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https://www.readbyqxmd.com/read/28551381/a-specific-mutational-signature-associated-with-dna-8-oxoguanine-persistence-in-mutyh-defective-colorectal-cancer
#1
Alessandra Viel, Alessandro Bruselles, Ettore Meccia, Mara Fornasarig, Michele Quaia, Vincenzo Canzonieri, Eleonora Policicchio, Emanuele Damiano Urso, Marco Agostini, Maurizio Genuardi, Emanuela Lucci-Cordisco, Tiziana Venesio, Aline Martayan, Maria Grazia Diodoro, Lupe Sanchez-Mete, Vittoria Stigliano, Filomena Mazzei, Francesca Grasso, Alessandro Giuliani, Marta Baiocchi, Roberta Maestro, Giuseppe Giannini, Marco Tartaglia, Ludmil B Alexandrov, Margherita Bignami
8-Oxoguanine, a common mutagenic DNA lesion, generates G:C>T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours...
April 13, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28511912/inhibition-of-kdm4a-activity-as-a-strategy-to-suppress-interleukin-6-production-and-attenuate-colitis-induction
#2
Kazuhiro Ishiguro, Osamu Watanabe, Masanao Nakamura, Takeshi Yamamura, Masanobu Matsushita, Hidemi Goto, Yoshiki Hirooka
4-Chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) functions as a hapten and fluoresces upon binding to proteins. Therefore, fluorescence visualization of hapten-proteins is a feature of the colitis induced by NBD-Cl. Using this colitis model, we located activated fibroblasts in the vicinity of hapten-proteins upon colitis induction and observed interleukin (IL)-6 production in the activated fibroblasts. We screened herbal ingredients using primary fibroblasts stimulated with tumor necrosis factor α (TNF-α) and found the suppressive action of Atractylodin on IL-6 production...
July 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28483946/p53-maintains-baseline-expression-of-multiple-tumor-suppressor-genes
#3
Kyrie Pappas, Jia Xu, Sakellarios Zairis, Lois Resnick-Silverman, Francesco Abate, Nicole Steinbach, Sait Ozturk, Lao H Saal, Tao Su, Pamela Cheung, Hank Schmidt, Stuart A Aaronson, Hanina Hibshoosh, James J Manfredi, Raul Rabadan, Ramon Parsons
TP53 is the most commonly mutated tumor suppressor gene and its mutation drives tumorigenesis. Using ChIP-seq for p53 in the absence of acute cell stress, we found that wild-type but not mutant p53 binds and activates numerous tumor suppressor genes including PTEN, STK11(LKB1), miR-34a, KDM6A(UTX), FOXO1, PHLDA3, and TNFRSF10B through consensus binding sites in enhancers and promoters. Depletion of p53 reduced expression of these target genes, and analysis across 18 tumor types showed that mutation of TP53 associated with reduced expression of many of these genes...
May 8, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28442529/coinheritance-of-novel-mutations-in-scn1a-causing-gefs-and-in-kdm6a-causing-kabuki-syndrome-in-a-family
#4
Jisun Kim, Cha Gon Lee
Because the differentiation between phenotypic expansion and blended phenotypes is not clear, the mixed phenotypes of blended rare genetic diseases make diagnosis difficult. We describe a family with the co-existence and co-segregation of generalized epilepsy with febrile seizures plus (GEFS+) and Kabuki syndrome (KS). The proband, a 7-year-old male, presented with GEFS+, dysmorphic facial features, short stature, developmental delay, and intellectual disability. Two novel missense mutations: p.G325A in the KDM6A gene responsible for KS and p...
March 2017: Annals of Clinical and Laboratory Science
https://www.readbyqxmd.com/read/28415684/the-long-noncoding-rna-linc-ned125-controls-the-expression-of-medulloblastoma-driver-genes-by-microrna-sponge-activity
#5
Pietro Laneve, Agnese Po, Annarita Favia, Ivano Legnini, Vincenzo Alfano, Jessica Rea, Valerio Di Carlo, Valeria Bevilacqua, Evelina Miele, Angela Mastronuzzi, Andrea Carai, Franco Locatelli, Irene Bozzoni, Elisabetta Ferretti, Elisa Caffarelli
Long noncoding RNAs (lncRNAs) are major regulators of physiological and disease-related gene expression, particularly in the central nervous system. Dysregulated lncRNA expression has been documented in several human cancers, and their tissue-specificity makes them attractive candidates as diagnostic/prognostic biomarkers and/or therapeutic agents. Here we show that linc-NeD125, which we previously characterized as a neuronal-induced lncRNA, is significantly overexpressed in Group 4 medulloblastomas (G4 MBs), the largest and least well characterized molecular MB subgroup...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28365159/genetic-alterations-in-the-molecular-subtypes-of-bladder-cancer-illustration-in-the-cancer-genome-atlas-dataset
#6
REVIEW
Woonyoung Choi, Andrea Ochoa, David J McConkey, Mattias Aine, Mattias Höglund, William Y Kim, Francisco X Real, Anne E Kiltie, Ian Milsom, Lars Dyrskjøt, Seth P Lerner
CONTEXT: Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors. The molecular subtypes in other solid tumors are enriched with specific mutations and copy number aberrations that are thought to underlie their distinct progression patterns, and biological and clinical properties...
March 29, 2017: European Urology
https://www.readbyqxmd.com/read/28339163/next-generation-sequencing-of-urine-specimens-a-novel-platform-for-genomic-analysis-in-patients-with-non-muscle-invasive-urothelial-carcinoma-treated-with-bacille-calmette-gu%C3%A3-rin
#7
Sasinya N Scott, Irina Ostrovnaya, Caroline M Lin, Nancy Bouvier, Bernard H Bochner, Gopakumar Iyer, David Solit, Michael F Berger, Oscar Lin
BACKGROUND: Biopsies from patients with high-risk (HR) non-muscle-invasive urothelial carcinoma (NMIUC), especially flat urothelial carcinoma in situ, frequently contain scant diagnostic material or denuded mucosa only, and this precludes further extensive genomic analysis. This study evaluated the use of next-generation sequencing (NGS) analysis of urine cytology material from patients with HR NMIUC in an attempt to identify genetic alterations that might correlate with clinical features and responses to bacille Calmette-Guérin (BCG) treatment...
June 2017: Cancer
https://www.readbyqxmd.com/read/28284523/demethylase-kdm6a-epigenetically-promotes-il-6-and-ifn-%C3%AE-production-in-macrophages
#8
Xia Li, Qian Zhang, Qingzhu Shi, Yin Liu, Kai Zhao, Qicong Shen, Yang Shi, Xingguang Liu, Chunmei Wang, Nan Li, Yuanfang Ma, Xuetao Cao
Molecular regulation of innate signal-initiated proinflammatory cytokine production has been extensively investigated. However, the roles of epigenetic modifiers and their underlying mechanisms in regulating innate inflammatory response and development of autoimmune diseases need to be further understood. Demethylase Kdm6a promotes gene transcription in cell-lineage specification through demethylating histone H3 lysine di/tri-methylation (H3K27me2/3), and loss of Kdm6a results in developmental defects. However, the function of Kdm6a in innate immunity and inflammation remains largely unknown...
March 8, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28256057/interrupted-bipartite-clavicle-as-a-diagnostic-clue-in-kabuki-syndrome
#9
Maria Haanpää, Helena Schlecht, Gauri Batra, Jill Clayton-Smith, Sofia Douzgou
Kabuki syndrome is a rare developmental disorder characterized by typical facial features, postnatal growth deficiency, mild to moderate intellectual disability, and minor skeletal anomalies. It is caused by mutations of the KMT2D and KDM6A genes while recently RAP1A and RAP1B mutations have been shown to rarely contribute to the pathogenesis. We report two patients' presentation of Kabuki syndrome caused by different KMT2D mutations, both including an interrupted/bipartite clavicle. The clinical diagnosis of Kabuki syndrome may be challenging, especially in younger patients and we suggest that the observation of a bipartite clavicle may be an additional diagnostic clue to prompt investigation for Kabuki syndrome...
April 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28249646/chromosomal-abnormalities-and-molecular-landscape-of-metastasizing-mucinous-salivary-adenocarcinoma
#10
Alex Panaccione, Yi Zhang, Yanfang Mi, Yoshitsugu Mitani, Guo Yan, Manju L Prasad, W Hayes McDonald, Adel K El-Naggar, Wendell G Yarbrough, Sergey V Ivanov
BACKGROUND: Mucinous adenocarcinoma of the salivary gland (MAC) is a lethal cancer with unknown molecular etiology and a high propensity to lymph node metastasis. Mostly due to its orphan status, MAC remains one of the least explored cancers that lacks cell lines and mouse models that could help translational and pre-clinical studies. Surgery with or without radiation remains the only treatment modality but poor overall survival (10-year, 44%) underscores the urgent need for mechanism-based therapies...
March 2017: Oral Oncology
https://www.readbyqxmd.com/read/28228601/loss-of-tumor-suppressor-kdm6a-amplifies-prc2-regulated-transcriptional-repression-in-bladder-cancer-and-can-be-targeted-through-inhibition-of-ezh2
#11
Lian Dee Ler, Sujoy Ghosh, Xiaoran Chai, Aye Aye Thike, Hong Lee Heng, Ee Yan Siew, Sucharita Dey, Liang Kai Koh, Jing Quan Lim, Weng Khong Lim, Swe Swe Myint, Jia Liang Loh, Pauline Ong, Xin Xiu Sam, Dachuan Huang, Tony Lim, Puay Hoon Tan, Sanjanaa Nagarajan, Christopher Wai Sam Cheng, Henry Ho, Lay Guat Ng, John Yuen, Po-Hung Lin, Cheng-Keng Chuang, Ying-Hsu Chang, Wen-Hui Weng, Steven G Rozen, Patrick Tan, Caretha L Creasy, See-Tong Pang, Michael T McCabe, Song Ling Poon, Bin Tean Teh
Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, KDM6A (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of KDM6A mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type...
February 22, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28209718/demethylation-of-h3k27-is-essential-for-the-induction-of-direct-cardiac-reprogramming-by-mir-combo
#12
Sophie Dal-Pra, Conrad P Hodgkinson, Maria Mirotsou, Imke Kirste, Victor J Dzau
RATIONALE: Direct reprogramming of cardiac fibroblasts to cardiomyocytes has recently emerged as a novel and promising approach to regenerate the injured myocardium. We have previously demonstrated the feasibility of this approach in vitro and in vivo using a combination of 4 microRNAs (miR-1, miR-133, miR-208, and miR-499) that we named miR combo. However, the mechanism of miR combo mediated direct cardiac reprogramming is currently unknown. OBJECTIVE: Here, we investigated the possibility that miR combo initiated direct cardiac reprogramming through an epigenetic mechanism...
April 28, 2017: Circulation Research
https://www.readbyqxmd.com/read/28197626/kdm6a-and-kdm6b-altered-expression-in-malignant-pleural-mesothelioma
#13
Sian Cregan, Maeve Breslin, Gerard Roche, Sigrid Wennstedt, Lauren MacDonagh, Cinaria Albadri, Yun Gao, Kenneth J O'Byrne, Sinead Cuffe, Stephen P Finn, Steven G Gray
Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura primarily associated with prior exposure to asbestos. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Inflammation is thought to be a key element in the pathogenesis of MPM, and recently Kdm6 family members (Kdm6a and Kdm6b) have been identified as playing important roles in inflammatory processes...
March 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28139835/unraveling-molecular-pathways-shared-by-kabuki-and-kabuki-like-syndromes
#14
REVIEW
C Lintas, A M Persico
Kabuki syndrome (KS) is a rare genetic syndrome characterized by a typical facial gestalt, variable degrees of intellectual disability, organ malformations, postnatal growth retardation and skeletal abnormalities. So far, KMT2D or KDM6A mutation has been identified as the main cause of KS, accounting for 56%-75% and 3%-8% of cases, respectively. Patients without mutations in 1 of the 2 causative KS genes are often referred to as affected by Kabuki-like syndrome. Overall, they represent approximately 30% of KS cases, pointing toward substantial genetic heterogeneity for this condition...
January 31, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28031467/maternal-sall4-is-indispensable-for-epigenetic-maturation-of-mouse-oocytes
#15
Kai Xu, Xia Chen, Hui Yang, Yiwen Xu, Yuanlin He, Chenfei Wang, Hua Huang, Baodong Liu, Wenqiang Liu, Jingyi Li, Xiaochen Kou, Yanhong Zhao, Kun Zhao, Linfeng Zhang, Zhenzhen Hou, Hong Wang, Hailin Wang, Jing Li, Hengyu Fan, Fengchao Wang, Yawei Gao, Yong Zhang, Jiayu Chen, Shaorong Gao
Sall4 (Splat-like 4) plays important roles in maintaining pluripotency of embryonic stem cells and in various developmental processes. Here, we find that Sall4 is highly expressed in oocytes and early embryos. To investigate the roles of SALL4 in oogenesis, we generated Sall4 maternal specific knock-out mice by using CRISPR/Cas9 system, and we find that the maternal deletion of Sall4 causes developmental arrest of oocytes at germinal vesicle stage with non-surrounded nucleus, and the subsequent meiosis resumption is prohibited...
February 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27999180/a-ketogenic-diet-rescues-hippocampal-memory-defects-in-a-mouse-model-of-kabuki-syndrome
#16
Joel S Benjamin, Genay O Pilarowski, Giovanni A Carosso, Li Zhang, David L Huso, Loyal A Goff, Hilary J Vernon, Kasper D Hansen, Hans T Bjornsson
Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d(+/βGeo)). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic...
January 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27989769/adaptive-chromatin-remodeling-drives-glioblastoma-stem-cell-plasticity-and-drug-tolerance
#17
Brian B Liau, Cem Sievers, Laura K Donohue, Shawn M Gillespie, William A Flavahan, Tyler E Miller, Andrew S Venteicher, Christine H Hebert, Christopher D Carey, Scott J Rodig, Sarah J Shareef, Fadi J Najm, Peter van Galen, Hiroaki Wakimoto, Daniel P Cahill, Jeremy N Rich, Jon C Aster, Mario L Suvà, Anoop P Patel, Bradley E Bernstein
Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling...
February 2, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/27905513/whole-genome-scanning-for-the-litter-size-trait-associated-genes-and-snps-under-selection-in-dairy-goat-capra-hircus
#18
Fang-Nong Lai, Hong-Li Zhai, Ming Cheng, Jun-Yu Ma, Shun-Feng Cheng, Wei Ge, Guo-Liang Zhang, Jun-Jie Wang, Rui-Qian Zhang, Xue Wang, Ling-Jiang Min, Jiu-Zhou Song, Wei Shen
Dairy goats are one of the most utilized domesticated animals in China. Here, we selected extreme populations based on differential fecundity in two Laoshan dairy goat populations. Utilizing deep sequencing we have generated 68.7 and 57.8 giga base of sequencing data, and identified 12,458,711 and 12,423,128 SNPs in the low fecundity and high fecundity groups, respectively. Following selective sweep analyses, a number of loci and candidate genes in the two populations were scanned independently. The reproduction related genes CCNB2, AR, ADCY1, DNMT3B, SMAD2, AMHR2, ERBB2, FGFR1, MAP3K12 and THEM4 were specifically selected in the high fecundity group whereas KDM6A, TENM1, SWI5 and CYM were specifically selected in the low fecundity group...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27869828/tumor-suppressor-genes-that-escape-from-x-inactivation-contribute-to-cancer-sex-bias
#19
Andrew Dunford, David M Weinstock, Virginia Savova, Steven E Schumacher, John P Cleary, Akinori Yoda, Timothy J Sullivan, Julian M Hess, Alexander A Gimelbrant, Rameen Beroukhim, Michael S Lawrence, Gad Getz, Andrew A Lane
There is a striking and unexplained male predominance across many cancer types. A subset of X-chromosome genes can escape X-inactivation, which would protect females from complete functional loss by a single mutation. To identify putative 'escape from X-inactivation tumor-suppressor' (EXITS) genes, we examined somatic alterations from >4,100 cancers across 21 tumor types for sex bias. Six of 783 non-pseudoautosomal region (PAR) X-chromosome genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) harbored loss-of-function mutations more frequently in males (based on a false discovery rate < 0...
January 2017: Nature Genetics
https://www.readbyqxmd.com/read/27819678/tet2-binds-the-androgen-receptor-and-loss-is-associated-with-prostate-cancer
#20
M L Nickerson, S Das, K M Im, S Turan, S I Berndt, H Li, H Lou, S A Brodie, J N Billaud, T Zhang, A J Bouk, D Butcher, Z Wang, L Sun, K Misner, W Tan, A Esnakula, D Esposito, W Y Huang, R N Hoover, M A Tucker, J R Keller, J Boland, K Brown, S K Anderson, L E Moore, W B Isaacs, S J Chanock, M Yeager, M Dean, T Andresson
Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumour genomes to identify molecular markers at this lethal stage of disease. Previously, we characterized somatic alterations in metastatic tumours in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), which is altered in 5-15% of myeloid, kidney, colon and PCas. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We perform fine-mapping of PCa risk across TET2 using genotypes from the PEGASUS case-control cohort and identify six new risk variants in introns 1 and 2...
April 2017: Oncogene
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