Multi Gene Mutation Signatures in Colorectal Cancer
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Thesis Template
Functional and Structural Characterization Reveals Novel FBXW7 Biology by Tonny Chao Huang A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Medical Biophysics University of Toronto © Copyright by Tonny Chao Huang 2018 Functional and Structural Characterization Reveals Novel FBXW7 Biology Tonny Chao Huang Master of Science Department of Medical Biophysics University of Toronto 2018 Abstract This thesis aims to examine aspects of FBXW7 biology, a protein that is frequently mutated in a variety of cancers. The first part of this thesis describes the characterization of FBXW7 isoform and mutant substrate profiles using a proximity-dependent biotinylation assay. Isoform-specific substrates were validated, revealing the involvement of FBXW7 in the regulation of several protein complexes. Characterization of FBXW7 mutants also revealed site- and residue-specific consequences on the binding of substrates and, surprisingly, possible neo-substrates. In the second part of this thesis, we utilize high-throughput peptide binding assays and statistical modelling to discover novel features of the FBXW7-binding phosphodegron. In contrast to the canonical motif, a possible preference of FBXW7 for arginine residues at the +4 position was discovered. I then attempted to validate this feature in vivo and in vitro on a novel substrate discovered through BioID. ii Acknowledgments The past three years in the Department of Medical Biophysics have defied expectations. I not only had the opportunity to conduct my own independent research, but also to work with distinguished collaborators and to explore exciting complementary fields. I experienced the freedom to guide my own academic development, as well as to pursue my extracurricular interests. -
Inactivation of Fbxw7 Impairs Dsrna Sensing and Confers Resistance to PD-1 Blockade
Published OnlineFirst May 5, 2020; DOI: 10.1158/2159-8290.CD-19-1416 RESEARCH ARTICLE Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade Cécile Gstalder1,2, David Liu1,3, Diana Miao1, Bart Lutterbach1,2, Alexander L. DeVine1,2, Chenyu Lin4, Megha Shettigar1,2, Priya Pancholi1,2, Elizabeth I. Buchbinder1, Scott L. Carter5,6, Michael P. Manos1, Vanesa Rojas-Rudilla7, Ryan Brennick1, Evisa Gjini8, Pei-Hsuan Chen8, Ana Lako8, Scott Rodig8,9, Charles H. Yoon10, Gordon J. Freeman1, David A. Barbie1, F. Stephen Hodi1, Wayne Miles4, Eliezer M. Van Allen1, and Rizwan Haq1,2 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst May 5, 2020; DOI: 10.1158/2159-8290.CD-19-1416 ABSTRACT The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti–PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7, whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti–PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG1, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7-deficient cells was suffi- cient to sensitize them to anti–PD-1. -
Mutational Landscape Differences Between Young-Onset and Older-Onset Breast Cancer Patients Nicole E
Mealey et al. BMC Cancer (2020) 20:212 https://doi.org/10.1186/s12885-020-6684-z RESEARCH ARTICLE Open Access Mutational landscape differences between young-onset and older-onset breast cancer patients Nicole E. Mealey1 , Dylan E. O’Sullivan2 , Joy Pader3 , Yibing Ruan3 , Edwin Wang4 , May Lynn Quan1,5,6 and Darren R. Brenner1,3,5* Abstract Background: The incidence of breast cancer among young women (aged ≤40 years) has increased in North America and Europe. Fewer than 10% of cases among young women are attributable to inherited BRCA1 or BRCA2 mutations, suggesting an important role for somatic mutations. This study investigated genomic differences between young- and older-onset breast tumours. Methods: In this study we characterized the mutational landscape of 89 young-onset breast tumours (≤40 years) and examined differences with 949 older-onset tumours (> 40 years) using data from The Cancer Genome Atlas. We examined mutated genes, mutational load, and types of mutations. We used complementary R packages “deconstructSigs” and “SomaticSignatures” to extract mutational signatures. A recursively partitioned mixture model was used to identify whether combinations of mutational signatures were related to age of onset. Results: Older patients had a higher proportion of mutations in PIK3CA, CDH1, and MAP3K1 genes, while young- onset patients had a higher proportion of mutations in GATA3 and CTNNB1. Mutational load was lower for young- onset tumours, and a higher proportion of these mutations were C > A mutations, but a lower proportion were C > T mutations compared to older-onset tumours. The most common mutational signatures identified in both age groups were signatures 1 and 3 from the COSMIC database. -
S41467-020-18249-3.Pdf
ARTICLE https://doi.org/10.1038/s41467-020-18249-3 OPEN Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain Lei Zhao1,2,17, Zhongqi Li 1,2,17, Joaquim S. L. Vong2,3,17, Xinyi Chen1,2, Hei-Ming Lai1,2,4,5,6, Leo Y. C. Yan1,2, Junzhe Huang1,2, Samuel K. H. Sy1,2,7, Xiaoyu Tian 8, Yu Huang 8, Ho Yin Edwin Chan5,9, Hon-Cheong So6,8, ✉ ✉ Wai-Lung Ng 10, Yamei Tang11, Wei-Jye Lin12,13, Vincent C. T. Mok1,5,6,14,15 &HoKo 1,2,4,5,6,8,14,16 1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovas- cular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation- dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which pro- minently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed tran- scriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible. -
Ncomms3787.Pdf
ARTICLE Received 6 Aug 2013 | Accepted 17 Oct 2013 | Published 14 Nov 2013 DOI: 10.1038/ncomms3787 OPEN Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin Matthias Zebisch1, Yang Xu2,3, Christos Krastev1, Bryan T. MacDonald2, Maorong Chen2, Robert J.C. Gilbert1,XiHe2 & E. Yvonne Jones1 The four R-spondin (Rspo) proteins are secreted agonists of Wnt signalling in vertebrates, functioning in embryogenesis and adult stem cell biology. Through ubiquitination and degradation of Wnt receptors, the transmembrane E3 ubiquitin ligase ZNRF3 and related RNF43 antagonize Wnt signalling. Rspo ligands have been reported to inhibit the ligase activity through direct interaction with ZNRF3 and RNF43. Here we report multiple crystal structures of the ZNRF3 ectodomain (ZNRF3ecto), a signalling-competent Furin1–Furin2 (Fu1–Fu2) fragment of Rspo2 (Rspo2Fu1–Fu2), and Rspo2Fu1–Fu2 in complex with ZNRF3ecto,or RNF43ecto. A prominent loop in Fu1 clamps into equivalent grooves in the ZNRF3ecto and RNF43ecto surface. Rspo binding enhances dimerization of ZNRF3ecto but not of RNF43ecto. Comparison of the four Rspo proteins, mutants and chimeras in biophysical and cellular assays shows that their signalling potency depends on their ability to recruit ZNRF3 or RNF43 via Fu1 into a complex with LGR receptors, which interact with Rspo via Fu2. 1 Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. 2 F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. 3 Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, College of Life Science, Jilin University, Changchun 130012, China. -
P53 and FBXW7: Sometimes Two Guardians Are Worse Than One
cancers Perspective p53 and FBXW7: Sometimes Two Guardians Are Worse than One María Galindo-Moreno 1, Servando Giráldez 1 , M. Cristina Limón-Mortés 1, Alejandro Belmonte-Fernández 1, Carmen Sáez 2,3 , Miguel Á. Japón 2,3, Maria Tortolero 1 and Francisco Romero 1,* 1 Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, E-41012 Sevilla, Spain; [email protected] (M.G.-M.); [email protected] (S.G.); [email protected] (M.C.L.-M.); [email protected] (A.B.-F.); [email protected] (M.T.) 2 Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, E-41013 Sevilla, Spain; [email protected] (C.S.); [email protected] (M.Á.J.) 3 Departamento de Anatomía Patológica, Hospital Universitario Virgen del Rocío, E-41013 Sevilla, Spain * Correspondence: [email protected]; Tel.: +34-954557119 Received: 10 February 2020; Accepted: 13 April 2020; Published: 16 April 2020 Abstract: Too much of a good thing can become a bad thing. An example is FBXW7, a well-known tumor suppressor that may also contribute to tumorigenesis. Here, we reflect on the results of three laboratories describing the role of FBXW7 in the degradation of p53 and the possible implications of this finding in tumor cell development. We also speculate about the function of FBXW7 as a key player in the cell fate after DNA damage and how this could be exploited in the treatment of cancer disease. Keywords: FBXW7; p53; tumor suppressor; cancer; proliferation; ubiquitylation FBXW7 (F-box and WD repeat domain-containing 7) is the subunit of the SCF (SKP1-CUL1-F-box protein) (FBXW7) ubiquitin ligase responsible for recruiting substrates. -
Rho Guanine Nucleotide Exchange Factors: Regulators of Rho Gtpase Activity in Development and Disease
Oncogene (2014) 33, 4021–4035 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc REVIEW Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease DR Cook1, KL Rossman2,3 and CJ Der1,2,3 The aberrant activity of Ras homologous (Rho) family small GTPases (20 human members) has been implicated in cancer and other human diseases. However, in contrast to the direct mutational activation of Ras found in cancer and developmental disorders, Rho GTPases are activated most commonly in disease by indirect mechanisms. One prevalent mechanism involves aberrant Rho activation via the deregulated expression and/or activity of Rho family guanine nucleotide exchange factors (RhoGEFs). RhoGEFs promote formation of the active GTP-bound state of Rho GTPases. The largest family of RhoGEFs is comprised of the Dbl family RhoGEFs with 70 human members. The multitude of RhoGEFs that activate a single Rho GTPase reflects the very specific role of each RhoGEF in controlling distinct signaling mechanisms involved in Rho activation. In this review, we summarize the role of Dbl RhoGEFs in development and disease, with a focus on Ect2 (epithelial cell transforming squence 2), Tiam1 (T-cell lymphoma invasion and metastasis 1), Vav and P-Rex1/2 (PtdIns(3,4,5)P3 (phosphatidylinositol (3,4,5)-triphosphate)-dependent Rac exchanger). Oncogene (2014) 33, 4021–4035; doi:10.1038/onc.2013.362; published online 16 September 2013 Keywords: Rac1; RhoA; Cdc42; guanine nucleotide exchange factors; cancer; -
Truncating PREX2 Mutations Activate Its GEF Activity and Alter Gene
Truncating PREX2 mutations activate its GEF activity PNAS PLUS and alter gene expression regulation in NRAS-mutant melanoma Yonathan Lissanu Deribea,1,2, Yanxia Shia,b,1, Kunal Raia, Luigi Nezia, Samir B. Amina, Chia-Chin Wua, Kadir C. Akdemira, Mozhdeh Mahdavia, Qian Penga, Qing Edward Changc, Kirsti Hornigoldd, Stefan T. Arolde, Heidi C. E. Welchd, Levi A. Garrawayf,g, and Lynda China,c,2 aDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; bSun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborate Center for Cancer Medicine, Guangzhou 510060, China; cInstitute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, TX 77030; dThe Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom; eDivision of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, 23955-6900 Saudi Arabia; fDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; and gBroad Institute of MIT and Harvard, Boston, MA 02141 Edited by Dennis A. Carson, University of California at San Diego, La Jolla, CA, and approved January 26, 2016 (received for review July 14, 2015) PREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac- To date, the most obvious connection between PREX2 and exchange factor 2) is a PTEN (phosphatase and tensin homolog cancer relevant pathways is through its physical interaction with deleted on chromosome 10) binding protein that is significantly PTEN (7). PTEN catalyzes the conversion of phosphatidylino- mutated in cutaneous melanoma and pancreatic ductal adenocar- sitol-3,4,5-trisphosphate to phosphatidylinositol-4,5 bisphosphate. -
Insights Into MYC Biology Through Investigation of Synthetic Lethal Interactions with MYC Deregulation
Insights into MYC biology through investigation of synthetic lethal interactions with MYC deregulation Mai Sato Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Mai Sato All Rights Reserved ABSTRACT Insights into MYC biology through investigation of synthetic lethal interactions with MYC deregulation Mai Sato MYC (or c-myc) is a bona fide “cancer driver” oncogene that is deregulated in up to 70% of human tumors. In addition to its well-characterized role as a transcription factor that can directly promote tumorigenic growth and proliferation, MYC has transcription-independent functions in vital cellular processes including DNA replication and protein synthesis, contributing to its complex biology. MYC expression, activity, and stability are highly regulated through multiple mechanisms. MYC deregulation triggers genome instability and oncogene-induced DNA replication stress, which are thought to be critical in promoting cancer via mechanisms that are still unclear. Because regulated MYC activity is essential for normal cell viability and MYC is a difficult protein to target pharmacologically, targeting genes or pathways that are essential to survive MYC deregulation offer an attractive alternative as a means to combat tumor cells with MYC deregulation. To this end, we conducted a genome-wide synthetic lethal shRNA screen in MCF10A breast epithelial cells stably expressing an inducible MYCER transgene. We identified and validated FBXW7 as a high-confidence synthetic lethal (MYC-SL) candidate gene. FBXW7 is a component of an E3 ubiquitin ligase complex that degrades MYC. FBXW7 knockdown in MCF10A cells selectively induced cell death in MYC-deregulated cells compared to control. -
The TAL1 Complex Targets the FBXW7 Tumor Suppressor by Activating Mir-223 in Human T Cell Acute Lymphoblastic Leukemia
Article The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia Marc R. Mansour,1,3 Takaomi Sanda,1,4 Lee N. Lawton,5 Xiaoyu Li,2 Taras Kreslavsky,2 Carl D. Novina,2,6 Marjorie Brand,7,8 Alejandro Gutierrez,1,9 Michelle A. Kelliher,10 Catriona H.M. Jamieson,11 Harald von Boehmer,2 Richard A. Young,5,12 and A. Thomas Look1,9 Downloaded from http://rupress.org/jem/article-pdf/210/8/1545/1211584/jem_20122516.pdf by guest on 30 September 2021 1Department of Pediatric Oncology and 2Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02216 3Department of Haematology, University College London Cancer Institute, University College London, WC1E 6BT, England, UK 4Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599 5Whitehead Institute for Biomedical Research, , Cambridge, MA 02142 6Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142 7The Sprott Center for Stem Cell Research, Department of Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario K1Y 4E9, Canada 8Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada 9Division of Hematology/Oncology, Children’s Hospital, Boston, MA 02115 10Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605 11Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093 12Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142 The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. -
Investigation of the Atypical FBXW7 Mutation Spectrum in Human
Gut Online First, published on May 15, 2013 as 10.1136/gutjnl-2013-304719 Colorectal cancer ORIGINAL ARTICLE Gut: first published as 10.1136/gutjnl-2013-304719 on 15 May 2013. Downloaded from Investigation of the atypical FBXW7 mutation spectrum in human tumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines Hayley Davis,1 Annabelle Lewis,1 Axel Behrens,2 Ian Tomlinson1 ▸ Additional material is ABSTRACT published online only. To view Objective FBXW7 encodes the substrate recognition Significance of this study please visit the journal online (http://dx.doi.org/10.1136/ component of a ubiquitin ligase that degrades targets gutjnl-2013-304719). such as Notch1, c-Jun, c-Myc and cyclin E. FBXW7 mutations occur in several tumour types, including 1Molecular and Population What is already known about this subject? Genetics Laboratory, Wellcome colorectal cancers. The FBXW7 mutation spectrum in ▸ FBXW7 is commonly mutated in tumours of Trust Centre for Human cancers is unusual. Some tumours have biallelic loss of diverse origins, including colorectal cancer. Genetics, Oxford University, function mutations but most have monoallelic missense ▸ FBXW7 is classed as a tumour suppressor, but Oxford, UK fi 2 mutations involving speci c arginine residues at has an unusual mutation spectrum whereby Mammalian Genetics β Laboratory, London Research -propellor tips involved in substrate recognition. biallelic, simple loss-of-function mutations are Institute, Cancer Research UK, Design FBXW7 functional studies have generally rare; instead, most mutations are monoallelic London, UK used null systems. In order to analyse the most missense changes involving specific arginine common mutations in human tumours, we created a residues at β-sheet propellor tips that allow the Correspondence to Fbxw7fl(R482Q)/+ mouse and conditionally expressed this Professor I Tomlinson, FBXW7 protein to recognise its substrates. -
FBXW7/Hcdc4 Is a General Tumor Suppressor in Human Cancer
Priority Report FBXW7/hCDC4 Is a General Tumor Suppressor in Human Cancer Shahab Akhoondi,1 Dahui Sun,2 Natalie von der Lehr,1 Sophia Apostolidou,3 Kathleen Klotz,2 Alena Maljukova,1 Diana Cepeda,1 Heidi Fiegl,3 Dimitra Dofou,3 Christian Marth,4 Elisabeth Mueller-Holzner,4 Martin Corcoran,1 Markus Dagnell,1 Sepideh Zabihi Nejad,5 Babak Noori Nayer,5 Mohammad Reza Zali,5 Johan Hansson,1 Susanne Egyhazi,1 Fredrik Petersson,1 Per Sangfelt,6 Hans Nordgren,6 Dan Grander,1 Steven I. Reed,7 Martin Widschwendter,3 Olle Sangfelt,1 and Charles Spruck2 1Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden; 2Department of Tumor Cell Biology, Sidney Kimmel Cancer Center, San Diego, California; 3Department of Gynaecological Oncology, Institute for Women’s Health, University College London, London, United Kingdom; 4Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria; 5Research Center for Gastrointestinal and Liver Disease, Taleghani Hospital, Tehran, Iran; 6Department of Medical Sciences, Pathology, and Gastroenterology, Uppsala University Hospital, Uppsala, Sweden; and 7Department of Molecular Biology, The Scripps Research Institute, La Jolla, California Abstract cycle progression, and cellular division (1). The latter processes are The ubiquitin-proteasome system is a major regulatory primarily regulated by two ubiquitin ligases known as the pathway of protein degradation and plays an important role anaphase-promoting complex (APC) and SCF. SCF ubiquitin ligases in cellular division. Fbxw7 (or hCdc4), a member of the F-box are composed of Cul1, Rbx1 (also called Roc1 or Hrt1), and Skp1 family of proteins, which are substrate recognition compo- bound to a member of the F-box protein family, which provide substrate specificity.