRX or DAXX, which both encode chromatin remodeling proteins in telomeric region, and their relationship to ALT were examined in NBLs.
METHODS: Our previous report on 121 NBLs revealed 11 NBLs with elongated telomeres by ALT. In these NBLs, ATRX or DAXX gene alterations were identified using next-generation sequencing and compared to clinical and other biological factors.
RESULTS: In 11 ALT cases, DAXX mutations were detected in one case, and ATRX alterations were detected in 10 cases. Except for one case, no DAXX or ATRX alterations were detected in 110 tumors with normal or shortened telomeres. MYCN amplification was not detected in ATRX altered tumors. In ALT cases, three infants showed ATRX deletions, and all seven cases detected after 18months of age showed poor prognosis.
CONCLUSIONS: In NBLs, ALT was caused by ATRX or DAXX alterations. ATRX altered cases without MYCN amplification detected at greater than 18months showed poor prognosis, suggesting that ATRX or DAXX alterations are a particular NBL subtype. Since these tumors showed chemo-resistance and late recurrence, complete resection in a surgical approach should be performed to improve patient prognosis.

Appin CL, Brat DJ
Molecular pathways in gliomagenesis and their relevance to neuropathologic diagnosis.
Adv Anat Pathol. 2015; 22(1):50-8 [PubMed] Related Publications
Gliomas are a large and diverse group of primary brain tumors that include those that are diffusely infiltrative and others that are well-circumscribed and low grade. Diffuse gliomas are currently classified by the World Health Organization as astrocytomas, oligodendrogliomas, or oligoastrocytomas and range in grade from II to IV. Glioblastoma (GBM), World Health Organization grade IV, is the highest grade and most common form of astrocytoma. In the past, the diagnosis of gliomas was almost exclusively based on histopathologic features. More recently, improved understanding of molecular genetic underpinnings has led to ancillary molecular studies becoming standard for classification, prognostication, and predicting therapy response. Isocitrate dehydrogenase (IDH) mutations are frequent in grade II and III infiltrating gliomas and secondary GBMs. Infiltrating astrocytomas and secondary GBMs are characterized by IDH, TP53, and ATRX mutations, whereas oligodendrogliomas demonstrate 1p/19q codeletion and mutations in IDH, CIC, FUBP1, and the telomerase reverse transcriptase (TERT) promoter. Primary GBMs typically lack IDH mutations and are instead characterized by EGFR, PTEN, TP53, PDGFRA, NF1, and CDKN2A/B alterations and TERT promoter mutations. Pediatric GBMs differ from those in adults and frequently have mutations in H3F3A, ATRX, and DAXX, but not IDH. In contrast, circumscribed, low-grade gliomas of childhood, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma, often harbor mutations or activating gene rearrangements in BRAF. Neuropathologic assessment of gliomas increasingly relies on ancillary testing of molecular alterations for proper classification and patient management.

Geis C, Fendrich V, Rexin P, et al.
Ileal neuroendocrine tumors show elevated activation of mammalian target of rapamycin complex.
J Surg Res. 2015; 194(2):388-93 [PubMed] Related Publications
BACKGROUND: Neuroendocrine tumors (NETs) of the ileum are sporadic tumors derived from submucosal gastrointestinal stem cells. They often show clinical symptoms only after hepatic metastasation when curative therapy is limited or impossible. In this study, we analyzed the expression of the candidate genes mammalian target of rapamycin (mTOR), alpha thalassemia/mental retardation syndrome X-linked (ATRX), and death domain-associated protein (DAXX) to investigate the specific oncogenetics and potential therapeutic options for ileal NETs.
METHODS: In a prospective database, all patients who underwent surgical removal of a NET of the ileum between 2001 and 2011 were specified. Expression analysis was performed for mTOR, ATRX, and DAXX by immunohistochemistry of paraffin-embedded tumor samples. To evaluate the results the immunoreactive score was applied. Normal tissue and tumor tissue were analyzed for the comparison of gene expression levels using quantitative-real-time polymerase chain reaction for ATRX and mTOR genes. Results were correlated under pathologic and clinical aspects.
RESULTS: A total of 69 patients were admitted to the study. Positive cytosolic expression of the potential oncogene mTOR was immunohistochemically detected in 76.2% of the human probes. A loss of nuclear ATRX expression was detected in 13.0% of the samples. A nonexpression of the DAXX-protein in cell nuclei was not found (0%). Gene transcript levels did not show a significant alteration in ileal NETs in comparison with normal tissue.
CONCLUSIONS: mTOR is overexpressed in ileal NETs. Additionally, the loss of ATRX expression was registered, thus underlying a tumorigenic role in a subgroup of these tumors. To enable potential therapeutic application of mTOR inhibitors, further trials with larger study groups are needed.

Suvà ML
Genetics and epigenetics of gliomas.
Swiss Med Wkly. 2014; 144:w14018 [PubMed] Related Publications
Gliomas are the most common primary intrinsic brain tumours. Their classification is based on phenotypic resemblance to normal glial cells (astrocytomas, oligodendrogliomas, mixed oligoastrocytomas) and pathological grading. Whereas this system is clinically relevant and has been the basis for our understanding of gliomas, systematic use of next-generation sequencing has transformed our knowledge of their pathogenesis and has uncovered genetic changes in an unanticipated number of genes and regulatory elements. In the past few years, in-depth analysis of low-grade astrocytomas and glioblastomas in both paediatric and adult populations has clarified our molecular understanding of these diseases, with distinct molecular events occurring in different age groups. In oligodendrogliomas, recent studies have highlighted mutations in candidate tumour suppressor genes located on 1p/19q, chromosome arms frequently deleted in this tumour. In this review, we discuss recent discoveries in the genetics of adult and paediatric gliomas, and highlight how some of the founding genetic mutations reshape the cancer epigenome. These studies provide an in-depth view of the molecular routes leading to brain tumour development and will be key for refining classification systems and improving clinical care.

Sato S, Tsuchikawa T, Nakamura T, et al.
Impact of the tumor microenvironment in predicting postoperative hepatic recurrence of pancreatic neuroendocrine tumors.
Oncol Rep. 2014; 32(6):2753-9 [PubMed] Related Publications
The disease frequency of pancreatic neuroendocrine tumors (PNETs) has been growing, and postoperative hepatic recurrence (PHR) is one of the factors affecting patient prognosis. The present study aimed to investigate biomarkers of PNETs in the primary disease site to predict PHR using immunohistochemical analysis for tumor-infiltrating lymphocytes (TILs: CD3, CD8 and CD45RO), human leukocyte antigen (HLA) class I, α-thalassemia/mental retardation X-linked (ATRX), death domain-associated protein (DAXX), mammalian target of rapamycin (mTOR) and phospho-mTOR (p-mTOR). Correlations were analyzed between TILs and the biomarkers, clinicopathological features and prognosis. Sixteen patients with PNETs who underwent radical surgery at our hospital were reviewed. We analyzed the correlation between PHR and immunohistochemical characteristics, and also between disease-free survival (DFS) or overall survival (OS) and the immunohistochemical characteristics. We found that PHR was associated with the expression patterns of DAXX and p-mTOR. No association was found between PHR and patient background, TILs or other biomarkers. DFS was found to be associated with ATRX, DAXX and p-mTOR. OS was associated only with p-mTOR. In conclusion, ATRX, DAXX and p-mTOR are useful molecular biomarkers for predicting PHR in patients who undergo radical surgery for PNETs. Use of these biomarkers will enable earlier decisions on which patients may benefit from adjuvant therapy.

Gielen GH, Gessi M, Buttarelli FR, et al.
Genetic Analysis of Diffuse High-Grade Astrocytomas in Infancy Defines a Novel Molecular Entity.
Brain Pathol. 2015; 25(4):409-17 [PubMed] Related Publications
Pediatric high-grade gliomas are considered to be different when compared to adult high-grade gliomas in their pathogenesis and biological behavior. Recently, common genetic alterations, including mutations in the H3F3A/ATRX/DAXX pathway, have been described in approximately 30% of the pediatric cases. However, only few cases of infant high-grade gliomas have been analyzed so far. We investigated the molecular features of 35 infants with diffuse high-grade astrocytomas, including 8 anaplastic astrocytomas [World Health Organization (WHO) grade III] and 27 glioblastomas (WHO grade IV) by immunohistochemistry, multiplex ligation probe-dependent amplification (MLPA), pyrosequencing of glioma-associated genes and molecular inversion probe (MIP) assay. MIP and MLPA analyses showed that chromosomal alterations are significantly less frequent in infants compared with high-grade gliomas in older children and adults. We only identified H3F3A K27M in 2 of 34 cases (5.9%), with both tumors located in the posterior fossa. PDGFRA amplifications were absent, and CDKN2A loss could be observed only in two cases. Conversely, 1q gain (22.7%) and 6q loss (18.2%) were identified in a subgroup of tumors. Loss of SNORD located on chromosome 14q32 was observed in 27.3% of the infant tumors, a focal copy number change not previously described in gliomas. Our findings indicate that infant high-grade gliomas appear to represent a distinct genetic entity suggesting a different pathogenesis and biological behavior.

Liau JY, Tsai JH, Jeng YM, et al.
Leiomyosarcoma with alternative lengthening of telomeres is associated with aggressive histologic features, loss of ATRX expression, and poor clinical outcome.
Am J Surg Pathol. 2015; 39(2):236-44 [PubMed] Related Publications
Leiomyosarcoma is an aggressive soft tissue sarcoma with poor patient survival. Recently, it was shown that 53% to 62% of leiomyosarcomas use the alternative lengthening of telomeres (ALT) as their telomere maintenance mechanism. The molecular basis of this mechanism has not been elucidated. Studies of pancreatic neuroendocrine tumor have suggested that the inactivation of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein is associated with the ALT phenotype. In this study, we sought to determine the clinicopathologic features of leiomyosarcoma with the ALT phenotype and the possible relationship between this phenotype and ATRX/DAXX expression. Telomerase reverse transcriptase gene (TERT) promoter mutation analysis was also performed. Ninety-two leiomyosarcomas derived from the uterus, retroperitoneum/intra-abdomen, and various other sites were analyzed. Telomere-specific fluorescence in situ hybridization revealed that 59% (51/86) of leiomyosarcomas had the ALT phenotype. Loss of ATRX expression was observed in 33% of the tumors (30/92), and all but 2 ATRX-deficient tumors were ALT positive. Both the ALT phenotype and loss of ATRX expression were associated with epithelioid/pleomorphic cell morphology, tumor necrosis, and poor differentiation. None of the 92 cases lost DAXX expression. No TERT promoter mutation was detected (n=39). For survival analysis, poor differentiation, high FNCLCC grade, tumor size, and ALT phenotype were correlated with poor overall survival in univariate analysis. Tumor size and ALT phenotype remained independent prognostic factors in multivariate analysis. We concluded that the ALT phenotype in the leiomyosarcoma is associated with aggressive histologic features, loss of ATRX expression, and poor clinical outcome.

Yuan F, Shi M, Ji J, et al.
KRAS and DAXX/ATRX gene mutations are correlated with the clinicopathological features, advanced diseases, and poor prognosis in Chinese patients with pancreatic neuroendocrine tumors.
Int J Biol Sci. 2014; 10(9):957-65 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND AIM: Pancreatic neuroendocrine tumor (pNET) is a clinically rare and heterogeneous group of tumors; its pharmacogenetic characteristics are not fully understood. This study was designed to examine the relationship between key gene variations and disease development and prognosis among Chinese patients with pNET.
METHODS: Various pNET associated genes such as DAXX/ATRX, KRAS, MEN1, PTEN, TSC2, SMAD4/DPC, TP53 and VHL were analyzed in high-throughput sequencing. The links between the gene mutations and the clinicopathological features and prognosis of the patients were determined.
RESULTS: The somatic mutation frequencies of the DAXX/ATRX, KRAS, MEN1, mTOR pathway genes (PTEN and TSC2), SMAD4/DPC, TP53, and VHL in Chinese pNET patients were 54.05%, 10.81%, 35.14%, 54.05%, 2.70%, 13.51%, and 40.54%, respectively, while the same figures in Caucasians pNET patients were 43%, 0%, 44%, 15%, 0%, 3%, and 0%, respectively. The numbers of mutated genes were from 0 to 6; 4 patients with more than 3 mutated genes had higher proliferation (Ki-67) index or nerve vascular invasion or organ involvement, but only 9 of 27 patients with 3 or few mutated genes had such features. Mutations in KRAS and DAXX/ATRX, but not other genes analyzed, were associated with a shortened survival.
CONCLUSION: The mutation rates of these genes in Chinese pNET patients are different from those in Caucasians. A higher number of gene mutations and the DAXX/ATRX and KRAS gene mutations are correlated with a poor prognosis of patients with pNET.

Korf K, Wodrich H, Haschke A, et al.
The PML domain of PML-RARα blocks senescence to promote leukemia.
Proc Natl Acad Sci U S A. 2014; 111(33):12133-8 [PubMed] Free Access to Full Article Related Publications
In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia protein-retinoic acid receptor α (PML-RARα) fusion gene. Although expression of the human PML fusion in mice promotes leukemia, its efficiency is rather low. Unexpectedly, we find that simply replacing the human PML fusion with its mouse counterpart results in a murine PML-RARα (mPR) hybrid protein that is transformed into a significantly more leukemogenic oncoprotein. Using this more potent isoform, we show that mPR promotes immortalization by preventing cellular senescence, impeding up-regulation of both the p21 and p19(ARF) cell-cycle regulators. This induction coincides with a loss of the cancer-associated ATRX/Daxx-histone H3.3 predisposition complex and suggests inhibition of senescence as a targetable mechanism in APL therapy.

Ross JS, Wang K, Rand JV, et al.
Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies.
J Clin Pathol. 2014; 67(11):968-73 [PubMed] Free Access to Full Article Related Publications
AIMS: Adrenocortical carcinoma (ACC) carries a poor prognosis and current systemic cytotoxic therapies result in only modest improvement in overall survival. In this retrospective study, we performed a comprehensive genomic profiling of 29 consecutive ACC samples to identify potential targets of therapy not currently searched for in routine clinical practice.
METHODS: DNA from 29 ACC was sequenced to high, uniform coverage (Illumina HiSeq) and analysed for genomic alterations (GAs).
RESULTS: At least one GA was found in 22 (76%) ACC (mean 2.6 alterations per ACC). The most frequent GAs were in TP53 (34%), NF1 (14%), CDKN2A (14%), MEN1 (14%), CTNNB1 (10%) and ATM (10%). APC, CCND2, CDK4, DAXX, DNMT3A, KDM5C, LRP1B, MSH2 and RB1 were each altered in two cases (7%) and EGFR, ERBB4, KRAS, MDM2, NRAS, PDGFRB, PIK3CA, PTEN and PTCH1 were each altered in a single case (3%). In 17 (59%) of ACC, at least one GA was associated with an available therapeutic or a mechanism-based clinical trial.
CONCLUSIONS: Next-generation sequencing can discover targets of therapy for relapsed and metastatic ACC and shows promise to improve outcomes for this aggressive form of cancer.

Assié G, Letouzé E, Fassnacht M, et al.
Integrated genomic characterization of adrenocortical carcinoma.
Nat Genet. 2014; 46(6):607-12 [PubMed] Related Publications
Adrenocortical carcinomas (ACCs) are aggressive cancers originating in the cortex of the adrenal gland. Despite overall poor prognosis, ACC outcome is heterogeneous. We performed exome sequencing and SNP array analysis of 45 ACCs and identified recurrent alterations in known driver genes (CTNNB1, TP53, CDKN2A, RB1 and MEN1) and in genes not previously reported in ACC (ZNRF3, DAXX, TERT and MED12), which we validated in an independent cohort of 77 ACCs. ZNRF3, encoding a cell surface E3 ubiquitin ligase, was the most frequently altered gene (21%) and is a potential new tumor suppressor gene related to the β-catenin pathway. Our integrated genomic analyses further identified two distinct molecular subgroups with opposite outcome. The C1A group of ACCs with poor outcome displayed numerous mutations and DNA methylation alterations, whereas the C1B group of ACCs with good prognosis displayed specific deregulation of two microRNA clusters. Thus, aggressive and indolent ACCs correspond to two distinct molecular entities driven by different oncogenic alterations.

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