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Background: With a prevalence of 170 000 adults in the US alone, meningiomas are the most common primary intracranial tumors. The management of skull base meningiomas is challenging due to their complexity and proximity to crucial nearby structures. The identification of oncogenic mutations has provided further insights into the tumorigenesis of meningioma and the possibility of targeted therapy. This study aimed to further investigate the association of mutational profiles with anatomical distribution, histological subtype, WHO grade, and recurrence in patients with meningioma. Methods: Tissue samples were collected from 71 patients diagnosed with meningioma from 2008 to 2016. A total of 51 cases were skull based. Samples were subjected to targeted sequencing using a next generation customized cancer gene panel (n = 66 genes analyzed). Results: We detected genomic alterations (GAs) in 68 tumors, averaging 1.56 ± 1.07 genomic alterations (GAs) per sample. NF2 was the most frequently altered gene (36/71 cases). Interestingly, we identified a number of mutations in non-NF2 genes, including a hotspot TERTp c.-124: G > A mutation that may be related to poor prognosis and FGFR3 mutations that may represent biomarkers of a favorable prognosis as reported in other cancers. Conclusions: We demonstrate that comprehensive genomic profiling in our population can reveal a potential new prognostic biomarkers of skull base meningioma. These mutations can enhance diagnostic accuracy and clinical decision-making. Among our findings were the identification of a TERTp mutation and the first report of FGFR3 mutations that may represent biomarkers for the identification of skull base meningioma patients with a favorable prognosis.

Aberrant expression of proteins involved in cell division is a constant feature in multiple myeloma (MM), especially in high-risk disease. Increasingly, therapy of myeloma is moving towards individualization based on underlying genetic abnormalities. Aurora kinases are important mediators of cell cycle and are up regulated in MM. Functional loss of Aurora kinases results in genetic instability and dysregulated division leading to cellular aneuploidy and growth arrest. We investigated the role of Aurora kinase inhibition in MM, using a small molecule inhibitor A1014907. Low nanomolar A1014907 concentrations induced aneuploidy in MM cell lines independent of underlying cytogenetic abnormalities by inhibiting Aurora Kinases. However, A1014907 induced more pronounced and dose dependent apoptosis in cell lines with t(4;14) translocation. Translocation t(4;14) is observed in about 15% of patients with MM leading to constitutive activation of FGFR3 in two-thirds of these patients. Further investigation of the mechanism of action of A1014907 revealed potent FGFR3 pathway inhibition only in the sensitive cell lines. Thus, our results show that aurora kinase inhibition causes cell cycle arrest and aneuploidy with minimal apoptosis whereas inhibiting both aurora kinase and FGFR3 activity induced potent apoptosis in MM cells. These results support clinical evaluation of A1014907 in MM patients with t(4;14) translocation and/or FGFR3 expression.

// Julia Elisabeth Fromme 1, * , Katja Schmitz 1, * , Astrid Wachter 2 , Marius Grzelinski 3 , Dirk Zielinski 3 , Christina Koppel 3 , Lena-Christin Conradi 4 , Kia Homayounfar 4 , Tabea Hugo 1 , Sara Hugo 1 , Laura Lukat 1 , Josef Ruschoff 3 , Philipp Strobel 1 , Michael Ghadimi 4 , Tim Beisbarth 2 , Kirsten Reuter-Jessen 1, ** , Annalen Bleckmann 2, 5, ** and Hans-Ulrich Schildhaus 1, 3, ** 1 Institute of Pathology, University Hospital Gottingen, Gottingen, Germany 2 Department of Medical Statistics, University Medical Center Gottingen, Gottingen, Germany 3 Targos Molecular Pathology Inc., Kassel, Germany 4 Department of General, Visceral and Pediatric Surgery, University Medical Center Gottingen, Georg-August-University, Goettingen, Germany 5 Department for Hematology and Medical Oncology, University Hospital Gottingen, Gottingen, Germany * These authors have contributed equally to this work ** KRJ, AB, HUS share senior authorship Correspondence to: Hans-Ulrich Schildhaus, email: Hans-Ulrich.Schildhaus@med.uni-goettingen.de Keywords: colorectal cancer; metastases; FGFR3; fibroblast growth factor receptors; RNA in situ hybridization Received: March 26, 2018 Accepted: July 12, 2018 Published: August 14, 2018 ABSTRACT Objectives: Metastatic colorectal cancer (CRC) remains a leading cause of cancer related deaths. Patients with oligometastatic liver disease represent a clinical subgroup with heterogeneous course. Until now, biomarkers to characterize outcome and therapeutic options have not been fully established. Methods: We investigated the prevalence of FGFR alterations in a total of 140 primary colorectal tumors and 63 liver metastases of 55 oligometastatic CRC patients. FGF receptors ( FGFR1-4 ) and their ligands ( FGF3, 4 and 19 ) were analyzed for gene amplifications and rearrangements as well as for RNA overexpression in situ . Results were correlated with clinico-pathologic data and molecular subtypes. Results: Primary tumors showed FGFR1 (6.3%) and FGF3,4,19 (2.2%) amplifications as well as FGFR1 (10.1%), FGFR2 (5.5%) and FGFR3 (16.2%) overexpression. In metastases, we observed FGFR1 amplifications (4.8%) as well as FGFR1 (8.5%) and FGFR3 (14.9%) overexpression. Neither FGFR2-4 amplifications nor gene rearrangements were observed. FGFR3 overexpression was significantly associated with shorter overall survival in metastases (mOS 19.9 vs. 47.4 months, HR=3.14, p=0.0152), but not in primary CRC (HR=1.01, p=0.985). Although rare, also FGFR1 amplification was indicative of worse outcome (mOS 12.6 vs. 47.4 months, HR=8.83, p=0.00111). Conclusions: We provide the so far most comprehensive analysis of FGFR alterations in primary and metastatic CRC. We describe FGFR3 overexpression in 15% of CRC patients with oligometastatic liver disease as a prognosticator for poor outcome. Recently FGFR3 overexpression has been shown to be a potential therapeutic target. Therefore, we suggest focusing on this subgroup in upcoming clinical trials with FGFR-targeted therapies.

// Zheng Wang 1, 2, 6 , Chuanbao Zhang 1, 2, 6 , Lihua Sun 1, 6 , Jingshan Liang 1, 6 , Xing Liu 1, 2, 6 , Guanzhang Li 1, 2, 6 , Kun Yao 3, 6 , Wei Zhang 2, 4, 5, 6 , Tao Jiang 1, 2, 4, 5, 6 1 Beijing Neurosurgical Institute, Capital Medical University, Beijing, China 2 Beijing Tiantan Hospital, Capital Medical University, Beijing, China 3 Sanbo Brain Hospital, Capital Medical University, Beijing, China 4 Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, China 5 China National Clinical Research Center for Neurological Diseases, Beijing, China 6 Chinese Glioma Genome Atlas network (CGGA), Beijing, China Correspondence to: Tao Jiang, email: taojiang1964@163.com Keywords: FGFR3, receptor tyrosine kinase, FGFR-TACC fusion genes, glioma Received: March 21, 2016 Accepted: October 26, 2016 Published: November 05, 2016 ABSTRACT Background: Activation of receptor tyrosine kinases is common in Malignancies. FGFR3 fusion with TACC3 has been reported to have transforming effects in primary glioblastoma and display oncogenic activity in vitro and in vivo . We set out to investigate the role of FGFR3 in glioma through transcriptomic analysis. Results: FGFR3 increased in Classical subtype and Neural subtype consistently in CGGA and TCGA cohort. Similar patterns of FGFR3 distribution through subtypes were observed in CGGA and TCGA samples. Gene ontology analysis was performed with genes that were significantly correlated with FGFR3 expression. We found that positively associated biological processes of FGFR3 were focused on differentiated cellular functions and neuronal activities, while negatively correlated biological processes focused on mitosis and cell cycle phase. Clinical investigation showed that higher FGFR3 expression predicted improved survival for glioma patients, especially in Proneural subtype. Moreover, FGFR3 showed very limited relevance with other receptor tyrosine kinases in glioma at transcriptome level. Materials and Methods: FGFR3 expression data of glioma was obtained from Chinese Glioma Genome Atlas (CGGA) and TCGA (The Cancer Genome Atlas). In total, RNA sequencing data of 325 glioma samples and mRNA microarray data of 301 samples from CGGA dataset were enrolled into this study. To consolidate the findings that we have revealed in CGGA dataset, RNA-seq data of 672 glioma samples from TCGA dataset were used as a validation cohort. R language was used as the main tool to perform statistical analysis and graphical work. Conclusions: FGFR3 expression increased in classical and neural subtypes and was associated with differentiated cellular functions. FGFR3 showed very limited correlation with other common receptor tyrosine kinases, and predicted improved survival for glioma patients.

OncoTarget 7(44), 71429-71439 (2016). doi:10.18632/oncotarget.12198, Published by Impact Journals LLC, [S.l.]

// Shingo Inaguma 1 , Hideaki Ito 1 , Miho Riku 1 , Hiroshi Ikeda 1 and Kenji Kasai 1 1 Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan Correspondence to: Kenji Kasai, email: // Shingo Inaguma, email: // Keywords : ZIC2, GLI1, ANXA8, FGFR3, apoptosis Received : June 06, 2015 Accepted : July 03, 2015 Published : July 22, 2015 Abstract Activity of GLI transcription factors of Hedgehog signaling is key for various cancer cell properties, especially in pancreatic ductal adenocarcinoma (PDAC). Zinc-finger transcriptional regulators ZIC1 to ZIC5 of ZIC gene family were demonstrated to associate with GLI to increase the nuclear accumulation and transcriptional activity of GLI. Notwithstanding this supportive role for GLI-dependent transcription, it was not fully understood whether ZIC plays an independent role in cancer cell biology. Here, we found that ZIC2 is indispensable in the regulation of PDAC cell apoptosis. We found that human PDAC cell lines uniquely express ZIC2. ZIC2 knockdown induced PDAC cell apoptosis; conversely, ZIC2 over-expression enhanced the cellular proliferation. Through a comprehensive screening, we identified fibroblast growth factor receptor 3 ( FGFR3 ) and ANNEXIN A8 ( ANXA8 ) as genes up-regulated by ZIC2 in PDAC cells. The forced expression of these two genes cooperatively rescued the apoptosis of ZIC2 -knockdown cells. Immunohistochemical analyses further supported the correlation of ZIC2 expression and these genes in human pancreata harboring PDAC. Intriguingly, the ZIC2-mediated up-regulation of FGFR3 and ANXA8 was indicated to be GLI -independent. This evidence highlights the indispensable role of ZIC2 in regulating cellular proliferation and apoptosis during PDAC development and suggests a potential therapeutic target for PDAC.

// Baolai Zhang 1,2 , Shuhong Dong 2 , Ruiming Zhu 1 , Chunyan Hu 1 , Jing Hou 1 , Yan Li 1 , Qian Zhao 1 , Xue Shao 1 , Qian Bu 1 , Hongyu Li 1 , Yongjie Wu 2 , Xiaobo Cen 1 and Yinglan Zhao 1 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China 2 Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China Correspondence to: Yinglan Zhao, email: // Xiaobo Cen, email: // Keywords : PRMT5, AMI-1, colorectal cancer, FGFR3, eIF4E Received : February 04, 2015 Accepted : May 25, 2015 Published : June 02, 2015 Abstract Protein arginine methyltransferases (PRMTs) plays critical roles in cancer. PRMT5 has been implicated in several types of tumors. However, the role of PRMT5 in cancer development remains to be fully elucidated. Here, we provide evidence that PRMT5 is overexpressed in colorectal cancer (CRC) cells and patient-derived primary tumors, correlated with increased cell growth and decreased overall patient survival. Arginine methyltransferase inhibitor 1 (AMI-1)strongly inhibited tumor growth, increased the ratio of Bax/Bcl-2, and induced apoptosis in mouse CRC xenograt model. AMI-1 also induced apoptosis and decreased the migratory activity in several CRC cells. In CRC xenografts AMI-1 significantly decreased symmetric dimethylation of histone 4 (H4R3me2s), a histone mark of type II PRMT5, but not the expression of H4R3me2a, a histone mark of type I PRMTs. These results suggest that the inhibition of PRMT5 contributes to the antitumor efficacy of AMI-1. Chromatin immunoprecipitation (ChIP) identified FGFR3 and eIF4E as two key genes regulated by PRMT5. PRMT5 knockdown reduced the levels of H4R3me2s and H3R8me2s methylation on FGFR3 and eIF4E promoters, leading to decreased expressions of FGFR3 and eIF4E. Collectively, our findings provide new evidence that PRMT5 plays an important role in CRC pathogenesis through epigenetically regulating arginine methylation of oncogenes such as eIF4E and FGFR3.

// Ross M. Drayton 1 , Stefan Peter 1 , Katie Myers 1 , Saiful Miah 1,2 , Ewa Dudziec 1,2 Helen E. Bryant 1 and James W. F. Catto 1,2 1 Academic Unit of Molecular Oncology, University of Sheffield, UK 2 Academic Urology Unit, University of Sheffield, UK Correspondence: James Catto, email: // Keywords : FOXA1, Urothelial cancer, Bladder cancer, FGFR3 Received : July 4, 2014 Accepted : July 13, 2014 Published : July 15, 2014 Abstract Urothelial cell carcinoma of the bladder (UCC) is a common disease often characterized by FGFR3 dysregulation. Whilst upregulation of this oncogene occurs most frequently in low-grade non-invasive tumors, recent data reveal increased FGFR3 expression characterizes a common sub-type of invasive UCC sharing molecular similarities with breast cancer. These similarities include upregulation of the FOXA1 transcription factor and reduced expression of microRNAs-99a/100. We have previously identified direct regulation of FGFR3 by these two microRNAs and now search for further targets. Using a microarray meta-database we find potential FOXA1 regulation by microRNAs-99a/100. We confirm direct targeting of the FOXA1 3’UTR by microRNAs-99a/100 and also potential indirect regulation through microRNA-485-5p/SOX5/JUN-D/FOXL1 and microRNA-486/FOXO1a. In 292 benign and malignant urothelial samples, we find an inverse correlation between the expression of FOXA1 and microRNAs-99a/100 (r=-0.33 to -0.43, p