Gene Summary

Gene:ARHGAP26; Rho GTPase activating protein 26
Summary:Interaction of a cell with the extracellular matrix triggers integrin cell surface receptors to begin signaling cascades that regulate the organization of the actin-cytoskeleton. One of the proteins involved in these cascades is focal adhesion kinase. The protein encoded by this gene is a GTPase activating protein that binds to focal adhesion kinase and mediates the activity of the GTP binding proteins RhoA and Cdc42. Defects in this gene are a cause of juvenile myelomonocytic leukemia (JMML). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:rho GTPase-activating protein 26
Source:NCBIAccessed: 16 March, 2017

Cancer Overview

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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

Latest Publications: ARHGAP26 (cancer-related)

Ludwig N, Werner TV, Backes C, et al.
Combining miRNA and mRNA Expression Profiles in Wilms Tumor Subtypes.
Int J Mol Sci. 2016; 17(4):475 [PubMed] Free Access to Full Article Related Publications
Wilms tumor (WT) is the most common childhood renal cancer. Recent findings of mutations in microRNA (miRNA) processing proteins suggest a pivotal role of miRNAs in WT genesis. We performed miRNA expression profiling of 36 WTs of different subtypes and four normal kidney tissues using microarrays. Additionally, we determined the gene expression profile of 28 of these tumors to identify potentially correlated target genes and affected pathways. We identified 85 miRNAs and 2107 messenger RNAs (mRNA) differentially expressed in blastemal WT, and 266 miRNAs and 1267 mRNAs differentially expressed in regressive subtype. The hierarchical clustering of the samples, using either the miRNA or mRNA profile, showed the clear separation of WT from normal kidney samples, but the miRNA pattern yielded better separation of WT subtypes. A correlation analysis of the deregulated miRNA and mRNAs identified 13,026 miRNA/mRNA pairs with inversely correlated expression, of which 2844 are potential interactions of miRNA and their predicted mRNA targets. We found significant upregulation of miRNAs-183, -301a/b and -335 for the blastemal subtype, and miRNAs-181b, -223 and -630 for the regressive subtype. We found marked deregulation of miRNAs regulating epithelial to mesenchymal transition, especially in the blastemal subtype, and miRNAs influencing chemosensitivity, especially in regressive subtypes. Further research is needed to assess the influence of preoperative chemotherapy and tumor infiltrating lymphocytes on the miRNA and mRNA patterns in WT.

Kenny C, Bausenwein S, Lazaro A, et al.
Mutually exclusive BCOR internal tandem duplications and YWHAE-NUTM2 fusions in clear cell sarcoma of kidney: not the full story.
J Pathol. 2016; 238(5):617-20 [PubMed] Related Publications
Internal tandem duplication within the BCOR gene sequence that encodes the PUFD domain, important in the formation of the non-canonical or variant polycomb repressor complex 1 (v-PRC1), was very recently described in 100% of 20 clear cell sarcomas of kidney (CCSKs). None of those 20 cases bore the YWHAE-NUTM2 transcript, previously described by us in CCSK, and which constitutes the only other recurrent genetic aberration observed in CCSK, prompting consideration that these mutations might be mutually exclusive in CCSK. We analysed a cohort of 159 CCSKs and can now not only confirm that there is indeed mutual exclusivity of these BCOR and YWHAE mutations, but also show that a substantial proportion (in this series 11.8%) of CCSKs bear neither mutation when tested by these assays, raising the possibility of distinct aetiologies for subsets of CCSK. Clinical differences observed between the subsets support this notion. As CCSK may show poor chemo-responsiveness, and current treatment protocols mandate the use of doxorubicin with its associated side-effects, advances in understanding the disease biology with a view to more targeted and personalized treatment is a pressing need.

Anguita A, García-Remesal M, Graf N, Maojo V
A method and software framework for enriching private biomedical sources with data from public online repositories.
J Biomed Inform. 2016; 60:177-86 [PubMed] Related Publications
Modern biomedical research relies on the semantic integration of heterogeneous data sources to find data correlations. Researchers access multiple datasets of disparate origin, and identify elements-e.g. genes, compounds, pathways-that lead to interesting correlations. Normally, they must refer to additional public databases in order to enrich the information about the identified entities-e.g. scientific literature, published clinical trial results, etc. While semantic integration techniques have traditionally focused on providing homogeneous access to private datasets-thus helping automate the first part of the research, and there exist different solutions for browsing public data, there is still a need for tools that facilitate merging public repositories with private datasets. This paper presents a framework that automatically locates public data of interest to the researcher and semantically integrates it with existing private datasets. The framework has been designed as an extension of traditional data integration systems, and has been validated with an existing data integration platform from a European research project by integrating a private biological dataset with data from the National Center for Biotechnology Information (NCBI).

Gooskens SL, Kenny C, Lazaro A, et al.
The clinical phenotype of YWHAE-NUTM2B/E positive pediatric clear cell sarcoma of the kidney.
Genes Chromosomes Cancer. 2016; 55(2):143-7 [PubMed] Related Publications
Clear cell sarcoma of the kidney (CCSK) although uncommon, is the second most frequent renal malignancy of childhood. Until now, the sole recurrent genetic aberration identified in CCSKs is t(10;17)(q22;p13), which gives rise to a fusion transcript of YWHAE and NUTM2B/E. So far, the clinical relevance of this fusion transcript is unknown. The aim of this descriptive study was to determine the clinical phenotype of t(10;17)(q22;p13) positive CCSKs. Snap-frozen tissues, formalin-fixed paraffin-embedded tissues or RNA previously extracted from CCSK samples throughout European, North-American and Japanese study groups were screened by RT-PCR for the YWHAE-NUTM2B/E transcript. Clinical characteristics, tumor characteristics, and outcome of patients with and without the fusion transcript were studied. The cohort comprised 51 previously published cases to which were added 139 internationally collected CCSK samples. RNA from 57 of these additionally collected cases was of sufficient quality to be successfully screened for the YWHAE-NUTM2B/E transcript. In total, seven of the 108 cases harbored the fusion transcript. Patients with tumors containing the fusion transcript were relatively young (median age 10 months), had associated low median tumor volumes and stage I disease was not observed in these patients. Two of seven patients relapsed and one of seven patients died of disease. Ranges of values were not overtly different between patients with and without the fusion transcript; however, the number of fusion transcript positive cases turned out to be too small to permit reliable statistical analysis. The current study did not identify an explicit clinical phenotype of CCSK cases harboring the YWHAE-NUTM2B/E fusion transcript.

Schneider L, Stöckel D, Kehl T, et al.
DrugTargetInspector: An assistance tool for patient treatment stratification.
Int J Cancer. 2016; 138(7):1765-76 [PubMed] Related Publications
Cancer is a large class of diseases that are characterized by a common set of features, known as the Hallmarks of cancer. One of these hallmarks is the acquisition of genome instability and mutations. This, combined with high proliferation rates and failure of repair mechanisms, leads to clonal evolution as well as a high genotypic and phenotypic diversity within the tumor. As a consequence, treatment and therapy of malignant tumors is still a grand challenge. Moreover, under selective pressure, e.g., caused by chemotherapy, resistant subpopulations can emerge that then may lead to relapse. In order to minimize the risk of developing multidrug-resistant tumor cell populations, optimal (combination) therapies have to be determined on the basis of an in-depth characterization of the tumor's genetic and phenotypic makeup, a process that is an important aspect of stratified medicine and precision medicine. We present DrugTargetInspector (DTI), an interactive assistance tool for treatment stratification. DTI analyzes genomic, transcriptomic, and proteomic datasets and provides information on deregulated drug targets, enriched biological pathways, and deregulated subnetworks, as well as mutations and their potential effects on putative drug targets and genes of interest. To demonstrate DTI's broad scope of applicability, we present case studies on several cancer types and different types of input -omics data. DTI's integrative approach allows users to characterize the tumor under investigation based on various -omics datasets and to elucidate putative treatment options based on clinical decision guidelines, but also proposing additional points of intervention that might be neglected otherwise. DTI can be freely accessed at

Yao F, Kausalya JP, Sia YY, et al.
Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity.
Cell Rep. 2015; 12(2):272-85 [PubMed] Related Publications
Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). Fusion-positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix adhesion, retarded wound healing, and inhibition of RHOA. Gain of invasion was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H(+) leakage, and the fusion might contribute to invasiveness once a cell is transformed.

Lehnhardt A, Karnatz C, Ahlenstiel-Grunow T, et al.
Clinical and molecular characterization of patients with heterozygous mutations in wilms tumor suppressor gene 1.
Clin J Am Soc Nephrol. 2015; 10(5):825-31 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND OBJECTIVES: The Wilms tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of WT1 mutations with renal function and proteinuria have been observed in world-wide cohorts with nephrotic syndrome or Wilms tumor (WT). This study analyzed mid-European patients with known constitutional heterozygous mutations in WT1, including patients without proteinuria or WT.
DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Retrospective analysis of genotype, phenotype, and treatment of 53 patients with WT1 mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012.
RESULTS: Median age was 12.4 (interquartile range [IQR], 6-19) years. Forty-four of 53 (83%) patients had an exon mutation (36 missense, eight truncating), and nine of 53 (17%) had an intronic lysine-threonine-serine (KTS) splice site mutation. Fifty of 53 patients (94%) had proteinuria, which occurred at an earlier age in patients with missense mutations (0.6 [IQR, 0.1-1.5] years) than in those with truncating (9.7 [IQR, 5.7-11.9]; P<0.001) and splice site (4.0 [IQR, 2.6-6.6]; P=0.004) mutations. Thirteen of 50 (26%) were treated with steroids and remained irresponsive, while three of five partially responded to cyclosporine A. Seventy-three percent of all patients required RRT, those with missense mutations significantly earlier (at 1.1 [IQR, 0.01-9.3] years) than those with truncating mutations (16.5 [IQR, 16.5-16.8]; P<0.001) and splice site mutations (12.3 [IQR, 7.9-18.2]; P=0.002). Diffuse mesangial sclerosis was restricted to patients with missense mutations, while focal segmental sclerosis occurred in all groups. WT occurred only in patients with exon mutations (n=19). Fifty of 53 (94%) patients were karyotyped: Thirty-one (62%) had XY and 19 (38%) had XX chromosomes, and 96% of male karyotypes had urogenital malformations.
CONCLUSIONS: Type and location of WT1 mutations have predictive value for the development of proteinuria, renal insufficiency, and WT. XY karyotype was more frequent and associated with urogenital malformations in most cases.

Ludwig N, Nourkami-Tutdibi N, Backes C, et al.
Circulating serum miRNAs as potential biomarkers for nephroblastoma.
Pediatr Blood Cancer. 2015; 62(8):1360-7 [PubMed] Related Publications
BACKGROUND: Nephroblastoma (or Wilms tumor-WT) is the most common childhood kidney cancer. In Europe, nephroblastoma is treated with preoperative chemotherapy without histological confirmation by biopsy. Therefore, minimal-invasive diagnostic markers confirming nephroblastoma diagnosis are highly warranted.
PROCEDURE: In our study, we aim to identify circulating miRNAs with diagnostic potential for differentiating nephroblastoma from controls. We determined the level of 19 miRNAs in serum of 32 patients with nephroblastoma and 12 controls with quantitative real-time PCR. Three miRNAs were further tested in an independent validation set including sera of patients with renal tumors other than Wilms.
RESULTS: In total, 14 miRNAs showed significantly higher abundance in serum of patients with nephroblastoma than in controls. The miRNAs with highest diagnostic potentials included miRs-130b-3p, -100-5p, and -143-3p with an AUC of 0.94, 0.90, and 0.89, respectively. A signature based on these three miRNAs to differentiated patients from controls with an accuracy of 84.58%, a sensitivity of 76.67%, and a specificity of 92.5%. Higher expression of miRs-100-5p and -130b-3p was confirmed in an independent validation set. The signature based on miRs-100-5p and -130b-3p differentiated patients with nephroblastoma from healthy controls with an accuracy, sensitivity, and specificity of 79.6%, 69.2%, and 90.0%, respectively.
CONCLUSION: In summary, we provide first evidence that serum miR-100-5p and -130b-3p hold potential as biomarker for WT irrespective of the subtype and that expression level of these miRNA in serum is unaffected by differences in serum collection.

Williams RD, Chagtai T, Alcaide-German M, et al.
Multiple mechanisms of MYCN dysregulation in Wilms tumour.
Oncotarget. 2015; 6(9):7232-43 [PubMed] Free Access to Full Article Related Publications
Genomic gain of the proto-oncogene transcription factor gene MYCN is associated with poor prognosis in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT), demonstrating that gain of this gene is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. Using whole exome and gene-specific sequencing, together with methylation and expression profiling, we show that MYCN is targeted by other mechanisms, including a recurrent somatic mutation, P44L, and specific DNA hypomethylation events associated with MYCN overexpression in tumours with high risk histologies. We describe parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumours of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolve over time. We report a second bilateral case in which MYCN gain is a germline aberration. Our results suggest a significant role for MYCN dysregulation in the molecular biology of Wilms tumour. We conclude that MYCN gain is prognostically significant, and suggest that the novel P44L somatic variant is likely to be an activating mutation.

Kratz CP, Franke L, Peters H, et al.
Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes.
Br J Cancer. 2015; 112(8):1392-7 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown.
METHODS: We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry.
RESULTS: We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4.
CONCLUSIONS: These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.

Sardina JL, Graf T
A new path to leukemia with WIT.
Mol Cell. 2015; 57(4):573-4 [PubMed] Related Publications
In this issue, Wang et al., 2015 describes that WT1 recruits TET2 to the DNA, an important feature of a new regulatory pathway linked to the development of acute myeloid leukemia (AML). This pathway consists of WT1, IDH1/2, and TET2 (WIT) genes, with exclusive mutations of the three genes inducing myeloid cell proliferation.

Wegert J, Ishaque N, Vardapour R, et al.
Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors.
Cancer Cell. 2015; 27(2):298-311 [PubMed] Related Publications
Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find therapeutic leads for this subgroup, we analyzed 58 blastemal type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large replication cohort. Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX1 and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases); mutations in the DROSHA/DGCR8 microprocessor genes (18.2% of blastemal cases); mutations in DICER1 and DIS3L2; and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations strongly altered miRNA expression patterns in tumors, which was functionally validated in cell lines expressing mutant DROSHA.

Modelska A, Turro E, Russell R, et al.
The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape.
Cell Death Dis. 2015; 6:e1603 [PubMed] Free Access to Full Article Related Publications
Human mRNA DeXD/H-box helicases are ubiquitous molecular motors that are required for the majority of cellular processes that involve RNA metabolism. One of the most abundant is eIF4A, which is required during the initiation phase of protein synthesis to unwind regions of highly structured mRNA that would otherwise impede the scanning ribosome. Dysregulation of protein synthesis is associated with tumorigenesis, but little is known about the detailed relationships between RNA helicase function and the malignant phenotype in solid malignancies. Therefore, immunohistochemical analysis was performed on over 3000 breast tumors to investigate the relationship among expression of eIF4A1, the helicase-modulating proteins eIF4B, eIF4E and PDCD4, and clinical outcome. We found eIF4A1, eIF4B and eIF4E to be independent predictors of poor outcome in ER-negative disease, while in contrast, the eIF4A1 inhibitor PDCD4 was related to improved outcome in ER-positive breast cancer. Consistent with these data, modulation of eIF4A1, eIF4B and PCDC4 expression in cultured MCF7 cells all restricted breast cancer cell growth and cycling. The eIF4A1-dependent translatome of MCF7 cells was defined by polysome profiling, and was shown to be highly enriched for several classes of oncogenic genes, including G-protein constituents, cyclins and protein kinases, and for mRNAs with G/C-rich 5'UTRs with potential to form G-quadruplexes and with 3'UTRs containing microRNA target sites. Overall, our data show that dysregulation of mRNA unwinding contributes to the malignant phenotype in breast cancer via preferential translation of a class of genes involved in pro-oncogenic signaling at numerous levels. Furthermore, immunohistochemical tests are promising biomarkers for tumors sensitive to anti-helicase therapies.

Heppt MV, Tietze JK, Graf SA, Berking C
Combination therapy of melanoma using kinase inhibitors.
Curr Opin Oncol. 2015; 27(2):134-40 [PubMed] Related Publications
PURPOSE OF REVIEW: Treatment options for metastatic melanoma depend on the clinical course of the disease and the molecular profile such as mutations of the BRAF gene. In this article, we review the current state of targeted therapy with kinase inhibitors.
RECENT FINDINGS: Despite major advancements in targeted therapy of metastatic melanoma, most patients relapse and show progressive disease after 5-7 months with single inhibition of BRAF or MEK. Acquired resistance is virtually universal and mediated by diverse mitogen-activated protein kinase-dependent or independent mechanisms. Recent evidence favours concurrent targeting of BRAF and MEK in patients with BRAFV600-mutated melanoma instead of BRAF inhibitor monotherapy. The combination delays the onset of acquired resistance, resulting in increased progression-free and overall survival. A growing number of early trials evaluate the efficacy of inhibitors targeting additional pathways such as phospho-inositide 3-kinase/AKT in conjunction with BRAF or MEK. Even though consistent and mature phase III study results are not yet available for these combinations, the repertoire of targeted therapy in metastatic melanoma is wide and promising.
SUMMARY: The short era of single BRAF inhibition in BRAF-mutated melanoma is soon taken over by dual concurrent inhibition of MEK and BRAF.

Neumann M, Vosberg S, Schlee C, et al.
Mutational spectrum of adult T-ALL.
Oncotarget. 2015; 6(5):2754-66 [PubMed] Free Access to Full Article Related Publications
Novel target discovery is warranted to improve treatment in adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We provide a comprehensive study on mutations to enhance the understanding of therapeutic targets and studied 81 adult T-ALL patients. NOTCH1 exhibitedthe highest mutation rate (53%). Mutation frequencies of FBXW7 (10%), WT1 (10%), JAK3 (12%), PHF6 (11%), and BCL11B (10%) were in line with previous reports. We identified recurrent alterations in transcription factors DNM2, and RELN, the WNT pathway associated cadherin FAT1, and in epigenetic regulators (MLL2, EZH2). Interestingly, we discovered novel recurrent mutations in the DNA repair complex member HERC1, in NOTCH2, and in the splicing factor ZRSR2. A frequently affected pathway was the JAK/STAT pathway (18%) and a significant proportion of T-ALL patients harboured mutations in epigenetic regulators (33%), both predominantly found in the unfavourable subgroup of early T-ALL. Importantly, adult T-ALL patients not only showed a highly heterogeneous mutational spectrum, but also variable subclonal allele frequencies implicated in therapy resistance and evolution of relapse. In conclusion, we provide novel insights in genetic alterations of signalling pathways (e.g. druggable by γ-secretase inhibitors, JAK inhibitors or EZH2 inhibitors), present in over 80% of all adult T-ALL patients, that could guide novel therapeutic approaches.

Backes C, Harz C, Fischer U, et al.
New insights into the genetics of glioblastoma multiforme by familial exome sequencing.
Oncotarget. 2015; 6(8):5918-31 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is the most aggressive and malignant subtype of human brain tumors. While a family clustering of GBM has long been acknowledged, relevant hereditary factors still remained elusive. Exome sequencing of families offers the option to discover respective genetic factors.We sequenced blood samples of one of the rare affected families: while both parents were healthy, both children were diagnosed with GBM. We report 85 homozygous non-synonymous single nucleotide variations (SNVs) in both siblings that were heterozygous in the parents. Beyond known key players for GBM such as ERBB2, PMS2, or CHI3L1, we identified over 50 genes that have not been associated to GBM so far. We also discovered three accumulative effects potentially adding to the tumorigenesis in the siblings: a clustering of multiple variants in single genes (e.g., PTPRB, CROCC), the aggregation of affected genes on specific molecular pathways (e.g., Focal adhesion or ECM receptor interaction) and genomic proximity (e.g., chr22.q12.2, chr1.p36.33). We found a striking accumulation of SNVs in specific genes for the daughter, who developed not only a GBM at the age of 12 years but was subsequently diagnosed with a pilocytic astrocytoma, a common acute lymphatic leukemia and a diffuse pontine glioma.The reported variants underline the relevance of genetic predisposition and cancer development in this family and demonstrate that GBM has a complex and heterogeneous genetic background. Sequencing of other affected families will help to further narrow down the driving genetic causes for this disease.

Reincke M, Sbiera S, Hayakawa A, et al.
Mutations in the deubiquitinase gene USP8 cause Cushing's disease.
Nat Genet. 2015; 47(1):31-8 [PubMed] Related Publications
Cushing's disease is caused by corticotroph adenomas of the pituitary. To explore the molecular mechanisms of endocrine autonomy in these tumors, we performed exome sequencing of 10 corticotroph adenomas. We found somatic mutations in the USP8 deubiquitinase gene in 4 of 10 adenomas. The mutations clustered in the 14-3-3 protein binding motif and enhanced the proteolytic cleavage and catalytic activity of USP8. Cleavage of USP8 led to increased deubiqutination of the EGF receptor, impairing its downregulation and sustaining EGF signaling. USP8 mutants enhanced promoter activity of the gene encoding proopiomelanocortin. In summary, our data show that dominant mutations in USP8 cause Cushing's disease via activation of EGF receptor signaling.

Aissani B, Zhang K, Wiener H
Follow-up to genome-wide linkage and admixture mapping studies implicates components of the extracellular matrix in susceptibility to and size of uterine fibroids.
Fertil Steril. 2015; 103(2):528-34.e13 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To conduct a follow-up association mapping to independent genome-wide linkage and admixture mapping studies of uterine leiomyoma.
DESIGN: Case-control, cross-sectional study.
SETTING: Not applicable.
PATIENT(S): A total of 1,045 premenopausal North American participants in the National Institute of Environmental Health Sciences Uterine Fibroid Study.
MAIN OUTCOME MEASURE(S): We genotyped 2,772 single-nucleotide polymorphisms from candidate genes located in peaks of linkage (2q37, 3p21, 5p13, 10p11, 11p15, 12q14, and 17q25) or admixture linkage disequilibrium (2q37, 4p16.1, and 10q26) mapping and reported to have regulated expression in uterine fibroids.
RESULT(S): We report significant associations of variant members of the collagen gene family with risk and tumor size, including missense variants in COL6A3 and COL13A, with replications in African American and European American study groups. Furthermore, the cell-matrix Rho GTPase-encoding ARHGAP26 gene, and MAN1C1, a gene encoding a Golgi mannosidase involved in the maturation of procollagens, emerged as new candidate uterine leiomyoma genes affecting both risk and tumor size.
CONCLUSION(S): Our data converge onto a possible model of uterine leiomyoma pathogenesis resulting from altered regulation, maintenance, and/or renewal of the extracellular matrix.

Vollan HK, Rueda OM, Chin SF, et al.
A tumor DNA complex aberration index is an independent predictor of survival in breast and ovarian cancer.
Mol Oncol. 2015; 9(1):115-27 [PubMed] Free Access to Full Article Related Publications
Complex focal chromosomal rearrangements in cancer genomes, also called "firestorms", can be scored from DNA copy number data. The complex arm-wise aberration index (CAAI) is a score that captures DNA copy number alterations that appear as focal complex events in tumors, and has potential prognostic value in breast cancer. This study aimed to validate this DNA-based prognostic index in breast cancer and test for the first time its potential prognostic value in ovarian cancer. Copy number alteration (CNA) data from 1950 breast carcinomas (METABRIC cohort) and 508 high-grade serous ovarian carcinomas (TCGA dataset) were analyzed. Cases were classified as CAAI positive if at least one complex focal event was scored. Complex alterations were frequently localized on chromosome 8p (n = 159), 17q (n = 176) and 11q (n = 251). CAAI events on 11q were most frequent in estrogen receptor positive (ER+) cases and on 17q in estrogen receptor negative (ER-) cases. We found only a modest correlation between CAAI and the overall rate of genomic instability (GII) and number of breakpoints (r = 0.27 and r = 0.42, p < 0.001). Breast cancer specific survival (BCSS), overall survival (OS) and ovarian cancer progression free survival (PFS) were used as clinical end points in Cox proportional hazard model survival analyses. CAAI positive breast cancers (43%) had higher mortality: hazard ratio (HR) of 1.94 (95%CI, 1.62-2.32) for BCSS, and of 1.49 (95%CI, 1.30-1.71) for OS. Representations of the 70-gene and the 21-gene predictors were compared with CAAI in multivariable models and CAAI was independently significant with a Cox adjusted HR of 1.56 (95%CI, 1.23-1.99) for ER+ and 1.55 (95%CI, 1.11-2.18) for ER- disease. None of the expression-based predictors were prognostic in the ER- subset. We found that a model including CAAI and the two expression-based prognostic signatures outperformed a model including the 21-gene and 70-gene signatures but excluding CAAI. Inclusion of CAAI in the clinical prognostication tool PREDICT significantly improved its performance. CAAI positive ovarian cancers (52%) also had worse prognosis: HRs of 1.3 (95%CI, 1.1-1.7) for PFS and 1.3 (95%CI, 1.1-1.6) for OS. This study validates CAAI as an independent predictor of survival in both ER+ and ER- breast cancer and reveals a significant prognostic value for CAAI in high-grade serous ovarian cancer.

Sänger N, Ruckhäberle E, Györffy B, et al.
Acid ceramidase is associated with an improved prognosis in both DCIS and invasive breast cancer.
Mol Oncol. 2015; 9(1):58-67 [PubMed] Related Publications
Acid ceramidase (ASAH1) a key enzyme of sphingolipid metabolism converting pro-apoptotic ceramide to sphingosine has been shown to be overexpressed in various cancers. We previously demonstrated higher expression of ASAH1 in ER positive compared to ER negative breast cancer. In the current study we performed subtype specific analyses of ASAH1 gene expression in invasive and non invasive breast cancer. We show that expression of ASAH1 is mainly associated with luminal A - like cancers which are known to have the best prognosis of all breast cancer subtypes. Moreover tumors with high ASAH1 expression among the other subtypes are also characterized by an improved prognosis. The good prognosis of tumors with high ASAH1 is independent of the type of adjuvant treatment in breast cancer and is also detected in non small cell lung cancer patients. Moreover, even in pre-invasive DCIS of the breast ASAH1 is associated with a luminal phenotype and a reduced frequency of recurrences. Thus, high ASAH1 expression is generally associated with an improved prognosis in invasive breast cancer independent of adjuvant treatment and could also be valuable as prognostic factor for pre-invasive DCIS.

Aly RM, Ghazy HF
High expression of GTPase regulator associated with the focal adhesion kinase (GRAF) is a favorable prognostic factor in acute myeloid leukemia.
Blood Cells Mol Dis. 2014; 53(4):185-8 [PubMed] Related Publications
BACKGROUND: GRAF is a recognized tumor suppressor gene that was found inactivated in AML. However, the prognostic role of a GRAF transcript has not been studied in patients with AML.
METHODS: In this study, we investigated the expression of the GRAF transcript by real time quantitative PCR in 60 AML patients and 30 healthy age and sex matched controls.
RESULTS: GRAF expression was significantly lower in patients with AML when compared to controls (P=0.008). There were no significant differences in clinical features, FAB subtypes and cytogenetic risk subgroups between patients with high and low GRAF expression levels. Kaplan-Meier analysis showed that patients with high GRAF expression had longer overall survival (OS). Multivariate analysis revealed that, besides WBC count, GRAF expression was also an independent prognostic factor for AML.
CONCLUSION: We provide evidence that high GRAF expression is a favorable prognostic marker in patients with AML.

Herold T, Metzeler KH, Vosberg S, et al.
Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis.
Blood. 2014; 124(8):1304-11 [PubMed] Related Publications
In acute myeloid leukemia (AML), isolated trisomy 13 (AML+13) is a rare chromosomal abnormality whose prognostic relevance is poorly characterized. We analyzed the clinical course of 34 AML+13 patients enrolled in the German AMLCG-1999 and SAL trials and performed exome sequencing, targeted candidate gene sequencing and gene expression profiling. Relapse-free (RFS) and overall survival (OS) of AML+13 patients were inferior compared to other ELN Intermediate-II patients (n=855) (median RFS, 7.8 vs 14.1 months, P = .006; median OS 9.3 vs. 14.8 months, P = .004). Besides the known high frequency of RUNX1 mutations (75%), we identified mutations in spliceosome components in 88%, including SRSF2 codon 95 mutations in 81%. Recurring mutations were detected in ASXL1 (44%) and BCOR (25%). Two patients carried mutations in CEBPZ, suggesting that CEBPZ is a novel recurrently mutated gene in AML. Gene expression analysis revealed a homogeneous expression profile including upregulation of FOXO1 and FLT3 and downregulation of SPRY2. This is the most comprehensive clinical and biological characterization of AML+13 to date, and reveals a striking clustering of lesions in a few genes, defining AML+13 as a genetically homogeneous subgroup with alterations in a few critical cellular pathways. identifiers: AMLCG-1999: NCT00266136; AML96: NCT00180115; AML2003: NCT00180102; and AML60+: NCT00893373.

Dzikiewicz-Krawczyk A, Macieja A, Mały E, et al.
Polymorphisms in microRNA target sites modulate risk of lymphoblastic and myeloid leukemias and affect microRNA binding.
J Hematol Oncol. 2014; 7:43 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNA dysregulation is a common event in leukemia. Polymorphisms in microRNA-binding sites (miRSNPs) in target genes may alter the strength of microRNA interaction with target transcripts thereby affecting protein levels. In this study we aimed at identifying miRSNPs associated with leukemia risk and assessing impact of these miRSNPs on miRNA binding to target transcripts.
METHODS: We analyzed with specialized algorithms the 3' untranslated regions of 137 leukemia-associated genes and identified 111 putative miRSNPs, of which 10 were chosen for further investigation. We genotyped patients with acute myeloid leukemia (AML, n = 87), chronic myeloid leukemia (CML, n = 140), childhood acute lymphoblastic leukemia (ALL, n = 101) and healthy controls (n = 471). Association between SNPs and leukemia risk was calculated by estimating odds ratios in the multivariate logistic regression analysis. For miRSNPs that were associated with leukemia risk we performed luciferase reporter assays to examine whether they influence miRNA binding.
RESULTS: Here we show that variant alleles of TLX1_rs2742038 and ETV6_rs1573613 were associated with increased risk of childhood ALL (OR (95% CI) = 3.97 (1.43-11.02) and 1.9 (1.16-3.11), respectively), while PML_rs9479 was associated with decreased ALL risk (OR = 0.55 (0.36-0.86). In adult myeloid leukemias we found significant associations between the variant allele of PML_rs9479 and decreased AML risk (OR = 0.61 (0.38-0.97), and between variant alleles of IRF8_ rs10514611 and ARHGAP26_rs187729 and increased CML risk (OR = 2.4 (1.12-5.15) and 1.63 (1.07-2.47), respectively). Moreover, we observed a significant trend for an increasing ALL and CML risk with the growing number of risk genotypes with OR = 13.91 (4.38-44.11) for carriers of ≥3 risk genotypes in ALL and OR = 4.9 (1.27-18.85) for carriers of 2 risk genotypes in CML. Luciferase reporter assays revealed that the C allele of ARHGAP26_rs187729 creates an illegitimate binding site for miR-18a-3p, while the A allele of PML_rs9479 enhances binding of miR-510-5p and the C allele of ETV6_rs1573613 weakens binding of miR-34c-5p and miR-449b-5p.
CONCLUSIONS: Our study implicates that microRNA-binding site polymorphisms modulate leukemia risk by interfering with the miRNA-mediated regulation. Our findings underscore the significance of variability in 3' untranslated regions in leukemia.

Kempf W, Kazakov DV, Buechner SA, et al.
Primary cutaneous marginal zone lymphoma in children: a report of 3 cases and review of the literature.
Am J Dermatopathol. 2014; 36(8):661-6 [PubMed] Related Publications
: Primary cutaneous marginal zone lymphoma (PCMZL) is one of the most common cutaneous B-cell lymphomas. It affects mostly patients in their fourth decade and manifests with multifocal nodules mostly on the arms and upper trunk in more than half of the patients. PCMZL is, however, rare in children and adolescents, with only 20 cases reported in patients aged 20 and younger. The authors present 3 cases of PCMZL in teenagers. The patients were 2 girls aged 18 and 13 and a 17-year-old boy. Two patients presented with multiple lesions involving various anatomic sites, whereas in 1 patient, 2 small closely opposed papules on the abdomen were seen. Histopathologically, the characteristic appearance of PCMZL was found in 3 of 4 specimens, with nodular infiltrates composed of small lymphocytes in the interfollicular compartment, reactive germinal centers, and plasma cells in small clusters mainly at the periphery of the infiltrates, whereas 1 specimen showed a dense lymphocytic infiltrate with small granulomas. Clonality was demonstrated by monotypic immunoglobulin light chain expression and/or monoclonal rearrangement of the immunoglobulin heavy chain genes. No Borrelia burgdorferi was identified on serology or by polymerase chain reaction in any of the cases. Treatment included excision or administration of antibiotics with complete remission in all the 3 patients indicating that PCMZL in children and young adolescents follows the same indolent course with a tendency for recurrences, but excellent prognosis as in adults. The pertinent literature on PCZL in childhood and adolescence is reviewed.

Graf SA, Busch C, Bosserhoff AK, et al.
SOX10 promotes melanoma cell invasion by regulating melanoma inhibitory activity.
J Invest Dermatol. 2014; 134(8):2212-20 [PubMed] Related Publications
The transcription factor SOX10 (SRY (sex determining region Y)-box 10) has a key role in the embryonic development of melanocytes. Recently, it has been suggested that SOX10 is highly relevant for melanoma development and survival. However, the distinct functions and downstream targets of SOX10 in melanoma remain widely unknown. In this study, we inhibited SOX10 via RNA interference in different human melanoma cell lines and found a significantly reduced invasion capacity in vitro and in the chick embryo model. At later time points, SOX10 inhibition reduced proliferation and induced cell death. We identified melanoma inhibitory activity (MIA) as a direct target gene of SOX10, which is an essential protein for melanoma cell migration and invasion. Expression levels of SOX10 and MIA strictly correlated in melanoma cell lines, and SOX10 inhibition reduced MIA expression and promoter activity. Direct binding of SOX10 to the MIA promoter was demonstrated by electrophoretic mobility shift assay and chromatin immunoprecipitation. Ectopic expression of MIA in SOX10-inhibited melanoma cells restored the invasion capacity, supporting the hypothesis that MIA is responsible for SOX10-mediated melanoma cell invasion. Our data provide evidence for a critical role of SOX10 in melanoma cell invasion through the regulation of MIA and highlight its role as a therapeutic target in melanoma.

Heitzer E, Artl M, Filipits M, et al.
Differential survival trends of stage II colorectal cancer patients relate to promoter methylation status of PCDH10, SPARC, and UCHL1.
Mod Pathol. 2014; 27(6):906-15 [PubMed] Related Publications
Surgical excision of colorectal cancer at early clinical stages is highly effective, but 20-30% of patients relapse. Therefore, it is of clinical relevance to identify patients at high risk for recurrence, who would benefit from adjuvant chemotherapy. The objective of this study was to identify prognostic and/or predictive methylation markers in stage II colorectal cancer patients. Therefore, we selected six gene promoters (FZD9, PCDH10 (protocadherin 10), SFRP2, SPARC (secreted protein acidic and rich in cysteine), UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), and WIF1) for methylation analysis in formalin-fixed, paraffin-embedded primary tumor samples of colorectal cancer patients (n=143) who were enrolled in a prospective randomized phase III trial of the Austrian Breast and Colorectal cancer Study Group. Patients were randomized to adjuvant chemotherapy with 5-fluorouracil and leucovorin or surveillance only. Survival analyses revealed that combined evaluation of three promoters (PCDH10, SPARC, and UCHL1) showed differential effects with regard to disease-free survival and overall survival in the two treatment groups (significance level 0.007). In the chemotherapy arm, a statistically insignificant trend for patients without methylation toward longer survival was observed (P=0.069 for disease-free survival and P=0.139 for overall survival). Contrary, patients in the surveillance arm without methylation in their gene promoters had shorter disease-free survival and overall survival (P=0.031 for disease-free survival and P=0.003 for overall survival), indicating a prognostic effect of methylation in this group (test for interaction, P=0.006 for disease-free survival and P=0.018 for overall survival). These results indicate that promoter methylation status of PCDH10, SPARC, and UCHL1 may be used both as prognostic and predictive molecular marker for colorectal cancer patients and, therefore, may facilitate treatment decisions for stage II colorectal cancer.

Li J, Xu YH, Lu Y, et al.
Identifying differentially expressed genes and small molecule drugs for prostate cancer by a bioinformatics strategy.
Asian Pac J Cancer Prev. 2013; 14(9):5281-6 [PubMed] Related Publications
PURPOSE: Prostate cancer caused by the abnormal disorderly growth of prostatic acinar cells is the most prevalent cancer of men in western countries. We aimed to screen out differentially expressed genes (DEGs) and explore small molecule drugs for prostate cancer.
MATERIALS AND METHODS: The GSE3824 gene expression profile of prostate cancer was downloaded from Gene Expression Omnibus database which including 21 normal samples and 18 prostate cancer cells. The DEGs were identified by Limma package in R language and gene ontology and pathway enrichment analyses were performed. In addition, potential regulatory microRNAs and the target sites of the transcription factors were screened out based on the molecular signature database. In addition, the DEGs were mapped to the connectivity map database to identify potential small molecule drugs.
RESULTS: A total of 6,588 genes were filtered as DEGs between normal and prostate cancer samples. Examples such as ITGB6, ITGB3, ITGAV and ITGA2 may induce prostate cancer through actions on the focal adhesion pathway. Furthermore, the transcription factor, SP1, and its target genes ARHGAP26 and USF1 were identified. The most significant microRNA, MIR-506, was screened and found to regulate genes including ITGB1 and ITGB3. Additionally, small molecules MS-275, 8-azaguanine and pyrvinium were discovered to have the potential to repair the disordered metabolic pathways, abd furthermore to remedy prostate cancer.
CONCLUSIONS: The results of our analysis bear on the mechanism of prostate cancer and allow screening for small molecular drugs for this cancer. The findings have the potential for future use in the clinic for treatment of prostate cancer.

Wang Q, Hui H, Guo Z, et al.
ADAR1 regulates ARHGAP26 gene expression through RNA editing by disrupting miR-30b-3p and miR-573 binding.
RNA. 2013; 19(11):1525-36 [PubMed] Free Access to Full Article Related Publications
Rho GTPase activating protein 26 (ARHGAP26) is a negative regulator of the Rho family that converts the small G proteins RhoA and Cdc42 to their inactive GDP-bound forms. It is essential for the CLIC/GEEC endocytic pathway, cell spreading, and muscle development. The present study shows that ARHGAP26 mRNA undergoes extensive A-to-I RNA editing in the 3' UTR that is specifically catalyzed by ADAR1. Furthermore, the mRNA and protein levels of ARHGAP26 were decreased in cells in which ADAR1 was knocked down. Conversely, ADAR1 overexpression increased the abundance of ARHGAP26 mRNA and protein. In addition, we found that both miR-30b-3p and miR-573 target the ARHGAP26 gene and that RNA editing of ARHGAP26 mediated by ADAR1 abolished the repression of its expression by miR-30b-3p or miR-573. When ADAR1 was overexpressed, the reduced abundance of ARHGAP26 protein mediated by miR-30b-3p or miR-573 was rescued. Importantly, we also found that knocking down ADAR1 elevated RhoA activity, which was consistent with the reduced level of ARHGAP26. Conversely, when ADAR1 was overexpressed, the amount of RhoA-GTP decreased. The similar expression patterns of ARHGAP26 and ADAR1 in human tissue samples further confirmed our findings. Taken together, our results suggest that ADAR1 regulates the expression of ARHGAP26 through A-to-I RNA editing by disrupting the binding of miR-30b-3p and miR-573 within the 3' UTR of ARHGAP26. This study provides a novel insight into the mechanism by which ADAR1 and its RNA editing function regulate microRNA-mediated modulation of target genes.

Opatz S, Polzer H, Herold T, et al.
Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia.
Blood. 2013; 122(10):1761-9 [PubMed] Related Publications
The t(8;21) and inv(16)/t(16;16) rearrangements affecting the core-binding factors RUNX1 and CBFB, respectively, are found in 15% to 20% of adult de novo acute myeloid leukemia (AML) cases and are associated with a favorable prognosis. Since the expression of the fusion genes CBFB/MYH11 or RUNX1/RUNX1T1 alone is not sufficient to cause leukemia, we performed exome sequencing of an AML sample with an inv(16) to identify mutations, which may collaborate with the CBFB/MYH11 fusion during leukemogenesis. We discovered an N676K mutation in the adenosine triphosphate (ATP)-binding domain (tyrosine kinase domain 1 [TKD1]) of the fms-related tyrosine kinase 3 (FLT3) gene. In a cohort of 84 de novo AML patients with a CBFB/MYH11 rearrangement and in 36 patients with a RUNX1/RUNX1T1 rearrangement, the FLT3 N676K mutation was identified in 5 and 1 patients, respectively (5 [6%] of 84; 1 [3%] of 36). The FLT3-N676K mutant alone leads to factor-independent growth in Ba/F3 cells and, together with a concurrent FLT3-ITD (internal tandem duplication), confers resistance to the FLT3 protein tyrosine kinase inhibitors (PTKIs) PKC412 and AC220. Gene expression analysis of AML patients with CBFB/MYH11 rearrangement and FLT3 N676K mutation showed a trend toward a specific expression profile. Ours is the first report of recurring FLT3 N676 mutations in core-binding factor (CBF) leukemias and suggests a defined subgroup of CBF leukemias.

Rössle M, Weber CS, Züllig L, et al.
EGFR expression and copy number changes in low T-stage oral squamous cell carcinomas.
Histopathology. 2013; 63(2):271-8 [PubMed] Related Publications
AIMS: EGFR-directed therapies are used to treat patients with advanced head and neck squamous cell carcinoma (SCC). As it is still unclear whether or not EGFR amplification represents an early or late event in head and neck SCC progression, we aimed to determine the frequency of abnormalities of EGFR protein and gene copy numbers in early oral SCC.
METHODS AND RESULTS: A tissue microarray of cancer tissue from 120 patients with pT1/2 oral SCC was constructed. We investigated EGFR protein expression by immunohistochemistry. EGFR gene copy enumeration was performed using fluorescence in-situ hybridization (FISH) and the novel automated silver in-situ hybridization (SISH) technology. Of early oral SCC, 19.3% showed high, 57.1% moderate and 23.6% low EGFR expression. EGFR amplification/polysomy was identified in 8% and 9% of cases by FISH and SISH, respectively. EGFR-SISH had a high concordance with EGFR-FISH (kappa value = 1.0), and both methods showed high conformity with EGFR immunohistochemistry (P = 0.001 and P = 0.006, respectively). No correlation was found of EGFR protein expression or gene amplification status with pT or pN stage.
CONCLUSIONS: Only a small subgroup of early oral SCC is characterized by EGFR amplification, which can be identified reliably using EGFR-SISH technology. This finding suggests that EGFR gene amplification mostly occurs in advanced stages of oral SCC.

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