Ben Davidson

Oslo University Hospital, Kristiania (historical), Oslo, Norway

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Publications (281)1086.71 Total impact

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    ABSTRACT: The objective of this study was to investigate the expression and clinical role of 14 genes previously shown to be associated with chemotherapy response and/or progression-free survival in a smaller series of ovarian serous carcinoma effusions. Advanced-stage serous ovarian carcinoma effusions (n = 150) were analyzed for mRNA expression of AKR1C1, ABCA4, ABCA13, ABCB10, BIRC6, CASP9, CIAPIN1, FAS, MGMT, MUTYH, POLH, SRC, TBRKB and XPA using quantitative real-time PCR. mRNA expression was studied for association with clinicopathologic parameters, including chemotherapy response and survival. ABCA4 mRNA expression was significantly related to better (complete) chemotherapy response at diagnosis in the entire cohort (p = 0.018), whereas higher POLH mRNA levels were significantly related to better chemoresponse at diagnosis in analysis to 58 patients with pre-chemotherapy effusions treated with standard chemotherapy (carboplatin + paclitaxel; p = 0.023). In univariate survival analysis for patients with pre-chemotherapy effusions (n = 77), CIAPIN1 mRNA expression was significantly related to shorter overall (p = 0.007) and progression-free (p = 0.038) survival, whereas ABCA13 mRNA expression was significantly related to shorter OS (p = 0.024). Higher CIAPIN1 mRNA expression was an independent marker of poor overall survival in Cox multivariate analysis (p = 0.044). Our data identify ABCA4 and POLH as markers of better chemotherapy response in metastatic serous carcinoma. CIAPIN1 and ABCA13 may be novel markers of poor outcome in pre-chemotherapy serous carcinoma effusions.
    Molecular Cancer 12/2015; 14(1). DOI:10.1186/s12943-015-0317-1 · 5.40 Impact Factor
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    ABSTRACT: Malignant tumors of the vulva account for only 5% of cancers of the female genital tract in the USA. The most frequent cancers of the vulva are squamous cell carcinoma (SCC) and malignant melanoma (MM). Little is known about the genetic aberrations carried by these tumors. We report a detailed study of 25 vulva tumors [22 SCC, 2 MM, 1 atypical squamous cell hyperplasia (AH)] analyzed for expression of the high-mobility group AT-hook family member genes HMGA2 and HMGA1, for mutations in the IDH1, IDH2 and TERT genes, and for methylation of the MGMT promoter. The RT-PCR and immunohistochemistry analyses showed that HMGA2 was expressed in the great majority of analyzed samples (20 out of 24; SCC as well as MM) but not in the normal controls. HMGA1, on the other hand, was expressed in both tumors and normal tissues. Five of the 24 tumors (all SCC) showed the C228T mutation in the TERT promoter. Our results showed that HMGA2 and TERT may be of importance in the genesis and/or the progression of tumors of the vulva.
    Oncology Reports 03/2015; DOI:10.3892/or.2015.3882 · 2.19 Impact Factor
  • Ben Davidson
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    ABSTRACT: Malignant pleural mesothelioma (MPM) is a clinically aggressive tumor originating from mesothelial cells, which line the serosal cavities. Recent years have seen extensive research aimed at identifying new therapeutic targets, predictive markers and prognostic factors in this disease. These include both serum and tissue markers, and are related to multiple cellular pathways which affect cell survival, proliferation, apoptosis, angiogenesis, interaction with the immune response and DNA repair. Several of these molecules may become relevant for pathologists as part of the effort to select patient sub-populations for targeted therapy in the future. This review summarizes current data in this area and discusses their potential clinical relevance. Copyright © 2015. Published by Elsevier Inc.
    Human pathology 02/2015; 46(6). DOI:10.1016/j.humpath.2015.02.006 · 2.81 Impact Factor
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    ABSTRACT: No consensus treatment regime exists beyond surgery for malignant peripheral nerve sheath tumours (MPNST), and the purpose of the present study was to find new approaches to stratify patients with good and poor prognosis and to better guide therapeutic intervention for this aggressive soft tissue cancer. From a total of 67 MPNSTs from Scandinavian patients with and without neurofibromatosis type 1, 30 MPNSTs were investigated by genome-wide RNA expression profiling and 63 MPNSTs by immunohistochemical (IHC) analysis, and selected genes were submitted to analyses of disease-specific survival. The potential drug target genes survivin (BIRC5), thymidine kinase 1 (TK1), and topoisomerase 2-alpha (TOP2A), all encoded on chromosome arm 17q, were up-regulated in MPNST as compared to benign neurofibromas. Each of them was found to be independent prognostic markers on the gene expression level, as well as on the protein level. A prognostic profile was identified by combining the nuclear expression scores of the three proteins. For patients with completely resected tumours only 15% in the high risk group were alive after two years, as compared to 78% in the low risk group. In conclusion, we found a novel protein expression profile which identifies MPNST patients with inferior prognosis even after assumed curative surgery. The tested proteins are drug targets; therefore the expression profile may provide predictive information guiding the design of future clinical trials. Importantly, as the effect is seen on the protein level using IHC, the biomarker panel can be readily implemented in routine clinical testing. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
    Molecular Oncology 02/2015; 8(6). DOI:10.1016/j.molonc.2015.02.005 · 5.94 Impact Factor
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    ABSTRACT: Multicystic mesothelioma is a rare disease of unknown etiology and pathogenesis. Nothing has been known about the cytogenetic and molecular genetic features of these tumors. Here we present the first cytogenetically analyzed multicystic mesothelioma with the karyotype 46,XX,t(7;17)(p13;q23),t(8;11)(q23;p13). RNA-sequencing showed that the t(7;17)(p13;q23) generated a chimeric TNS3-MAP3K3 gene, which codes for a chimeric protein kinase, as well as the reciprocal MAP3K3-TNS3 in which the region of TNS3 coding for the SH2_Tensin_like region and the tensin phosphotyrosine-binding domain is under the control of the MAP3K3 promoter. The other translocation, t(8;11)(q23;p13), generated a chimeric ZFPM2-ELF5 gene which codes for a chimeric transcription factor in which the first 40 amino acids of ELF5 are replaced by the first 100 amino acid of ZFPM2. RT-PCR together with Sanger sequencing verified the presence of the above-mentioned fusion transcripts. The finding of acquired clonal chromosome abnormalities in cells cultured from the lesion and the presence of the TNS3-MAP3K3 chimeric protein kinase and the ZFPM2-ELF5 chimeric transcription factor confirm the neoplastic nature of multicystic mesothelioma. Copyright © 2014. Published by Elsevier Ireland Ltd.
    Cancer Letters 12/2014; 357(2). DOI:10.1016/j.canlet.2014.12.002 · 5.02 Impact Factor
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    ABSTRACT: We recently identified gene signatures which allow classification of ovarian carcinoma into 5 distinct clinically-relevant groups. In the present study, we investigated the clinical role of 10 protein products of the discriminating genes, with focus on epithelial-mesenchymal transition and stem cell markers. Expression of E-cadherin, N-cadherin, P-cadherin, Zeb1, HMGA2, Rab25, CD24, NCAM (CD56), Sox11 and vimentin was assessed in 100 advanced-stage (FIGO III-IV) serous ovarian carcinoma effusions using immunohistochemistry. Results were analyzed for association with clinicopathologic parameters, including chemotherapy response, and survival. All 10 proteins were frequently expressed in carcinoma cells. HMGA2 expression was related to older age (p = 0.015). HMGA2 and NCAM expression was related to stage III disease (p = 0.011 and p = 0.023, respectively) and NCAM was overexpressed in peritoneal compared to pleural effusions (p = 0.001). Vimentin and Zeb1 expression was significantly related to poor chemotherapy response at diagnosis (p = 0.005 and p = 0.017, respectively). The associations between NCAM and peritoneal localization and of vimentin and poor chemoresponse were retained after Bonferroni correction. NCAM expression was associated with a trend for shorter overall survival in univariate survival analysis (p = 0.187), but emerged as independent prognosticator in Cox multivariate analysis (p = 0.042). This study identifies Vimentin and Zeb1 as markers of poor chemoresponse in metastatic serous ovarian carcinoma effusions and suggests NCAM as potential prognostic marker in metastatic disease. The generally limited prognostic role of the studied markers emphasizes the difficulty in applying data obtained in studies of primary ovarian carcinomas to analyses of ovarian carcinoma effusions, reflecting the unique biology of the latter.
    Human pathology 10/2014; 46(1). DOI:10.1016/j.humpath.2014.10.004 · 2.81 Impact Factor
  • Ben Davidson, Claes G Tropé
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    ABSTRACT: Ovarian cancer remains the most lethal gynecologic malignancy, owing to late detection, intrinsic and acquired chemoresistance and remarkable heterogeneity. Despite optimization of surgical and chemotherapy protocols and initiation of clinical trials incorporating targeted therapy, only modest gains have been achieved in prolonging survival in this cancer. This review provides an update of recent developments in our understanding of the etiology, origin, diagnosis, progression and treatment of this malignancy, with emphasis on clinically relevant genetic classification approaches. In the authors' opinion, focused effort directed at understanding the molecular make-up of recurrent and metastatic ovarian cancer, while keeping in mind the unique molecular character of each of its histological types, is central to our effort to improve patient outcome in this cancer.
    Women s Health 09/2014; 10(5):519-33. DOI:10.2217/whe.14.37
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    ABSTRACT: Objective. Wee1-like kinase (Wee1) is a tyrosine kinase which negatively regulates entry into mitosis at the G2 to M-phase transition and has a role in inhibition of unscheduled DNA replication in S-phase. The present study investigated the clinical role of Wee1 in advanced-stage (FIGO III-IV) ovarian serous carcinoma. Methods. Wee1 protein expression was analyzed in 287 effusions using immunohistochemistry. Expression was analyzed for association with clinicopathologic parameters, including survival. Forty-five effusions were additionally studied using Western blotting. Wee1 was further silenced in SKOV3 and OVCAR8 cells by siRNA knockdown and proliferation was assessed. Results. Nuclear expression of Wee1 in tumor cells was observed in 265/287 (92%) and 45/45 (100%) effusions by immunohistochemistry and Western blotting, respectively. Wee1 expression by immunohistochemistry was significantly higher in post-chemotherapy disease recurrence compared to pre-chemotherapy effusions obtained at diagnosis (p = 0.002). Wee1 silencing in SKOV3 and OVCAR8 cells reduced proliferation. In univariate survival analysis of the entire cohort, a trend was observed between high (>25% of cells) Wee1 expression and poor overall survival (p = 0.083). Survival analysis for 109 patients with post-chemotherapy effusions showed significant association between Wee1 expression and poor overall survival (p = 0.004), a finding which retained its independent prognostic role in Cox multivariate analysis (p = 0.003). Conclusions. Wee1 is frequently expressed in ovarian serous carcinoma effusions, and its expression is significantly higher following exposure to chemotherapy. The present study is the first to report that Wee1 is an independent prognostic marker in serous ovarian carcinoma.
    Gynecologic Oncology 08/2014; 135(1). DOI:10.1016/j.ygyno.2014.07.102 · 3.69 Impact Factor
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    ABSTRACT: Background: Malignant peripheral nerve sheath tumour (MPNST) is a highly aggressive cancer, only 20−50% survive the first five years after diagnosis, and there is a lack of good prognostic markers and effective treatment options beyond surgery. MPNST generally have very complex karyotypes, often with a triploid or tetraploid chromosome number. DNA copy number gain of chromosome arm 17q harbouring the antiapoptotic gene BIRC5 (baculoviral IAP repeat containing 5/survivin) and loss of 10q harbouring the tumour suppressor gene PTEN (phosphatase and tensin homolog) have been found to be associated with aggressive disease in MPNST in previous studies. In this study we have investigated the copy number changes of these genes and the prognostic impact of their encoded products in a large series of MPNST. Material and Methods: Genome-Wide Human SNP Array 6.0 (Affymetrix) was used to analyse genomic copy number in 91 fresh frozen MPNSTs, using the PennCNV-Affy protocol for preprocessing and the Bioconductor package ‘Copynumber’ for segmentation. mRNA expression was analysed in 29 MPNSTs and eight neurofibromas (AB1700 microarray, Applied Biosystems), while protein expression was analysed by immunohistochemistry on formalin-fixed paraffin-embedded tissue material from 63 MPNST patients. Results: The overall profile for copy number changes across all 91 tumour samples was as expected from previous publications from us and others. In the present series, we found that 56% of the cases showed gain of the band on chromosome arm 17q harbouring BIRC5, and 40% had loss of the 10q sequences harbouring PTEN. Furthermore, we found a significant increase of BIRC5 mRNA expression in the malignant versus benign tumours (P = 3×10−7, Mann–Whitney U test, fold change 21), and a significant decrease in expression of PTEN (P = 3×10−5, Mann–Whitney U test, fold change 0.4). In univariate Cox regression analyses we also found a significant association between mRNA expression of BIRC5 and PTEN and 5-year disease-specific survival (HR 1.91; 95% CI 1.13–3.21; P = 0.015, and HR 0.52; 95% CI 0.31–0.89; P = 0.02, respectively). Expression of BIRC5 was validated on the protein level, and nuclear staining for BIRC5 showed significant association to poor disease-specific survival (HR 2.27; 95% CI 1.06–4.87; P = 0.03). Conclusions: A high resolution genome wide copy number profile is determined for the largest MPNSTs series to date, which can be used to confirm previous findings in smaller series and to detect new changes of importance to MPNST. Here we demonstrate that differential expression of BIRC5 and PTEN is best explained by copy number changes and that the product of these genes may serve as prognostic markers for MPNST patients.
    23rd Biennial Congress of the EUROPEAN ASSOCIATION FOR CANCER RESEARCH 2014, Munich; 07/2014
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    ABSTRACT: The involvement of VICKZ proteins has been implicated in a large number of cancers. The aim of the present study was to investigate the biological and clinical role of VICKZ proteins in ovarian carcinoma. VICKZ1-3 protein expression was analyzed in 82 serous ovarian carcinoma specimens (51 effusions, 14 primary carcinomas, 17 solid metastases) by immunoblotting. Protein localization was studied using immunohistochemistry in 101 tumors (40 effusions, 25 primary carcinomas, 36 solid metastases). The effect of VICKZ silencing using short hairpin RNA (shRNA) on collagenolytic activity and invasion was assessed in ES-2 ovarian carcinoma cells. VICKZ2 was the most frequently expressed family member in serous carcinomas. VICKZ levels measured by pan-VICKZ antibody were significantly higher in primary carcinomas and solid metastases compared to effusions (p<0.001). In contrast, VICKZ1 and VICKZ2 were overexpressed in effusions compared to primary carcinomas and solid metastases (p=0.016 and p=0.024, respectively), and higher VICKZ2 expression in effusions was associated with shorter overall survival in univariate analysis (p=0.01). All 3 proteins were localized to OC cells by immunohistochemistry, with tumor-specific expression observed for VICKZ1 and VICKZ2. VICKZ silencing in ES-2 cells led to reduced matrix metalloproteinase-9 activity and reduced invasion. In conclusion, VICKZ2 is the most frequently expressed VICKZ family member in serous ovarian carcinomas. VICKZ1 and VICKZ2 are overexpressed in effusions compared to primary carcinomas and solid metastases, suggesting a biological role at this anatomic site, and appear to have a role in proteolysis and invasion. VICKZ2 may be a prognostic marker in ovarian serous carcinoma effusions.
    Human pathology 07/2014; 45(7). DOI:10.1016/j.humpath.2014.03.005 · 2.81 Impact Factor
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    ABSTRACT: Objectives: We previously described the overexpression of APOA1 and GPX3 in ovarian/peritoneal serous carcinoma compared with breast carcinoma effusions using gene expression array analysis. The objective of the present study was to validate this finding and to analyze the association between these genes and clinicopathologic parameters, including survival, in advanced-stage ovarian serous carcinoma. Methods: APOA1 and GPX3 mRNA expression using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was analyzed in 121 effusions (101 ovarian, 20 breast carcinomas) and 85 solid ovarian carcinoma specimens (43 primary carcinomas, 42 metastases). Results: APOA1 and GPX3 transcript levels were significantly higher in ovarian carcinoma at all anatomic sites compared with breast carcinoma effusions (P < .001). GPX3 mRNA levels were significantly higher in primary carcinomas and solid metastases from patients who received neoadjuvant chemotherapy compared with chemo-naive tumors (P = .016). APOA1 and GPX3 mRNA levels in the entire effusion series were unrelated to clinicopathologic parameters. However, higher APOA1 mRNA levels in primary diagnosis pre-chemotherapy effusions were significantly related to better overall survival (P = .045), a finding that retained its significance in Cox multivariate analysis (P = .016). Conclusions: APOA1 and GPX3 mRNA levels on qRT-PCR effectively differentiate ovarian from breast carcinoma. APOA1 may be a novel prognostic marker in metastatic serous carcinoma.
    American Journal of Clinical Pathology 07/2014; 142(1):51-7. DOI:10.1309/AJCPD8NBSHXRXQL7 · 3.01 Impact Factor
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    ABSTRACT: Chromosome 19 is frequently rearranged in ovarian carcinomas, but the pathogenetic consequences of this are not clearly understood. We performed microarray gene expression analysis on 12 ovarian carcinomas that carry a rearranged chromosome 19 in their karyotype. These aberrant chromosomes have previously been microdissected and analyzed by array-based CGH. In the current study, we wanted to explore whether the genomic alterations thus detected correlated with changes in gene expression. The microarray gene expression analysis gave information on 407 genes mapping in gained genomic regions on chromosome 19, of which 92 showed association between DNA gain and upregulated expression. Of the genes showing this association, 39 (42%) showed gain in at least two samples. The majority of these 39 genes of interest (n = 24, 62%) encode zinc finger proteins, which otherwise make up only 15% of the approximately 1,400 genes on chromosome 19. The strongest association was found for ZNF223 which was upregulated in samples with genomic gain compared with samples without gain. We suggest that DNA copy number changes brought about by rearrangements of chromosome 19 contribute to ovarian carcinogenesis by leading to upregulation of ZNF223 and other zinc finger genes. © 2014 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 07/2014; 53(7). DOI:10.1002/gcc.22166 · 3.84 Impact Factor
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    ABSTRACT: The objective of this study was to analyze the expression, biological role and clinical relevance of exosomal microRNAs (miRNAs) from ovarian carcinoma effusion supernatants. Exosomal miRNA expression profiling was performed using miRNA Taqman arrays. Selected miRNAs were validated using quantitative PCR in 86 ovarian carcinoma effusion supernatants. The role of exosomal microRNA in this cancer was further studied using in vitro and in vivo models. miRNA profiling identified 99 miRNAs with high expression levels in exosomes from ovarian carcinoma effusion supernatants. Quantitative PCR validation of 11 miRNAs showed significant associations with effusion site (peritoneum vs. pleura) and FIGO stage. In univariate survival analysis, high levels of miRNAs 21, 23b and 29a were associated with poor progression-free survival (p=0.01, p=0.015 and p=0.009, respectively), whereas high expression of miRNA 21 correlated with poor overall survival (p=0.017). The latter association was retained in Cox multivariate analysis (p=0.001). Exposure of LP9 mesothelial cells and ES2 ovarian carcinoma cells to ovarian carcinoma effusion-derived exosomes inhibited tumor spheroid expansion and reduced mesothelial clearance area. Treatment of SCID mice with exosomes from ovarian carcinoma effusions prior to injection of tumor cells was associated with larger tumor load, more infiltrative tumors and shorter survival. Patient-derived ovarian carcinoma effusion exosomes contain multiple miRNAs, of which some may have clinical relevance. In experimental models, ovarian carcinoma exosomes affect both tumor cells and cells in the tumor microenvironment, and induce more aggressive disease. Collectively, these data demonstrate the central role of miRNAs and their content in the biology of this cancer.
    Carcinogenesis 06/2014; DOI:10.1093/carcin/bgu130 · 5.27 Impact Factor
  • Ben Davidson, Claes G Trope, Reuven Reich
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    ABSTRACT: The tumor microenvironment, consisting of stromal myofibroblasts, endothelial cells, and leukocytes, is growingly perceived to be a major contributor to the pathogenesis and disease progression in practically all cancer types. Stromal myofibroblasts produce angiogenic factors, proteases, growth factors, immune response-modulating proteins, anti-apoptotic proteins, and signaling molecules, and express surface receptors and respond to stimuli initiated in the tumor cells to establish a bi-directional communication network in the microenvironment to promote tumor cell invasion and metastasis. Many of these molecules are candidates for targeted therapy and the cancer stroma has been recently regarded as target for biological intervention. This review provides an overview of the biology and clinical role of the stroma in ovarian cancer.
    Frontiers in Oncology 05/2014; 4:104. DOI:10.3389/fonc.2014.00104
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    ABSTRACT: Background It is known that all tumors studied in sufficient number to draw conclusions show characteristic/specific chromosomal rearrangements, and the identification of these chromosomes and the genes rearranged behind the aberrations may ultimately lead to a tailor-made therapy for each cancer patient. Knowledge about the acquired genomic aberrations of ovarian carcinomas is still unsatisfactory. Methods We cytogenetically analyzed 110 new cases of ovarian carcinoma of different histological subtypes using karyotyping of G-banded chromosomes and high-resolution comparative genomic hybridization. We first compared the aberration patterns identified by the two genomic screening techniques using the so-called “classical” pathological classification in which the carcinomas are grouped as tumors of types I and II. We also broke down our findings according to the more “modern” classification which groups the carcinomas in five different categories. Results The chromosomal breakpoints identified by karyotyping tended to cluster to 19p/q and to 11q, but no unquestionably recurrent rearrangement could be seen. Common imbalances were scored as gains from 1q, 3q, 7q, and 8q and losses from 17p, 19q, and 22q. Gain of material from 8q23 and losses from 19q and 22q have previously been described at high frequencies in bilateral and borderline ovarian carcinomas. The fact that they were present both in “precursor” lesions, i.e., borderline tumors, as well as in tumors of more advanced stages, i.e., carcinomas, highlights the possibility of an adenoma-carcinoma sequence in ovarian carcinogenesis. Conclusion Based on the relatively simple genomic changes we identified in the low-grade serous carcinomas examined (n = 7) and which largely corresponded to the aberration pattern formerly identified in borderline tumors, one can interpret the cytogenetic data as supporting the view that the low-grade carcinomas represent a phenotypically more advanced stage of borderline tumors. Whether transition from low-grade to high-grade carcinoma also occurs, is a question about which the genomic data is still inconclusive.
    BMC Cancer 05/2014; 14(1):315. DOI:10.1186/1471-2407-14-315 · 3.32 Impact Factor
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    ABSTRACT: The objective of this study was to investigate the expression and clinical role of the spindle checkpoint kinase budding uninhibited by benzimidazole 1 (Bub1) in primary and metastatic advanced-stage ovarian serous carcinoma. BUB1 mRNA expression was analyzed in 178 tumors (88 effusions, 38 primary carcinomas, and 52 solid metastases) from 144 patients with advanced-stage disease using quantitative real-time polymerase chain reaction (PCR). Bub1 protein expression by Western blotting was studied in 63 carcinomas (30 effusions and 33 solid lesions). BUB1 mRNA expression at different anatomic sites was studied for association with clinicopathologic parameters, including chemotherapy resistance and survival. BUB1 mRNA was universally expressed in serous carcinomas, irrespective of anatomic site. BUB1 mRNA levels were uniformly low in six ovarian surface epithelium specimens analyzed for comparative purposes. Bub1 protein was expressed in 22/30 effusions and 28/33 solid lesions. BUB1 mRNA expression was significantly higher in chemo-naïve primary carcinomas and solid metastases compared to specimens obtained following neoadjuvant chemotherapy (p < 0.001) and was unrelated to chemotherapy exposure in effusions nor to chemoresponse or survival at any anatomic site. BUB1 mRNA levels in both effusions and solid lesions were strongly related to the mRNA levels of AURKA and AURKB previously studied in this cohort (p < 0.001 for both). Bub1 is widely expressed in primary and metastatic OC, suggesting a biological role in this cancer. BUB1 mRNA levels are lower following chemotherapy exposure in solid lesions, though its presence is unrelated to clinical behavior including response to chemotherapy and survival. BUB1 is co-expressed with AURKA and AURKB suggesting biological relationship between these spindle cell components.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2014; DOI:10.1007/s00428-014-1577-7 · 2.56 Impact Factor
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    ABSTRACT: The kinase Mnk2 is a substrate of the MAPK pathway and phosphorylates the translation initiation factor eIF4E. In humans, MKNK2, the gene encoding for Mnk2, is alternatively spliced yielding two splicing isoforms with differing last exons: Mnk2a, which contains a MAPK-binding domain, and Mnk2b, which lacks it. We found that the Mnk2a isoform is downregulated in breast, lung, and colon tumors and is tumor suppressive. Mnk2a directly interacts with, phosphorylates, activates, and translocates p38α-MAPK into the nucleus, leading to activation of its target genes, increasing cell death and suppression of Ras-induced transformation. Alternatively, Mnk2b is pro-oncogenic and does not activate p38-MAPK, while still enhancing eIF4E phosphorylation. We further show that Mnk2a colocalization with p38α-MAPK in the nucleus is both required and sufficient for its tumor-suppressive activity. Thus, Mnk2a downregulation by alternative splicing is a tumor suppressor mechanism that is lost in some breast, lung, and colon tumors.
    Cell Reports 04/2014; 7(2). DOI:10.1016/j.celrep.2014.03.041 · 7.21 Impact Factor
  • Ben Davidson, Claes G Tropé, Reuven Reich
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    ABSTRACT: MicroRNAs (miRNAs, miRs) are non-coding RNAs which post-transcriptionally regulate mRNA synthesis. Data regarding the expression and clinical relevance of miRNAs and the miRNA-regulating machinery in ovarian carcinoma has been rapidly expanding in recent years. This review presents current knowledge in this area. PubMed search was undertaken using the terms 'ovarian' and 'microRNA' RESULTS: A total of 492 papers were identified, of which approximately 100 were publications in English focusing exclusively or partly on clinical ovarian carcinoma specimens. These studies have identified multiple miRNAs with a potential role in the diagnosis, biology and progression of ovarian carcinoma, as well as on predicting chemoresponse and determining prognosis. The presented data support a clinical role for miRNAs in ovarian carcinoma and suggest that miRNA-regulated pathways may be of relevance for novel therapeutics. Novel technologies offer new possibilities for wide-scale miRNA-based classification of OC. Further genomic research focusing on larger series of tumors of similar histological type in combination with experimental approaches is likely to expand our understanding of the role of miRNAs in this cancer.
    Gynecologic Oncology 04/2014; DOI:10.1016/j.ygyno.2014.03.575 · 3.69 Impact Factor
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    ABSTRACT: The chimeric transcripts described in endometrial stromal sarcomas (ESS) are JAZF1/SUZ12, YWHAE/FAM22, ZC3H7/BCOR, MBTD1/CXorf67, and recombinations of PHF1 with JAZF1, EPC1, and MEAF6. The MEAF6/PHF1 fusion had hitherto been identified in only one tumor. We present two more ESS with MEAF6/PHF1 detected by transcriptome sequencing (case 1) and RT-PCR (case 2), proving that this fusion is recurrent in ESS. The transcript of both cases was an in-frame fusion between exon 5 of MEAF6 and exon 2 of PHF1. Both genes are involved in epigenetic modification, and this may well be their main pathogenetic theme also in ESS tumorigenesis.
    Cancer letters 02/2014; 347(1). DOI:10.1016/j.canlet.2014.01.030 · 5.02 Impact Factor
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    ABSTRACT: Improved insight into the molecular characteristics of the different ovarian cancer subgroups is needed for developing a more individualized and optimized treatment regimen. The aim of this study was to a) identify differentially expressed miRNAs in high-grade serous ovarian carcinoma (HGSC), clear cell ovarian carcinoma (CCC) and ovarian surface epithelium (OSE), b) evaluate selected miRNAs for association with clinical parameters including survival and c) map miRNA-mRNA interactions. Differences in miRNA expression between HGSC, CCC and OSE were analyzed by global miRNA expression profiling (Affymetrix GeneChip miRNA 2.0 Arrays, n = 12, 9 and 9, respectively), validated by RT-qPCR (n = 35, 19 and 9, respectively), and evaluated for associations with clinical parameters. For HGSC, differentially expressed miRNAs were linked to differentially expressed mRNAs identified previously. Differentially expressed miRNAs (n = 78) between HGSC, CCC and OSE were identified (FDR < 0.01%), of which 18 were validated (p < 0.01) using RT-qPCR in an extended cohort. Compared with OSE, miR-205-5p was the most overexpressed miRNA in HGSC. miR-200 family members and miR-182-5p were the most overexpressed in HGSC and CCC compared with OSE, whereas miR-383 was the most underexpressed. miR-205-5p and miR-200 members target epithelial-mesenchymal transition (EMT) regulators, apparently being important in tumor progression. miR-509-3-5p, miR-509-5p, miR-509-3p and miR-510 were among the strongest differentiators between HGSC and CCC, all being significantly overexpressed in CCC compared with HGSC. High miR-200c-3p expression was associated with poor progression-free (p = 0.031) and overall (p = 0.026) survival in HGSC patients. Interacting miRNA and mRNA targets, including those of a TP53-related pathway presented previously, were identified in HGSC. Several miRNAs differentially expressed between HGSC, CCC and OSE have been identified, suggesting a carcinogenetic role for these miRNAs. miR-200 family members, targeting EMT drivers, were mostly overexpressed in both subgroups, among which miR-200c-3p was associated with survival in HGSC patients. A set of miRNAs differentiates CCC from HGSC, of which miR-509-3-5p and miR-509-5p are the strongest classifiers. Several interactions between miRNAs and mRNAs in HGSC were mapped.
    BMC Cancer 02/2014; 14(1):80. DOI:10.1186/1471-2407-14-80 · 3.32 Impact Factor

Publication Stats

6k Citations
1,086.71 Total Impact Points

Institutions

  • 2009–2015
    • Oslo University Hospital
      • Department of Pathology
      Kristiania (historical), Oslo, Norway
  • 1999–2015
    • University of Oslo
      • • Institute of Clinical Medicine
      • • Department of Pathology (PAT)
      • • Faculty of Medicine
      • • Department of Oral Biology
      Kristiania (historical), Oslo, Norway
  • 2005–2013
    • National Cancer Institute (USA)
      • • Center for Cancer Research
      • • Laboratory of Pathology
      베서스다, Maryland, United States
  • 2005–2009
    • Johns Hopkins University
      • Department of Pathology
      Baltimore, MD, United States
  • 1999–2009
    • Tel Aviv University
      • • Department of Pathology
      • • Department of Obstetrics and Gynecology
      Tel Aviv, Tel Aviv, Israel
  • 2006–2008
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, MD, United States
  • 2007
    • National Institutes of Health
      • Center for Cancer Research
      Bethesda, MD, United States
  • 2004
    • Aalborg University
      Ålborg, North Denmark, Denmark
  • 1998–2004
    • Hebrew University of Jerusalem
      • • Department of Pharmacology
      • • Faculty of Medicine
      Jerusalem, Jerusalem District, Israel
  • 2003
    • Karolinska University Hospital
      Tukholma, Stockholm, Sweden
  • 1997–2001
    • Sheba Medical Center
      • Department of Pathology
      Gan, Tel Aviv, Israel
  • 2000
    • Det Norske Veritas
      Kristiania (historical), Oslo County, Norway