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James J Hsieh, David Chen, Patricia I Wang, Mahtab Marker, Almedina Redzematovic, Ying-Bei Chen, S Duygu Selcuklu, Nils Weinhold, Nancy Bouvier, Kety H Huberman, Umesh Bhanot, Michael S Chevinsky, Parul Patel, Patrizia Pinciroli, Helen H Won, Daoqi You, Agnes Viale, William Lee, A Ari Hakimi, Michael F Berger, Nicholas D Socci, Emily H Cheng, Jennifer Knox, Martin H Voss, Maurizio Voi, Robert J Motzer
BACKGROUND: Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial. OBJECTIVE: To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients...
October 14, 2016: European Urology
Yunhui Peng, Emil Alexov
The KDM5C gene (also known as JARID1C and SMCX) is located on the X chromosome and encodes a ubiquitously expressed 1560-aa protein, which plays an important role in lysine methylation (specifically reverses tri- and di-methylation of Lys4 of histone H3). Currently, 13 missense mutations in KDM5C have been linked to X-linked mental retardation. However, the molecular mechanism of disease is currently unknown due to the experimental difficulties in expressing such large protein and the lack of experimental 3D structure...
October 1, 2016: Proteins
Seung-Hyun Jung, Min Sung Kim, Chan Kwon Jung, Hyun-Chun Park, So Youn Kim, Jieying Liu, Ja-Seong Bae, Sung Hak Lee, Tae-Min Kim, Sug Hyung Lee, Yeun-Jun Chung
Follicular thyroid adenoma (FTA) precedes follicular thyroid carcinoma (FTC) by definition with a favorable prognosis compared to FTC. However, the genetic mechanism of FTA to FTC progression remains unknown. For this, it is required to disclose FTA and FTC genomes in mutational and evolutionary perspectives. We performed whole-exome sequencing and copy number profiling of 14 FTAs and 13 FTCs, which exhibited previously-known gene mutations (NRAS, HRAS, BRAF, TSHR and EIF1AX) and copy number alterations (CNAs) (22q loss and 1q gain) in follicular tumors...
September 9, 2016: Oncotarget
Yuanyuan Wang, Xingyi Guo, Michael J Bray, Zhiyong Ding, Zhongming Zhao
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Recent large-scale next-generation sequencing analyses reveal that PBRM1 is the second most frequently mutated gene harboring many truncated mutations and has a suspected tumor suppressor role in ccRCC. However, the biological consequences of PBRM1 somatic mutations (e.g., truncated mutations) that drive tumor progression in ccRCC remain unclear. METHODS: In this study, we proposed an integrative genomics approach to explore the functional consequences of PBRM1 truncated mutations in ccRCC by incorporating somatic mutations, mRNA expression, DNA methylation, and microRNA (miRNA) expression profiles from The Cancer Genome Atlas (TCGA)...
August 22, 2016: BMC Genomics
Gengze Wei, Xinxian Deng, Saurabh Agarwal, Shigeki Iwase, Christine Disteche, Jun Xu
The X-linked lysine (K)-specific demethylase 5C (KDM5C) gene plays an important role in brain development and behavior. It encodes a histone demethylase that is involved in gene regulation in neuronal differentiation and morphogenesis. When mutated, it causes neuropsychiatric symptoms, such as intellectual disability, delayed language development, epilepsy, and impulsivity. To better understand how the patient mutations affect neuronal development, we expressed KDM5C mutants in Neuro2a cells, a mouse neuroblastoma cell line...
September 2016: Journal of Molecular Neuroscience: MN
David R Raleigh, David A Solomon, Shane A Lloyd, Ann Lazar, Michael A Garcia, Penny K Sneed, Jennifer L Clarke, Michael W McDermott, Mitchel S Berger, Tarik Tihan, Daphne A Haas-Kogan
BACKGROUND: Pineal parenchymal tumors (PPTs) are rare neoplasms of the central nervous system, and data concerning clinical outcomes are limited. The purpose of this study was to define the clinical behavior of PPT according to current histopathologic criteria and identify prognostic factors to guide therapeutic decisions. METHODS: Seventy-five patients treated for PPT at a single institution between 1992 and 2015 were retrospectively identified. Forty-five resection specimens were available and re-reviewed...
June 9, 2016: Neuro-oncology
McKale R Davis, Juliane J Daggett, Agnes S Pascual, Jessica M Lam, Kathryn J Leyva, Kimbal E Cooper, Elizabeth E Hull
BACKGROUND: The BRM and BRG1 tumor suppressor genes are mutually exclusive ATPase subunits of the SWI/SNF chromatin remodeling complex. The human adrenal carcinoma SW13 cell line can switch between a subtype which expresses these subunits, SW13+, and one that expresses neither subunit, SW13-. Loss of BRM expression occurs post-transcriptionally and can be restored via histone deacetylase (HDAC) inhibition. However, most previously used HDAC inhibitors are toxic and broad-spectrum, providing little insight into the mechanism of the switch between subtypes...
2016: BMC Cancer
Thanh T H Lan, Jennifer Keller-Ramey, Carrie Fitzpatrick, Sabah Kadri, Jerome B Taxy, Jeremy P Segal, Larissa V Furtado, Tatjana Antic
Accurate subtyping of renal cell carcinomas (RCCs) has become clinically important for therapy and prognostication. RCC subtypes are defined by distinct morphologic and immunohistochemical profiles, and in some instances recurrent cytogenetic and molecular properties. However, some tumors exhibit overlapping morphologic and immunophenotypic features, frequent enough to pose diagnostic dilemmas. This report concerns six histologically unusual RCCs that showed tubulopapillary architecture, clear cell phenotype, and non-diagnostic immunohistochemical profiles...
July 2016: Virchows Archiv: An International Journal of Pathology
Qing Liu, Xinwen Wang, Yuan Liu, Minghui Wei, Lihua Chen
OBJECTIVE: Oral lichen planus (OLP) is a chronic inflammatory disease but aetiology and pathogenesis has not fully elucidated. To gain insight into the mechanism of OLP, bioinformatic analysis was performed in this study. DESIGN: GSE38616 and GSE38615 were downloaded from GEO, including 7 cases of OLP and 7 healthy controls. Differentially expressed genes (DEGs) and miRNAs (DEMs) between OLP and control were screened with package Limma of R. Potential regulatory miRNAs were screened via gene set enrichment analysis...
August 2016: Archives of Oral Biology
Hongjie Shen, Wenqi Xu, Rui Guo, Bowen Rong, Lei Gu, Zhentian Wang, Chenxi He, Lijuan Zheng, Xin Hu, Zhen Hu, Zhi-Ming Shao, Pengyuan Yang, Feizhen Wu, Yujiang Geno Shi, Yang Shi, Fei Lan
Regulation of enhancer activity is important for controlling gene expression programs. Here, we report that a biochemical complex containing a potential chromatin reader, RACK7, and the histone lysine 4 tri-methyl (H3K4me3)-specific demethylase KDM5C occupies many active enhancers, including almost all super-enhancers. Loss of RACK7 or KDM5C results in overactivation of enhancers, characterized by the deposition of H3K4me3 and H3K27Ac, together with increased transcription of eRNAs and nearby genes. Furthermore, loss of RACK7 or KDM5C leads to de-repression of S100A oncogenes and various cancer-related phenotypes...
April 7, 2016: Cell
A Fujita, C Waga, Y Hachiya, E Kurihara, S Kumada, E Takeshita, E Nakagawa, K Inoue, S Miyatake, Y Tsurusaki, M Nakashima, H Saitsu, Y-I Goto, N Miyake, N Matsumoto
Genetic reversion is the phenomenon of spontaneous gene correction by which gene function is partially or completely rescued. However, it is unknown whether this mechanism always correctly repairs mutations, or is prone to error. We investigated a family of three boys with intellectual disability, and among them we identified two different mutations in KDM5C, located at Xp11.22, using whole-exome sequencing. Two affected boys have c.633delG and the other has c.631delC. We also confirmed de novo germline (c...
September 2016: Clinical Genetics
Liming Xu, Wei Wu, Guilian Cheng, Mingjie Qian, Kewei Hu, Guojian Yin, Shaofeng Wang
Gastric cancer is a malignancy with high incidence and the second leading cause of cancer death worldwide. Development of efficient therapies against gastric cancer is urgent. Until now, the mechanisms of gastric cancer genesis remain elusive. The KDM5C is a histone demethylase that promotes cancer cell growth and is enriched in drug-resistant cancer cells. But the pathogenic breadth and mechanistic aspects of this effect relative to gastric cancer have not been defined. In present study, we found that KDM5C was overexpressed in gastric cancer cell lines and gastric cancer tissues but not in normal gastric tissues...
February 7, 2016: Technology in Cancer Research & Treatment
Shigeki Iwase, Emily Brookes, Saurabh Agarwal, Aimee I Badeaux, Hikaru Ito, Christina N Vallianatos, Giulio Srubek Tomassy, Tomas Kasza, Grace Lin, Andrew Thompson, Lei Gu, Kenneth Y Kwan, Chinfei Chen, Maureen A Sartor, Brian Egan, Jun Xu, Yang Shi
Mutations in a number of chromatin modifiers are associated with human neurological disorders. KDM5C, a histone H3 lysine 4 di- and tri-methyl (H3K4me2/3)-specific demethylase, is frequently mutated in X-linked intellectual disability (XLID) patients. Here, we report that disruption of the mouse Kdm5c gene recapitulates adaptive and cognitive abnormalities observed in XLID, including impaired social behavior, memory deficits, and aggression. Kdm5c-knockout brains exhibit abnormal dendritic arborization, spine anomalies, and altered transcriptomes...
February 9, 2016: Cell Reports
John R Horton, Amanda Engstrom, Elizabeth L Zoeller, Xu Liu, John R Shanks, Xing Zhang, Margaret A Johns, Paula M Vertino, Haian Fu, Xiaodong Cheng
The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases remove methyl groups from tri- and dimethylated lysine 4 of histone H3. Accumulating evidence from primary tumors and model systems supports a role for KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) as oncogenic drivers. The KDM5 family is unique among the Jumonji domain-containing histone demethylases in that there is an atypical insertion of a DNA-binding ARID domain and a histone-binding PHD domain into the Jumonji domain, which separates the catalytic domain into two fragments (JmjN and JmjC)...
February 5, 2016: Journal of Biological Chemistry
Hélène Denis, Olivier Van Grembergen, Benjamin Delatte, Sarah Dedeurwaerder, Pascale Putmans, Emilie Calonne, Françoise Rothé, Christos Sotiriou, François Fuks, Rachel Deplus
MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Alteration of miRNA levels is common in tumors and contributes to the pathogenesis of human malignancies. In the present study we examined the role played by miR-137 in breast tumorigenesis. We found miR-137 levels to be lower in breast cancer cells than in their non-tumorigenic counterparts and observed reduced proliferation and migration of breast cancer cells overexpressing miR-137. We further identified KDM5B, a histone demethylase known to be involved in breast cancer tumorigenesis, as a target of miR-137...
February 2016: Molecular BioSystems
A J Rodrigues, C Bessa, F Marques, F Pereira, A Amorim, F Lopes, P Maciel
No abstract text is available yet for this article.
December 2015: International Journal of Developmental Neuroscience
Corey Costantino, George V Thomas, Christopher Ryan, Fergus V Coakley, Megan L Troxell
PURPOSE: Metastatic renal cell carcinoma (RCC), without an identified kidney primary, has been reported rarely. We report a patient with RCC metastatic to bilateral adrenal glands and liver, without an apparent renal primary. We detail the immunohistochemical and molecular studies employed to substantiate the diagnosis of RCC and direct therapy. METHODS: Histopathologic findings were correlated with imaging data and supplemented by a panel of immunohistochemical stains, as well as tumor sequence analysis...
January 2016: International Urology and Nephrology
Xuening Ji, Shi Jin, Xiaotong Qu, Kejun Li, Hongjiang Wang, Hui He, Fuchao Guo, Lei Dong
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of tumor and is associated with high morbidity and mortality rates. Patients with HCC routinely undergo surgery followed by adjuvant radiation therapy and chemotherapy. Despite such aggressive treatment approaches, median survival times remain under 1 year in most cases. KDM5C is a member of the family of JmjC domain-containing proteins that removes methyl residues from methylated lysine 4 on histone H3 lysine 4 (H3K4)...
2015: BMC Cancer
Christopher J Ricketts, W Marston Linehan
Renal cell carcinoma (RCC) is diagnosed in >200,000 individuals worldwide each year, accounting for ~2% of all cancers, but the spread of this disease amongst genders is distinctly uneven. In the U.S. the male:female incidence ratio is approximately 2:1. A potential hypothesis is mutation spectra may differ between tumors dependent upon the gender of the patient, such as mutations of X chromosome encoded genes being more prevalent in male-derived tumors. Combined analysis of three recent large-scale clear cell renal cell carcinoma (CCRCC) mutation sequencing projects identified a significantly increased mutation frequency of PBRM1 and the X chromosome encoded KDM5C in tumors from male patients and BAP1 in tumors from female patients...
2015: PloS One
Baohu Ji, Kerin K Higa, John R Kelsoe, Xianjin Zhou
BACKGROUND: Psychiatric disorders are common mental disorders without a pathological biomarker. Classic genetic studies found that an extra X chromosome frequently causes psychiatric symptoms in patients with either Klinefelter syndrome (XXY) or Triple X syndrome (XXX). Over-dosage of some X-linked escapee genes was suggested to cause psychiatric disorders. However, relevance of these rare genetic diseases to the pathogenesis of psychiatric disorders in the general population of psychiatric patients is unknown...
August 2015: EBioMedicine
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