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https://www.readbyqxmd.com/read/28524162/targeted-sequencing-based-analyses-of-candidate-gene-variants-in-ulcerative-colitis-associated-colorectal-neoplasia
#1
Sanjiban Chakrabarty, Vinay Koshy Varghese, Pranoy Sahu, Pradyumna Jayaram, Bhadravathi M Shivakumar, Cannanore Ganesh Pai, Kapaettu Satyamoorthy
BACKGROUND: Long-standing ulcerative colitis (UC) leading to colorectal cancer (CRC) is one of the most serious and life-threatening consequences acknowledged globally. Ulcerative colitis-associated colorectal carcinogenesis showed distinct molecular alterations when compared with sporadic colorectal carcinoma. METHODS: Targeted sequencing of 409 genes in tissue samples of 18 long-standing UC subjects at high risk of colorectal carcinoma (UCHR) was performed to identify somatic driver mutations, which may be involved in the molecular changes during the transformation of non-dysplastic mucosa to high-grade dysplasia...
May 18, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28483418/mll3-and-mll4-facilitate-enhancer-rna-synthesis-and-transcription-from-promoters-independently-of-h3k4-monomethylation
#2
Kristel M Dorighi, Tomek Swigut, Telmo Henriques, Natarajan V Bhanu, Benjamin S Scruggs, Nataliya Nady, Christopher D Still, Benjamin A Garcia, Karen Adelman, Joanna Wysocka
Monomethylation of histone H3 at lysine 4 (H3K4me1) and acetylation of histone H3 at lysine 27 (H3K27ac) are correlated with transcriptionally engaged enhancer elements, but the functional impact of these modifications on enhancer activity is not well understood. Here we used CRISPR/Cas9 genome editing to separate catalytic activity-dependent and independent functions of Mll3 (Kmt2c) and Mll4 (Kmt2d, Mll2), the major enhancer H3K4 monomethyltransferases. Loss of H3K4me1 from enhancers in Mll3/4 catalytically deficient cells causes partial reduction of H3K27ac, but has surprisingly minor effects on transcription from either enhancers or promoters...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28440315/tet2-loss-leads-to-hypermutagenicity-in-haematopoietic-stem-progenitor-cells
#3
Feng Pan, Thomas S Wingo, Zhigang Zhao, Rui Gao, Hideki Makishima, Guangbo Qu, Li Lin, Miao Yu, Janice R Ortega, Jiapeng Wang, Aziz Nazha, Li Chen, Bing Yao, Can Liu, Shi Chen, Ophelia Weeks, Hongyu Ni, Brittany Lynn Phillips, Suming Huang, Jianlong Wang, Chuan He, Guo-Min Li, Tomas Radivoyevitch, Iannis Aifantis, Jaroslaw P Maciejewski, Feng-Chun Yang, Peng Jin, Mingjiang Xu
TET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2(-/-) mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2(-/-) tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies...
April 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28390392/emerging-role-of-mutations-in-epigenetic-regulators-including-mll2-derived-from-the-cancer-genome-atlas-for-cervical-cancer
#4
Xia Li
BACKGROUND: Cervical cancer is the second most common cause of cancer deaths in women worldwide. The aim of this study is to exploit novel pathogenic genes in cervical carcinogenesis. METHOD: The somatic mutations from 194 patients with cervical cancer were obtained from the Cancer Genome Atlas (TCGA) publically accessible exome-sequencing database. We investigated mutated gene enrichment in the 12 cancer core pathways and predicted possible post-translational modifications...
April 8, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28375985/distinct-functions-of-histone-h3-lysine-4-methyltransferases-in-normal-and-malignant-hematopoiesis
#5
Weiwei Yang, Patricia Ernst
PURPOSE OF REVIEW: Histone H3, lysine 4 (H3K4) methylation is one chromatin modification that defines distinct regulatory states of euchromatin. Mammals express six main histone methyltransferase (HMT) enzymes that modify H3K4 by monomethylation, dimethylation or trimethylation. Recent studies examine roles of some of these HMTs and their cofactors in hematopoiesis and leukemia. We discuss these emerging studies together with prior embryonic stem data, revealing how these enzymes function...
April 1, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28295288/overexpression-of-foxo3a-is-associated-with-glioblastoma-progression-and-predicts-poor-patient-prognosis
#6
Zhongrun Qian, Li Ren, Dingchang Wu, Xi Yang, Zhiyi Zhou, Quanmin Nie, Gan Jiang, Shuanglin Xue, Weiji Weng, Yongming Qiu, Yingying Lin
Forkhead transcription factor FoxO3a has been reported to have ambiguous functions and distinct mechanisms in various solid tumors, including glioblastoma (GBM). Although a preliminary analysis of a small sample of patients indicated that FoxO3a aberrations in glioma might be related to aggressive clinical behavior, the clinical significance of FoxO3a in glioblastoma remains unclear. We investigated the expression of FoxO3a in a cohort of 91 glioblastoma specimens and analyzed the correlations of protein expression with patient prognosis...
March 14, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28210881/comprehensive-genomic-profiling-of-malignant-phyllodes-tumors-of-the-breast
#7
Sahar Nozad, Christine E Sheehan, Laurie M Gay, Julia A Elvin, Jo-Anne Vergilio, James Suh, Shakti Ramkissoon, Alexa B Schrock, Kim M Hirshfield, Nadia Ali, Shridar Ganesan, Siraj M Ali, Vincent A Miller, Philip J Stephens, Jeffrey S Ross, Jon H Chung
PURPOSE: Malignant phyllodes tumors (MPT) are exceptionally rare, and the genomic drivers of these tumors are still being elucidated. We performed comprehensive genomic profiling (CGP) of MPT to identify genomic alterations that will inform approaches to targeted therapy for patients with MPT, including relapsed, refractory, and metastatic disease. METHODS: DNA was extracted from formalin-fixed, paraffin-embedded samples from 24 consecutive patient cases of MPT...
February 17, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28157506/not-all-h3k4-methylations-are-created-equal-mll2-compass-dependency-in-primordial-germ-cell-specification
#8
Deqing Hu, Xin Gao, Kaixiang Cao, Marc A Morgan, Gloria Mas, Edwin R Smith, Andrew G Volk, Elizabeth T Bartom, John D Crispino, Luciano Di Croce, Ali Shilatifard
The spatiotemporal regulation of gene expression is central for cell-lineage specification during embryonic development and is achieved through the combinatorial action of transcription factors/co-factors and epigenetic states at cis-regulatory elements. Here, we show that in addition to implementing H3K4me3 at promoters of bivalent genes, Mll2 (KMT2B)/COMPASS can also implement H3K4me3 at a subset of non-TSS regulatory elements, a subset of which shares epigenetic signatures of active enhancers. Our mechanistic studies reveal that association of Mll2's CXXC domain with CpG-rich regions plays an instrumental role for chromatin targeting and subsequent implementation of H3K4me3...
February 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28007623/small-cell-lung-cancer-exhibits-frequent-inactivating-mutations-in-the-histone-methyltransferase-kmt2d-mll2-calgb-151111-alliance
#9
Arnaud Augert, Qing Zhang, Breanna Bates, Min Cui, Xiaofei Wang, Gary Wildey, Afshin Dowlati, David MacPherson
INTRODUCTION: SCLC is a lethal neuroendocrine tumor type that is highly prone to metastasis. There is an urgency to understand the mutated genes that promote SCLC, as there are no approved targeted therapies yet available. SCLC is rarely resected, limiting the number of samples available for genomic analyses of somatic mutations. METHODS: To identify potential driver mutations in human SCLC we sequenced the whole exomes of 18 primary SCLCs and seven cell lines along with matched normal controls...
April 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27984602/-analysis-of-clinical-phenotypes-and-genetic-variations-in-a-chinese-family-affected-with-craniofacial-and-skeletal-deformities
#10
Huihui Sun, Naijun Wan
OBJECTIVE: To identify pathogenic mutation in a pedigree affected with craniofacial and skeletal abnormalities featuring an autosomal dominant inheritance. METHODS: Clinical data and peripheral venous blood samples of the pedigree were collected. A total of 326 exons of skeletal disease-related genes were screened using Roche NimbleGen probes, and the results were confirmed by Sanger sequencing. Suspected variants were analyzed by bioinformatic software. RESULTS: A novel heterozygous mutation c...
December 10, 2016: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/27922244/a-novel-de-novo-mutation-involving-the-mll2-gene-in-a-kabuki-syndrome-patient-presenting-with-seizures
#11
Can Ebru Bekircan-Kurt, Pelin Özlem Şimşek-Kiper, Koray Boduroğlu, Neşe Dericioğlu
Kabuki syndrome is a rare multiple congenital anomaly disorder. Although mental retardation is one of the main features, various neurological symptoms such as hypotonia and seizures can occur. Here we report on a 18-year-old Turkish male patient who was diagnosed previously as Kabuki syndrome. Molecular genetic analysis showed a novel de novo heterozygous mutation (c.12964C > T [p.Gln4322*] ) in the MLL2 gene, that leads to the synthesis of a truncated protein. The aim of the present report is to increase the awareness of Kabuki Syndrome among adult neurologists and to present a previously unreported non-sense mutation in the MLL2 gene...
2016: Turkish Journal of Pediatrics
https://www.readbyqxmd.com/read/27707786/chemo-genetic-interactions-between-histone-modification-and-the-antiproliferation-drug-aicar-are-conserved-in-yeast-and-humans
#12
Delphine Albrecht, Johanna Ceschin, Jim Dompierre, Florian Gueniot, Benoît Pinson, Bertrand Daignan-Fornier
Identifying synthetic lethal interactions has emerged as a promising new therapeutic approach aimed at targeting cancer cells directly. Here, we used the yeast Saccharomyces cerevisiae as a simple eukaryotic model to screen for mutations resulting in a synthetic lethality with 5-amino-4-imidazole carboxamide ribonucleoside (AICAR) treatment. Indeed, AICAR has been reported to inhibit the proliferation of multiple cancer cell lines. Here, we found that loss of several histone-modifying enzymes, including Bre1 (histone H2B ubiquitination) and Set1 (histone H3 lysine 4 methylation), greatly enhanced AICAR inhibition on growth via the combined effects of both the drug and mutations on G1 cyclins...
December 2016: Genetics
https://www.readbyqxmd.com/read/27687303/mutation-profiles-in-early-stage-lung-squamous-cell-carcinoma-with-clinical-follow-up-and-correlation-with-markers-of-immune-function
#13
M Choi, H Kadara, J Zhang, E P Cuentas, J R Canales, S G Gaffney, Z Zhao, C Behrens, J Fujimoto, C Chow, K Kim, N Kalhor, C Moran, D Rimm, S Swisher, D L Gibbons, J Heymach, E Kaftan, J P Townsend, T J Lynch, J Schlessinger, J Jack Lee, R P Lifton, R S Herbst, I I Wistuba
BACKGROUND: Lung squamous cell carcinoma (LUSC) accounts for 20-30% of non-small cell lung cancers (NSCLCs). There are limited treatment strategies for LUSC in part due to our inadequate understanding of the molecular underpinnings of the disease. We performed whole-exome sequencing (WES) and comprehensive immune profiling of a unique set of clinically annotated early-stage LUSCs to increase our understanding of the pathobiology of this malignancy. METHODS: Matched pairs of surgically resected stage I-III LUSCs and normal lung tissues (n=108) were analyzed by WES...
September 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27617035/pax6-associates-with-h3k4-specific-histone-methyltransferases-mll1-mll2-and-set1a-and-regulates-h3k4-methylation-at-promoters-and-enhancers
#14
Jian Sun, Yilin Zhao, Rebecca McGreal, Yamit Cohen-Tayar, Shira Rockowitz, Carola Wilczek, Ruth Ashery-Padan, David Shechter, Deyou Zheng, Ales Cvekl
BACKGROUND: Pax6 is a key regulator of the entire cascade of ocular lens formation through specific binding to promoters and enhancers of batteries of target genes. The promoters and enhancers communicate with each other through DNA looping mediated by multiple protein-DNA and protein-protein interactions and are marked by specific combinations of histone posttranslational modifications (PTMs). Enhancers are distinguished from bulk chromatin by specific modifications of core histone H3, including H3K4me1 and H3K27ac, while promoters show increased H3K4me3 PTM...
2016: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/27573763/a-novel-kmt2d-mutation-resulting-in-kabuki-syndrome-a-case-report
#15
Jun Lu, Guiling Mo, Yaojun Ling, Lijuan Ji
Kabuki syndrome (KS) is a rare genetic syndrome characterized by multiple congenital anomalies and varying degrees of mental retardation. Patients with KS often present with facial, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies and immunological defects. Mutation of the lysine methyltransferase 2D (KMT2D) gene (formerly known as MLL2) is the primary cause of KS. The present study reported the case of a 4‑year‑old Chinese girl who presented with atypical KS, including atypical facial features, unclear speech and suspected mental retardation...
October 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27568880/kabuki-syndrome-as-a-cause-of-non-immune-fetal-hydrops-ascites
#16
Ashleigh Long, Elena S Sinkovskaya, Andrew C Edmondson, Elaine Zackai, Samantha A Schrier Vergano
Kabuki syndrome (MIM 147920) is a well-described, multiple congenital anomaly syndrome characterized by growth and developmental delay, cardiac, renal, and vertebral anomalies, as well as persistent fetal finger pads and distinct facial features. Facies are characterized by long palpebral fissures with eversion of lateral third of the lower eyelid, resembling the "Kabuki make-up" theatre genre after which the syndrome is named. Kabuki syndrome is estimated to affect 1/32,000 births, with 55-80% of patients showing nonsense or frameshift mutations in the KMT2D (MLL2) gene, which encodes a histone transferase located on chromosome 12q...
August 29, 2016: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/27563068/targeted-disruption-of-the-interaction-between-wd-40-repeat-protein-5-wdr5-and-mixed-lineage-leukemia-mll-set1-family-proteins-specifically-inhibits-mll1-and-setd1a-methyltransferase-complexes
#17
Nilda L Alicea-Velázquez, Stephen A Shinsky, Daniel M Loh, Jeong-Heon Lee, David G Skalnik, Michael S Cosgrove
MLL1 belongs to the SET1 family of histone H3 lysine 4 (H3K4) methyltransferases, composed of MLL1-4 and SETd1A/B. MLL1 translocations are present in acute leukemias, and mutations in several family members are associated with cancer and developmental disorders. MLL1 associates with a subcomplex containing WDR5, RbBP5, ASH2L, and DPY-30 (WRAD), forming the MLL1 core complex required for H3K4 mono- and dimethylation and transcriptional activation. Core complex assembly requires interaction of WDR5 with the MLL1 Win (WDR5 interaction) motif, which is conserved across the SET1 family...
October 21, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27449094/gene-mutations-and-actionable-genetic-lesions-in-mantle-cell-lymphoma
#18
REVIEW
Makhdum Ahmed, Leo Zhang, Krystle Nomie, Laura Lam, Michael Wang
Mutations and epigenetic alterations are key events in transforming normal cells to cancer cells. Mantle cell lymphoma (MCL), a non-Hodgkin's lymphoma of the B-cell, is an aggressive malignancy with poor prognosis especially for those patients who are resistant to the frontline drugs. There is a great need to describe the molecular basis and mechanism of drug resistance in MCL to develop new strategies for treatment. We reviewed frequent somatic mutations and mutations involving the B-cell pathways in MCL and discussed clinical trials that attempted to disrupt these gene pathways and/or epigenetic events...
September 6, 2016: Oncotarget
https://www.readbyqxmd.com/read/27389057/combined-copy-number-and-mutation-analysis-identifies-oncogenic-pathways-associated-with-transformation-of-follicular-lymphoma
#19
A Bouska, W Zhang, Q Gong, J Iqbal, A Scuto, J Vose, M Ludvigsen, K Fu, D D Weisenburger, T C Greiner, R D Gascoyne, A Rosenwald, G Ott, E Campo, L M Rimsza, J Delabie, E S Jaffe, R M Braziel, J M Connors, C-I Wu, L M Staudt, F D'Amore, T W McKeithan, W C Chan
Follicular lymphoma (FL) is typically an indolent disease, but 30-40% of FL cases transform into an aggressive lymphoma (tFL) with a poor prognosis. To identify the genetic changes that drive this transformation, we sequenced the exomes of 12 cases with paired FL and tFL biopsies and identified 45 recurrently mutated genes in the FL-tFL data set and 39 in the tFL cases. We selected 496 genes of potential importance in transformation and sequenced them in 23 additional tFL cases. Integration of the mutation data with copy-number abnormality (CNA) data provided complementary information...
January 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27387124/single-cell-sequencing-reveals-variants-in-arid1a-gprc5a-and-mll2-driving-self-renewal-of-human-bladder-cancer-stem-cells
#20
Zhao Yang, Chong Li, Zusen Fan, Hongjie Liu, Xiaolong Zhang, Zhiming Cai, Liqin Xu, Jian Luo, Yi Huang, Luyun He, Chunxiao Liu, Song Wu
Cancer stem cells are considered responsible for many important aspects of tumors such as their self-renewal, tumor-initiating, drug-resistance and metastasis. However, the genetic basis and origination of human bladder cancer stem cells (BCSCs) remains unknown. Here, we conducted single-cell sequencing on 59 cells including BCSCs, bladder cancer non-stem cells (BCNSCs), bladder epithelial stem cells (BESCs) and bladder epithelial non-stem cells (BENSCs) from three bladder cancer (BC) specimens. Specifically, BCSCs demonstrate clonal homogeneity and suggest their origin from BESCs or BCNSCs through phylogenetic analysis...
January 2017: European Urology
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