DOCSLIB.ORG

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes Journal of Clinical Medicine Review Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes Mariona Terradas 1,2, Gabriel Capellá 1,2,3 and Laura Valle 1,2,3,* 1 Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; [email protected] (M.T.); [email protected] (G.C.) 2 Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain 3 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-93-260-7145 Received: 29 May 2020; Accepted: 18 June 2020; Published: 23 June 2020 Abstract: In the past two decades, multiple studies have been undertaken to elucidate the genetic cause of the predisposition to mismatch repair (MMR)-proficient nonpolyposis colorectal cancer (CRC). Here, we present the proposed candidate genes according to their involvement in specific pathways considered relevant in hereditary CRC and/or colorectal carcinogenesis. To date, only pathogenic variants in RPS20 may be convincedly linked to hereditary CRC. Nevertheless, accumulated evidence supports the involvement in the CRC predisposition of other genes, including MRE11, BARD1, POT1, BUB1B, POLE2, BRF1, IL12RB1, PTPN12, or the epigenetic alteration of PTPRJ. The contribution of the identified candidate genes to familial/early onset MMR-proficient nonpolyposis CRC, if any, is extremely small, suggesting that other factors, such as the accumulation of low risk CRC alleles, shared environmental exposures, and/or gene–environmental interactions, may explain the missing heritability in CRC. Keywords: hereditary cancer; colorectal cancer; mismatch repair proficiency; familial colorectal cancer type X; gene identification; cancer predisposition; cancer susceptibility; cancer genetics; molecular pathways 1. Introduction While estimates indicate that approximately 14% of all colorectal cancer (CRC) patients have at least one first-degree relative affected with the same tumor type [1,2], 4–8% of all CRC patients carry germline pathogenic variants in one of the known high penetrance genes for this tumor [3–6], with a relevant proportion of the familial aggregation of CRC remaining unexplained. The identification of a germline pathogenic variant in a colorectal cancer-predisposing gene has important consequences for the patients and their relatives, as they can be counseled and managed based on gene-specific guidelines. This is the main reason why large efforts have been and are still being made to identify the genetic cause of the increased CRC risk observed in some families. Figure1 shows the known causal genes for nonpolyposis and polyposis CRC predisposition and the molecular pathways in which they are involved. J. Clin. Med. 2020, 9, 1954; doi:10.3390/jcm9061954 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, 1954 2 of 19 J. Clin. Med. 2020, 9, x FOR PEER REVIEW 2 of 19 Figure 1. Schematic representation of colorectal cancer predisposing syndromes, causal genes, and Figure 1. Schematic representation of colorectal cancer predisposing syndromes, causal genes, and affected molecular pathways. Genes shaded in grey correspond to the most promising proposed affected molecular pathways. Genes shaded in grey correspond to the most promising proposed candidate genes. Abbreviations: BER, base excision repair; DSB, double strand breaks; meth, promoter candidate genes. Abbreviations: BER, base excision repair; DSB, double strand breaks; meth, promoter hypermethylation; MMR, DNA mismatch repair; SAC, spindle assembly checkpoint. hypermethylation; MMR, DNA mismatch repair; SAC, spindle assembly checkpoint. Classically, hereditary cancer studies were mainly based on genome-wide linkage analysis of largeClassically, individual orhereditary multiple pedigreescancer studies followed were by mainly positional based cloning on genome-wide and the study linkage of somatic analysis studies. of largeThis strategy individual led toor the multiple identification pedigrees of the followed most prominent by positional hereditary cloning cancer and genes, the includingstudy of thesomatic main studies.genes involved This strategy in nonpolyposis led to the colorectal identification cancer predisposition,of the most prominent i.e., the DNA hereditary mismatch cancer repair (MMR)genes, includinggenes MLH1 the, MSH2main ,genesMSH6, involvedand PMS2 in ;nonpolyposis however, it seemed colorectal unable cancer to identify predisposition, additional i.e., causal the genesDNA mismatchfor hereditary repair nonpolyposis (MMR) genes CRC MLH1 (HNPCC)., MSH2 In, fact,MSH6, while and genome-wide PMS2; however, linkage it seemed studies inunable families to withidentify CRC additional allowed causal the identification genes for hereditary of several nonpolyposis dominant predisposition CRC (HNPCC). loci In mappedfact, while to genome- different widechromosomal linkage regions,studies noin evidentfamilies causal with genesCRC haveallowed been the identified identification within theseof several loci [7]. dominant The poor predispositionperformance of loci these mapped techniques to different for the identification chromosoma ofl regions, additional no high-penetrantevident causal genesgenes responsiblehave been identifiedfor familial within CRC cases these could loci [7]. have The been poor caused performa by thence heterogeneity of these techniques of the clinical for the group, identification the existence of additionalof oligo- or high-penetrant polygenic modes genes of inheritance,responsible orfor the familial presence CRC of cases unconventional could have mechanisms been caused ofby gene the heterogeneityinactivation, among of the otherclinical possibilities. group, the existence of oligo- or polygenic modes of inheritance, or the presenceThanks of unconventional to the rapid development mechanisms of of gene massively inactivation, parallel among sequencing-based other possibilities. approaches and genome-wideThanks to copy the numberrapid development techniques, genomeof massivel sequencing,y parallel exome sequencing-based sequencing, orapproaches genome-wide and genome-widescanning of copy copy number number alterations, techniques, alone genome or in combinationsequencing, withexome linkage sequencing, analysis, or andgenome-wide applied to scanningisolated high-risk of copy number families alterations, or to multiple alone families or in combination or probands with with linkage common analysis, phenotypes, and applied are being to isolatedused for high-risk the identification families or of to causal multiple pathogenic families variants. or probands This with type common of study, phenotypes, performed inare the being last useddecade, for hasthe resultedidentification in the of identification causal pathogenic of numerous variants. candidate This type causal of study, genes performed for the nonpolyposis in the last decade,CRC predisposition. has resulted Inin parallelthe identification to these a of priori nume agnosticrous candidate analyses, causal candidate genes gene for studiesthe nonpolyposis have been CRCperformed predisposition. along the yearsIn parallel to assess to these the involvementa priori agnostic of specific analyses, genes candidate selected gene based studies on their have function been performedor involvement along in the molecular years to pathwaysassess the involvement deemed relevant of specific in colorectal genes selected carcinogenesis. based on their function or involvementHere, we aimed in molecular to provide pathways an overview deemed of relevant the proposed in colorectal candidate carcinogenesis. causal genes for hereditary colorectalHere, cancerwe aimed based to onprovide different an molecularoverview of entities the proposed and focused candidate on relevant causal molecular genes for pathways.hereditary colorectal cancer based on different molecular entities and focused on relevant molecular pathways. 2. RPS20 Mutations as a Rare Cause of Hereditary Nonpolyposis Colorectal Cancer 2. RPS20 Mutations as a Rare Cause of Hereditary Nonpolyposis Colorectal Cancer So far, the only new candidate gene that has shown consistent association with hereditary nonpolyposisSo far, the CRC only is newRPS20 candidate, which gene encodes that ahas component shown consistent (S20) of theassociation small ribosome with hereditary subunit. nonpolyposisBy combining geneticCRC is linkageRPS20, analysiswhich encodes and exome a component sequencing, (S20) Nieminen of the etsmall al. (2014) ribosome identified subunit. a novel By combiningtruncating geneticRPS20 variant,linkage analysis c.147dupA and (p.Val50Serfs*23), exome sequencing, in Nieminen a Finnish four-generationet al. (2014) identified CRC-a aff novelected truncatingfamily. The RPS20 variant variant, was present c.147dupA in seven (p.Val50Serfs*23), CRC-affected members in a Finnish but neither four-generation in four cancer-free CRC-affected members family.nor in one The relative variant diagnosed was present with in breast seven cancer CRC-affected at age 55. members All studied but tumors neither were in four MMR cancer-free proficient membersand despite nor not in showingone relative loss diagnosed of the RPS20 withwildtype breast cancer allele, at patients age 55. All carrying studied the tumorsRPS20 werec.147dupA MMR proficientvariant showed and despite a marked not increaseshowing of loss 21S of pre-rRNAs, the RPS20 supporting wildtype allele, a late patients pre-rRNA carrying processing
Load more

Recommended publications
  • Download Download
    Supplementary Figure S1. Results of flow cytometry analysis, performed to estimate CD34 positivity, after immunomagnetic separation in two different experiments. As monoclonal antibody for labeling the sample, the fluorescein isothiocyanate (FITC)- conjugated mouse anti-human CD34 MoAb (Mylteni) was used. Briefly, cell samples were incubated in the presence of the indicated MoAbs, at the proper dilution, in PBS containing 5% FCS and 1% Fc receptor (FcR) blocking reagent (Miltenyi) for 30 min at 4 C. Cells were then washed twice, resuspended with PBS and analyzed by a Coulter Epics XL (Coulter Electronics Inc., Hialeah, FL, USA) flow cytometer. only use Non-commercial 1 Supplementary Table S1. Complete list of the datasets used in this study and their sources. GEO Total samples Geo selected GEO accession of used Platform Reference series in series samples samples GSM142565 GSM142566 GSM142567 GSM142568 GSE6146 HG-U133A 14 8 - GSM142569 GSM142571 GSM142572 GSM142574 GSM51391 GSM51392 GSE2666 HG-U133A 36 4 1 GSM51393 GSM51394 only GSM321583 GSE12803 HG-U133A 20 3 GSM321584 2 GSM321585 use Promyelocytes_1 Promyelocytes_2 Promyelocytes_3 Promyelocytes_4 HG-U133A 8 8 3 GSE64282 Promyelocytes_5 Promyelocytes_6 Promyelocytes_7 Promyelocytes_8 Non-commercial 2 Supplementary Table S2. Chromosomal regions up-regulated in CD34+ samples as identified by the LAP procedure with the two-class statistics coded in the PREDA R package and an FDR threshold of 0.5. Functional enrichment analysis has been performed using DAVID (http://david.abcc.ncifcrf.gov/)
    [Show full text]
  • The UVB-Induced Gene Expression Profile of Human Epidermis in Vivo Is Different from That of Cultured Keratinocytes
    Oncogene (2006) 25, 2601–2614 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc ORIGINAL ARTICLE The UVB-induced gene expression profile of human epidermis in vivo is different from that of cultured keratinocytes CD Enk1, J Jacob-Hirsch2, H Gal3, I Verbovetski4, N Amariglio2, D Mevorach4, A Ingber1, D Givol3, G Rechavi2 and M Hochberg1 1Department of Dermatology, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 2Department of Pediatric Hemato-Oncology and Functional Genomics, Safra Children’s Hospital, Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University,Tel Aviv, Israel; 3Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel and 4The Laboratory for Cellular and Molecular Immunology, Department of Medicine, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel In order to obtain a comprehensive picture of the radiation. UVB, with a wavelength range between 290 molecular events regulating cutaneous photodamage of and 320 nm, represents one of the most important intact human epidermis, suction blister roofs obtained environmental hazards affectinghuman skin (Hahn after a single dose of in vivo ultraviolet (UV)B exposure and Weinberg, 2002). To protect itself against the were used for microarray profiling. We found a changed DNA-damaging effects of sunlight, the skin disposes expression of 619 genes. Half of the UVB-regulated genes over highly complicated cellular programs, including had returned to pre-exposure baseline levels at 72 h, cell-cycle arrest, DNA repair and apoptosis (Brash et al., underscoring the transient character of the molecular 1996). Failure in selected elements of these defensive cutaneous UVB response.
    [Show full text]
  • Histone-Related Genes Are Hypermethylated in Lung Cancer
    Published OnlineFirst October 1, 2019; DOI: 10.1158/0008-5472.CAN-19-1019 Cancer Genome and Epigenome Research Histone-Related Genes Are Hypermethylated in Lung Cancer and Hypermethylated HIST1H4F Could Serve as a Pan-Cancer Biomarker Shihua Dong1,Wei Li1, Lin Wang2, Jie Hu3,Yuanlin Song3, Baolong Zhang1, Xiaoguang Ren1, Shimeng Ji3, Jin Li1, Peng Xu1, Ying Liang1, Gang Chen4, Jia-Tao Lou2, and Wenqiang Yu1 Abstract Lung cancer is the leading cause of cancer-related deaths lated in all 17 tumor types from TCGA datasets (n ¼ 7,344), worldwide. Cytologic examination is the current "gold stan- which was further validated in nine different types of cancer dard" for lung cancer diagnosis, however, this has low sensi- (n ¼ 243). These results demonstrate that HIST1H4F can tivity. Here, we identified a typical methylation signature of function as a universal-cancer-only methylation (UCOM) histone genes in lung cancer by whole-genome DNA methyl- marker, which may aid in understanding general tumorigen- ation analysis, which was validated by The Cancer Genome esis and improve screening for early cancer diagnosis. Atlas (TCGA) lung cancer cohort (n ¼ 907) and was further confirmed in 265 bronchoalveolar lavage fluid samples with Significance: These findings identify a new biomarker for specificity and sensitivity of 96.7% and 87.0%, respectively. cancer detection and show that hypermethylation of histone- More importantly, HIST1H4F was universally hypermethy- related genes seems to persist across cancers. Introduction to its low specificity, LDCT is far from satisfactory as a screening tool for clinical application, similar to other currently used cancer Lung cancer is one of the most common malignant tumors and biomarkers, such as carcinoembryonic antigen (CEA), neuron- the leading cause of cancer-related deaths worldwide (1, 2).
    [Show full text]
  • A Yeast Phenomic Model for the Influence of Warburg Metabolism on Genetic Buffering of Doxorubicin Sean M
    Santos and Hartman Cancer & Metabolism (2019) 7:9 https://doi.org/10.1186/s40170-019-0201-3 RESEARCH Open Access A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin Sean M. Santos and John L. Hartman IV* Abstract Background: The influence of the Warburg phenomenon on chemotherapy response is unknown. Saccharomyces cerevisiae mimics the Warburg effect, repressing respiration in the presence of adequate glucose. Yeast phenomic experiments were conducted to assess potential influences of Warburg metabolism on gene-drug interaction underlying the cellular response to doxorubicin. Homologous genes from yeast phenomic and cancer pharmacogenomics data were analyzed to infer evolutionary conservation of gene-drug interaction and predict therapeutic relevance. Methods: Cell proliferation phenotypes (CPPs) of the yeast gene knockout/knockdown library were measured by quantitative high-throughput cell array phenotyping (Q-HTCP), treating with escalating doxorubicin concentrations under conditions of respiratory or glycolytic metabolism. Doxorubicin-gene interaction was quantified by departure of CPPs observed for the doxorubicin-treated mutant strain from that expected based on an interaction model. Recursive expectation-maximization clustering (REMc) and Gene Ontology (GO)-based analyses of interactions identified functional biological modules that differentially buffer or promote doxorubicin cytotoxicity with respect to Warburg metabolism. Yeast phenomic and cancer pharmacogenomics data were integrated to predict differential gene expression causally influencing doxorubicin anti-tumor efficacy. Results: Yeast compromised for genes functioning in chromatin organization, and several other cellular processes are more resistant to doxorubicin under glycolytic conditions. Thus, the Warburg transition appears to alleviate requirements for cellular functions that buffer doxorubicin cytotoxicity in a respiratory context.
    [Show full text]
  • Hidden Markov Models Predict Epigenetic Chromatin Domains
    Hidden Markov Models Predict Epigenetic Chromatin Domains The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Larson, Jessica. 2012. Hidden Markov Models Predict Epigenetic Chromatin Domains. Doctoral dissertation, Harvard University. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:10087396 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA ©2012- Jessica Lynn Larson All rights reserved Dissertation Advisor: Professor Guo-Cheng Yuan Jessica Lynn Larson Hidden Markov Models Predict Epigenetic Chromatin Domains Abstract Epigenetics is an important layer of transcriptional control necessary for cell-type specific gene regulation. We developed computational methods to analyze the combinatorial effect and large-scale organizations of genome-wide distributions of epigenetic marks. Throughout this dissertation, we show that regions containing multiple genes with similar epigenetic patterns are found throughout the genome, suggesting the presence of several chromatin domains. In Chapter 1, we develop a hidden Markov model (HMM) for detecting the types and locations of epigenetic domains from multiple histone modifications. We use this method to analyze a published ChIP-seq dataset of five histone modification marks in mouse embryonic stem cells. We successfully detect domains of consistent epigenetic patterns from ChIP-seq data, providing new insights into the role of epigenetics in long- range gene regulation. In Chapter 2, we expand our model to investigate the genome-wide patterns of histone modifications in multiple human cell lines.
    [Show full text]
  • A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family
    Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2018 A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family Linda Molla Follow this and additional works at: https://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Linda Molla June 2018 © Copyright by Linda Molla 2018 A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY Linda Molla, Ph.D. The Rockefeller University 2018 APOBEC2 is a member of the AID/APOBEC cytidine deaminase family of proteins. Unlike most of AID/APOBEC, however, APOBEC2’s function remains elusive. Previous research has implicated APOBEC2 in diverse organisms and cellular processes such as muscle biology (in Mus musculus), regeneration (in Danio rerio), and development (in Xenopus laevis). APOBEC2 has also been implicated in cancer. However the enzymatic activity, substrate or physiological target(s) of APOBEC2 are unknown. For this thesis, I have combined Next Generation Sequencing (NGS) techniques with state-of-the-art molecular biology to determine the physiological targets of APOBEC2. Using a cell culture muscle differentiation system, and RNA sequencing (RNA-Seq) by polyA capture, I demonstrated that unlike the AID/APOBEC family member APOBEC1, APOBEC2 is not an RNA editor. Using the same system combined with enhanced Reduced Representation Bisulfite Sequencing (eRRBS) analyses I showed that, unlike the AID/APOBEC family member AID, APOBEC2 does not act as a 5-methyl-C deaminase.
    [Show full text]
  • A Multiprotein Occupancy Map of the Mrnp on the 3 End of Histone
    Downloaded from rnajournal.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press A multiprotein occupancy map of the mRNP on the 3′ end of histone mRNAs LIONEL BROOKS III,1 SHAWN M. LYONS,2 J. MATTHEW MAHONEY,1 JOSHUA D. WELCH,3 ZHONGLE LIU,1 WILLIAM F. MARZLUFF,2 and MICHAEL L. WHITFIELD1 1Department of Genetics, Dartmouth Geisel School of Medicine, Hanover, New Hampshire 03755, USA 2Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599, USA 3Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina 27599, USA ABSTRACT The animal replication-dependent (RD) histone mRNAs are coordinately regulated with chromosome replication. The RD-histone mRNAs are the only known cellular mRNAs that are not polyadenylated. Instead, the mature transcripts end in a conserved stem– loop (SL) structure. This SL structure interacts with the stem–loop binding protein (SLBP), which is involved in all aspects of RD- histone mRNA metabolism. We used several genomic methods, including high-throughput sequencing of cross-linked immunoprecipitate (HITS-CLIP) to analyze the RNA-binding landscape of SLBP. SLBP was not bound to any RNAs other than histone mRNAs. We performed bioinformatic analyses of the HITS-CLIP data that included (i) clustering genes by sequencing read coverage using CVCA, (ii) mapping the bound RNA fragment termini, and (iii) mapping cross-linking induced mutation sites (CIMS) using CLIP-PyL software. These analyses allowed us to identify specific sites of molecular contact between SLBP and its RD-histone mRNA ligands. We performed in vitro crosslinking assays to refine the CIMS mapping and found that uracils one and three in the loop of the histone mRNA SL preferentially crosslink to SLBP, whereas uracil two in the loop preferentially crosslinks to a separate component, likely the 3′hExo.
    [Show full text]
  • Characterization of Chromatin Interaction in Mammalian Cells Jufen Zhu University of Connecticut - Storrs, [email protected]
    University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 1-8-2019 Characterization of Chromatin Interaction in Mammalian Cells Jufen Zhu University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Zhu, Jufen, "Characterization of Chromatin Interaction in Mammalian Cells" (2019). Doctoral Dissertations. 2053. https://opencommons.uconn.edu/dissertations/2053 Characterization of Chromatin Interaction in Mammalian Cells Jacqueline Jufen Zhu, Ph.D. University of Connecticut, 2019 Abstract Higher-order chromatin organization in cell nucleus is mysterious. Microscopy and high- throughput sequencing technologies have been applied to reveal the connections between genome structure and gene transcription, which is the main topic of my thesis. Higher-order chromatin organization differs across cell types and species, giving an insight into disease genesis and tumorigenesis. Despite an enormous progress has been made recently in epigenomic study, lots of things remain unknown. My dissertation reviews the current understanding of epigenomics, characterizes chromatin interaction in mammalian cells using different technologies, investigates chromatin reorganization in breast cancer cells, analyzes integrated genomic and epigenomic data in breast cancer metastasis and discusses results and future directions. Dissertation Jacqueline Jufen Zhu Characterization of Chromatin Interaction in Mammalian Cells Jacqueline Jufen Zhu B.E., Nanjing Agricultural University, 2010 M.S., Chinese Academy of Sciences, 2013 A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the University of Connecticut 2019 i Dissertation Jacqueline Jufen Zhu Copyright by Jacqueline Jufen Zhu 2019 ii Dissertation Jacqueline Jufen Zhu Approval Page Doctoral of Philosophy Dissertation Characterization of Chromatin Interaction in Mammalian Cells Presented by Jacqueline Jufen Zhu, M.S.
    [Show full text]
  • Molecular Characterisation of Metastatic Pancreatic Neuroendocrine Tumours (Pnets) Using Whole
    Downloaded from molecularcasestudies.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Metastatic PNET molecular characteristics Manuscript Research Report Molecular characterisation of metastatic pancreatic neuroendocrine tumours (PNETs) using whole genome and transcriptome sequencing Hui-li Wong1,2†, Kevin C. Yang3,4†, Yaoqing Shen4†, Eric Y. Zhao4, Jonathan M. Loree1, Hagen F. Kennecke1, Steve E. Kalloger2,5, Joanna M. Karasinska2, Howard J. Lim1, Andrew J. Mungall4, Xiaolan Feng6, Janine M. Davies1, Kasmintan Schrader7, Chen Zhou4, Aly Karsan4, Steven J.M. Jones4, Janessa Laskin1, Marco A. Marra4,7, David F. Schaeffer2,5‡, Sharon M. Gorski3,4‡, Daniel J. Renouf1,2‡ 1Division of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada 2Pancreas Centre BC, Vancouver, British Columbia, Canada 3Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, British Columbia, Canada 4Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada 5Division of Anatomical Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada 6Vancouver Island Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada 7Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada †These authors contributed equally to this work ‡These authors jointly supervised this work Corresponding author: Daniel J. Renouf Email: [email protected] Running title: Metastatic
    [Show full text]
  • Supplemental Data.Pdf
    Supplementary material -Table of content Supplementary Figures (Fig 1- Fig 6) Supplementary Tables (1-13) Lists of genes belonging to distinct biological processes identified by GREAT analyses to be significantly enriched with UBTF1/2-bound genes Supplementary Table 14 List of the common UBTF1/2 bound genes within +/- 2kb of their TSSs in NIH3T3 and HMECs. Supplementary Table 15 List of gene identified by microarray expression analysis to be differentially regulated following UBTF1/2 knockdown by siRNA Supplementary Table 16 List of UBTF1/2 binding regions overlapping with histone genes in NIH3T3 cells Supplementary Table 17 List of UBTF1/2 binding regions overlapping with histone genes in HMEC Supplementary Table 18 Sequences of short interfering RNA oligonucleotides Supplementary Table 19 qPCR primer sequences for qChIP experiments Supplementary Table 20 qPCR primer sequences for reverse transcription-qPCR Supplementary Table 21 Sequences of primers used in CHART-PCR Supplementary Methods Supplementary Fig 1. (A) ChIP-seq analysis of UBTF1/2 and Pol I (POLR1A) binding across mouse rDNA. UBTF1/2 is enriched at the enhancer and promoter regions and along the entire transcribed portions of rDNA with little if any enrichment in the intergenic spacer (IGS), which separates the rDNA repeats. This enrichment coincides with the distribution of the largest subunit of Pol I (POLR1A) across the rDNA. All sequencing reads were mapped to the published complete sequence of the mouse rDNA repeat (Gene bank accession number: BK000964). The graph represents the frequency of ribosomal sequences enriched in UBTF1/2 and Pol I-ChIPed DNA expressed as fold change over those of input genomic DNA.
    [Show full text]
  • Whole-Genome Sequencing Identifies New Genetic Alterations in Meningiomas
    www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 10), pp: 17070-17080 Research Paper Whole-genome sequencing identifies new genetic alterations in meningiomas Mei Tang1,*, Heng Wei2,*, Lu Han1,*, Jiaojiao Deng3, Yuelong Wang3, Meijia Yang1, Yani Tang1, Gang Guo1, Liangxue Zhou3, Aiping Tong1 1The State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China 2College of Life Science, Sichuan University, Chengdu 610064, China 3Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China *These authors have contributed equally to the work Correspondence to: Aiping Tong, email: [email protected] Liangxue Zhou, email: [email protected] Keywords: whole-genome sequencing, meningioma, chromosome instability, copy number alteration, mutation Received: October 24, 2016 Accepted: January 13, 2017 Published: February 03, 2017 ABSTRACT The major known genetic contributor to meningioma formation was NF2, which is disrupted by mutation or loss in about 50% of tumors. Besides NF2, several recurrent driver mutations were recently uncovered through next-generation sequencing. Here, we performed whole-genome sequencing across 7 tumor-normal pairs to identify somatic genetic alterations in meningioma. As a result, Chromatin regulators, including multiple histone members, histone-modifying enzymes and several epigenetic regulators, are the major category among all of the identified copy number variants and single nucleotide variants. Notably, all samples contained copy number variants in histone members. Recurrent chromosomal rearrangements were detected on chromosome 22q, 6p21-p22 and 1q21, and most of the histone copy number variants occurred in these regions.
    [Show full text]
  • Differential Mechanisms of Tolerance to Extreme Environmental
    www.nature.com/scientificreports OPEN Diferential mechanisms of tolerance to extreme environmental conditions in tardigrades Dido Carrero*, José G. Pérez-Silva , Víctor Quesada & Carlos López-Otín * Tardigrades, also known as water bears, are small aquatic animals that inhabit marine, fresh water or limno-terrestrial environments. While all tardigrades require surrounding water to grow and reproduce, species living in limno-terrestrial environments (e.g. Ramazzottius varieornatus) are able to undergo almost complete dehydration by entering an arrested state known as anhydrobiosis, which allows them to tolerate ionic radiation, extreme temperatures and intense pressure. Previous studies based on comparison of the genomes of R. varieornatus and Hypsibius dujardini - a less tolerant tardigrade - have pointed to potential mechanisms that may partially contribute to their remarkable ability to resist extreme physical conditions. In this work, we have further annotated the genomes of both tardigrades using a guided approach in search for novel mechanisms underlying the extremotolerance of R. varieornatus. We have found specifc amplifcations of several genes, including MRE11 and XPC, and numerous missense variants exclusive of R. varieornatus in CHEK1, POLK, UNG and TERT, all of them involved in important pathways for DNA repair and telomere maintenance. Taken collectively, these results point to genomic features that may contribute to the enhanced ability to resist extreme environmental conditions shown by R. varieornatus. Tardigrades are small
    [Show full text]