DOCSLIB.ORG

Sex Differences in Cancer Driver Genes and Biomarkers Constance H

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Sex Differences in Cancer Driver Genes and Biomarkers Constance H Cancer Genome and Epigenome Research Sex Differences in Cancer Driver Genes and Biomarkers Constance H. Li1,2, Syed Haider1, Yu-Jia Shiah1,2, Kevin Thai1, and Paul C. Boutros1,2,3 Abstract Cancer differs significantly between men and women; even and BAP1. Sex influenced biomarkers of patient outcome, after adjusting for known epidemiologic risk factors, the sexes where different genes were associated with tumor aggression differ in incidence, outcome, and response to therapy. These in each sex. These data call for increased study and consider- differences occur in many but not all tumor types, and their ation of the molecular role of sex in cancer etiology, progres- origins remain largely unknown. Here, we compare somatic sion, treatment, and personalized therapy. mutation profiles between tumors arising in men and in women. We discovered large differences in mutation density Significance: This study provides a comprehensive cata- and sex biases in the frequency of mutation of specific genes; log of sex differences in somatic alterations, including in these differences may be associated with sex biases in DNA cancer driver genes, which influence prognostic biomarkers mismatch repair genes or microsatellite instability. Sex-biased that predict patient outcome after definitive local therapy. genes include well-known drivers of cancer such as b-catenin Cancer Res; 78(19); 5527–37. Ó2018 AACR. Introduction advantage declines and disappears during menopause (11). Some of these differences in treatment response may be attributed to Sex differences in cancer have been known at least since 1949 differences in driver mutations between the sexes, and others to (1), with repeated demonstration that males have higher cancer differences in epigenetics or chromatin conformation. risk both in studies using North American (e.g., SEER; ref. 2) and The origins and mechanisms of these sex differences remain a international databases (e.g., IARC; ref. 3). Most, but not all tumor majorunresolvedquestionincancerbiology.Theymaybe types show increased incidence in men: thyroid cancer occurs caused by differences in the expression of genes on the sex 2.5 times more frequently in women. These differences remain chromosomes, in hormone levels, in developmental biology, after controlling for known epidemiologic risk factors (3). At most or in lifestyle features not reflected in current epidemiologic tumor sites, cancers arising in men induce higher mortality (4); for studies. Likely, a mixture of all these components contributes to example, there is a 3-fold increase in lethality from urinary sex differences in patient outcomes. We hypothesized that, bladder carcinomas in men relative to women (4). Further, there independent of their mechanism, sex differences in cancer are significant differences in response to treatment: female would be reflected by differences in somatic mutation profiles. patients with non–small cell lung cancer respond better to both That is, male and female tumors would acquire mutations at surgery (5, 6) and chemotherapy (7, 8), even after accounting for different rates and of different types. Recent intriguing data differences in variables such as subtype. Female patients with on missense mutations in melanoma support this hypothesis colorectal cancer respond better to surgery, and this difference is (12). We, therefore, undertook a systematic evaluation of sex- driven by improved female survival in the rectal cancer subgroup associated biases in mutations in cancer across a broad range (9). Similarly, female patients with colorectal also respond better of tumor types. Our study provides a comprehensive pan- to chemotherapy, which is partially attributed to differences in cancer catalog of sex-biased mutations and a perspective on tumor site and microsatellite instability (10). Finally, a propen- sex-specific prognostic biomarkers. sity-matched study of nasopharyngeal carcinoma found that females have a survival advantage regardless of tumor stage, Materials and Methods radiation technique, and chemotherapy regimen, but that this Data acquisition and processing mRNA abundance, DNA genome-wide somatic copy-number 1Computational Biology Program, Ontario Institute for Cancer Research, Tor- and somatic mutation profiles for the Cancer Genome Atlas 2 onto, Ontario, Canada. Department of Medical Biophysics, University of Tor- (TCGA) datasets were downloaded from Broad GDAC 3 onto, Toronto, Ontario, Canada. Department of Pharmacology and Toxicology, Firehose (https://gdac.broadinstitute.org/), release 2016-01-28. University of Toronto, Toronto, Ontario, Canada. For mRNA abundance, Illumina HiSeq rnaseqv2 level 3 RSEM- Note: Supplementary data for this article are available at Cancer Research normalized profiles were used. Genes with >75% of samples Online (http://cancerres.aacrjournals.org/). having zero reads were removed from the respective data set. Corresponding Author: Paul C. Boutros, Ontario Institute for Cancer Research, GISTIC v2 (13) level 4 data were used for somatic copy-number Toronto, ON M5G0A3, Canada. Phone: 647-258-4321; E-mail: analysis. mRNA abundance data were converted to log2 scale for [email protected] subsequent analyses. Mutational profiles were based on TCGA- doi: 10.1158/0008-5472.CAN-18-0362 reported MutSig v2.0 calls. All preprocessing was performed in R Ó2018 American Association for Cancer Research. statistical environment (v3.1.3). www.aacrjournals.org 5527 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Li et al. Patients younger than 18, older than 85 or lacking sex anno- used to reduce false positives that may arise from unbalanced tation were excluded from analysis, resulting in a sample size of tumor type subsets of the pan-cancer data. Multivariate logistic 7,131 across all tumor types for copy-number alterations (CNA; regression (MLR) was used to adjust ternary CNA data for sex, age, 1.5% excluded, Supplementary Table S1) and 6,073 for somatic race, and tumor type. The MLR sex term was tested for significance single-nucleotide variants (SNV; 1.5% excluded; Supplementary and FDR corrected to identify bins with pan-cancer sex biases (q < Table S1). Genes were excluded if they were mutated in fewer than 0.05). 20 patients (for CNAs) or 5% of patients (for SNVs). Gene filters The same approach was applied to each tumor type individ- were applied independently for pan-cancer and per individual ually. Proportions tests were used to select bins for multivariate tumor type data set. All analyses excluded genes on the X and Y analysis (q value < 0.1). MLR was again used to adjust ternary chromosomes. copy-number call for clinical variables. MLR modeling for each tumor type varies based on available clinical data. Tumor type– Mutation load specific models were fit independently per univariately significant Mutation load per patient was calculated as the sum of SNVs bin and variable significance for each bin was extracted from the across all genes on the autosomes. Mutation load was Box–Cox fitted models. FDR correction was used and an FDR threshold of transformed, and transformed values were compared between the 0.05 was used. A description of pan-cancer and tumor type– sexes using unpaired two-sided t tests for both pan-cancer and specific models, along with a breakdown of the data for each tumor type–specific analysis. A linear regression model was used group, can be found in Supplementary Table S1 and results can be to adjust mutation load for tumor type for the pan-cancer com- found in Supplementary Tables S3–S5. parison. Tumor type–specific P values were adjusted using the Benjamini–Hochberg false discovery rate procedure. Tumor types CNA-mRNA functional analysis with q values meeting an FDR threshold of 10% were further Genes in bins altered by sex-biased CNAs after multivariate analyzed using linear regression to adjust for tumor type–specific adjustment for kidney clear cell and kidney papillary cell cancers variables described in Supplementary Table S1. A multivariate were further investigated to determine sex-biased functional q value threshold of 0.05 was then used to determine statistical effects. Available mRNA samples were matched to those used in significance. Full results are in Supplementary Table S2. CNA analysis. For each gene affected by a sex-biased loss, its mRNA abundance was modeled against sex, copy-number loss Genome instability status, and a sex–copy-number loss interaction term. The inter- Genome instability was calculated as the percentage of the action term was used to identify genes with sex-biased mRNA genome affected by copy-number alterations. The number of base changes. FDR-adjusted P values and fold changes were extracted pairs for each CNA segment was summed to obtain a total number for visualization. A q value threshold of 0.05 was used for of base pairs altered per patient. The total number of base pairs statistical significance. For genes affected by sex-biased gains, the was divided by the number of assayed bases excluding the sex same procedure was applied using copy-number gains. chromosomes (7.8 million bp) to obtain the percentage of the genome altered (PGA). Box–Cox transformed PGA was treated as CNA-mRNA survival analysis a continuous variable and compared by sex using two-sided Genes found to have significant or trending (FDR threshold of unpaired t tests for all tumor types combined (pan-cancer) and 10%) sex biases in the CNA-mRNA functional analysis were separately (tumor type–specific). Linear regression models were further analyzed using Cox proportional hazards modeling. That used to adjust PGA for tumor type, age, and race for the pan-cancer is, we focused on genes that were both altered by sex-biased CNAs comparison. Tumor types where univariate testing indicated (MLR q value < 0.05) and showed mRNA abundance differences putative sex biases in PGA (FDR threshold of 10%) were also between the copy-number neutral and loss/gain groups for either adjusted for tumor type–specific variables (Supplementary sex (sex–loss interaction q < 0.1). For each gene, the mRNA Table S1).
Load more

Recommended publications
  • ARID2 Deficiency Promotes Tumor Progression and Is Associated with Higher
    bioRxiv preprint doi: https://doi.org/10.1101/2020.01.10.898726; this version posted January 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. ARID2 deficiency promotes tumor progression and is associated with higher sensitivity to PARP inhibition in lung cancer. Thaidy Moreno1, Laura González-Silva1, Beatriz Monterde1, Isabel Betancor-Fernández2, Carlos Revilla1, Antonio Agraz-Doblas1, Javier Freire3, Pablo Isidro4, Laura Quevedo1, Santiago Montes-Moreno3, Laura Cereceda3, Aurora Astudillo4, Berta Casar1,6, Piero Crespo1,6, Cristina Morales Torres5, Paola Scaffidi5,7, Javier Gomez-Roman3, Eduardo Salido2, and Ignacio Varela1* 1) Instituto de Biomedicina y Biotecnología de Cantabria. Universidad de Cantabria-CSIC. Santander, Spain. 2) Departamento de Patología, Centro de Investigación Biomédica en Red de Enfermedades Raras by impairing DNA repair. Importantly, our results indicate that ARID2-deficiency could be(CIBERER). Tenerife, Spain. 3) Servicio de Anatomía Patológica y Biobanco Valdecilla. HUMV/IDIVAL. Santander, Spain. 4) Biobanco del Principado de Asturias (BBPA). Hospital Universitario Central de Asturias. Oviedo, Spain. 5) Cancer Epigenetics Laboratory, The Francis Crick Institute. London, UK. 6) Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) 7) UCL Cancer Institute, London, UK. * To whom correspondence should be addressed: Ignacio Varela Instituto de Biomedicina y Biotecnología de Cantabria Universidad de Cantabria Albert Einstein 22, 39011 Santander Spain. Ph. +34 942203931 Email. [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2020.01.10.898726; this version posted January 10, 2020.
    [Show full text]
  • Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways
    biomolecules Article Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways Aayushi Srivastava 1,2,3,4 , Abhishek Kumar 1,5,6 , Sara Giangiobbe 1, Elena Bonora 7, Kari Hemminki 1, Asta Försti 1,2,3 and Obul Reddy Bandapalli 1,2,3,* 1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; [email protected] (A.S.); [email protected] (A.K.); [email protected] (S.G.); [email protected] (K.H.); [email protected] (A.F.) 2 Hopp Children’s Cancer Center (KiTZ), D-69120 Heidelberg, Germany 3 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), D-69120 Heidelberg, Germany 4 Medical Faculty, Heidelberg University, D-69120 Heidelberg, Germany 5 Institute of Bioinformatics, International Technology Park, Bangalore 560066, India 6 Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India 7 S.Orsola-Malphigi Hospital, Unit of Medical Genetics, 40138 Bologna, Italy; [email protected] * Correspondence: [email protected]; Tel.: +49-6221-42-1709 Received: 29 August 2019; Accepted: 10 October 2019; Published: 13 October 2019 Abstract: Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family.
    [Show full text]
  • Natural Genetic Variation Caused by Small Insertions and Deletions in the Human Genome
    Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Research Natural genetic variation caused by small insertions and deletions in the human genome Ryan E. Mills,1,8 W. Stephen Pittard,2 Julienne M. Mullaney,3,4 Umar Farooq,3 Todd H. Creasy,3 Anup A. Mahurkar,3 David M. Kemeza,3 Daniel S. Strassler,3 Chris P. Ponting,5 Caleb Webber,5 and Scott E. Devine1,3,4,6,7,9 1Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA; 2Bimcore, Emory University, Atlanta, Georgia 30322, USA; 3Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA; 4Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA; 5MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom; 6Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA; 7Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA Human genetic variation is expected to play a central role in personalized medicine. Yet only a fraction of the natural genetic variation that is harbored by humans has been discovered to date. Here we report almost 2 million small insertions and deletions (INDELs) that range from 1 bp to 10,000 bp in length in the genomes of 79 diverse humans. These variants include 819,363 small INDELs that map to human genes. Small INDELs frequently were found in the coding exons of these genes, and several lines of evidence indicate that such variation is a major determinant of human biological diversity.
    [Show full text]
  • 1 Novel Expression Signatures Identified by Transcriptional Analysis
    ARD Online First, published on October 7, 2009 as 10.1136/ard.2009.108043 Ann Rheum Dis: first published as 10.1136/ard.2009.108043 on 7 October 2009. Downloaded from Novel expression signatures identified by transcriptional analysis of separated leukocyte subsets in SLE and vasculitis 1Paul A Lyons, 1Eoin F McKinney, 1Tim F Rayner, 1Alexander Hatton, 1Hayley B Woffendin, 1Maria Koukoulaki, 2Thomas C Freeman, 1David RW Jayne, 1Afzal N Chaudhry, and 1Kenneth GC Smith. 1Cambridge Institute for Medical Research and Department of Medicine, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0XY, UK 2Roslin Institute, University of Edinburgh, Roslin, Midlothian, EH25 9PS, UK Correspondence should be addressed to Dr Paul Lyons or Prof Kenneth Smith, Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0XY, UK. Telephone: +44 1223 762642, Fax: +44 1223 762640, E-mail: [email protected] or [email protected] Key words: Gene expression, autoimmune disease, SLE, vasculitis Word count: 2,906 The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in Annals of the Rheumatic Diseases and any other BMJPGL products to exploit all subsidiary rights, as set out in their licence (http://ard.bmj.com/ifora/licence.pdf). http://ard.bmj.com/ on September 29, 2021 by guest. Protected copyright. 1 Copyright Article author (or their employer) 2009.
    [Show full text]
  • The Clinical Significance of Small Copy Number Variants In
    JMG Online First, published on August 8, 2014 as 10.1136/jmedgenet-2014-102588 Genome-wide studies J Med Genet: first published as 10.1136/jmedgenet-2014-102588 on 8 August 2014. Downloaded from ORIGINAL ARTICLE The clinical significance of small copy number variants in neurodevelopmental disorders Reza Asadollahi,1 Beatrice Oneda,1 Pascal Joset,1 Silvia Azzarello-Burri,1 Deborah Bartholdi,1 Katharina Steindl,1 Marie Vincent,1 Joana Cobilanschi,1 Heinrich Sticht,2 Rosa Baldinger,1 Regina Reissmann,1 Irene Sudholt,1 Christian T Thiel,3 Arif B Ekici,3 André Reis,3 Emilia K Bijlsma,4 Joris Andrieux,5 Anne Dieux,6 David FitzPatrick,7 Susanne Ritter,8 Alessandra Baumer,1 Beatrice Latal,8 Barbara Plecko,9 Oskar G Jenni,8 Anita Rauch1 ▸ Additional material is ABSTRACT complex syndromes.23Due to the extensive aetio- published online only. To view Background Despite abundant evidence for logical heterogeneity of NDDs, the majority of please visit the journal online (http://dx.doi.org/10.1136/ pathogenicity of large copy number variants (CNVs) in patients remain without aetiological diagnosis, jmedgenet-2014-102588). neurodevelopmental disorders (NDDs), the individual which hampers disease management, genetic coun- significance of genome-wide rare CNVs <500 kb has not selling and in-depth studies of the underlying For numbered affiliations see end of article. been well elucidated in a clinical context. molecular mechanisms. With the advent of new Methods By high-resolution chromosomal microarray genomic technologies, however, diagnostic yield is Correspondence to analysis, we investigated the clinical significance of all steadily improving and a rapidly growing number Professor Anita Rauch, Institute rare non-polymorphic exonic CNVs sizing 1–500 kb in a of novel, aetiologically defined disorders are of Medical Genetics, University of Zurich, Wagistrasse 12, cohort of 714 patients with undiagnosed NDDs.
    [Show full text]
  • RUVBL1 Antibody Cat
    RUVBL1 Antibody Cat. No.: 60-402 RUVBL1 Antibody Formalin-fixed and paraffin-embedded human skeletal Flow cytometry analysis of MCF-7 cells (bottom histogram) muscle reacted with RUVBL1 Antibody, which was compared to a negative control cell (top histogram).FITC- peroxidase-conjugated to the secondary antibody, conjugated goat-anti-rabbit secondary antibodies were followed by DAB staining. used for the analysis. Western blot analysis of RUVBL1 using rabbit polyclonal RUVBL1 Antibody using 293 cell lysates (2 ug/lane) either nontransfected (Lane 1) or transiently transfected (Lane 2) with the RUVBL1 gene. Specifications September 27, 2021 1 https://www.prosci-inc.com/ruvbl1-antibody-60-402.html HOST SPECIES: Rabbit SPECIES REACTIVITY: Human This RUVBL1 antibody is generated from rabbits immunized with human RUVBL1 IMMUNOGEN: recombinant protein. TESTED APPLICATIONS: Flow, IHC-P, WB For WB starting dilution is: 1:1000 APPLICATIONS: For IHC-P starting dilution is: 1:50~100 For FACS starting dilution is: 1:10~50 PREDICTED MOLECULAR 50 kDa WEIGHT: Properties This antibody is purified through a protein A column, followed by peptide affinity PURIFICATION: purification. CLONALITY: Polyclonal ISOTYPE: Rabbit Ig CONJUGATE: Unconjugated PHYSICAL STATE: Liquid BUFFER: Supplied in PBS with 0.09% (W/V) sodium azide. CONCENTRATION: batch dependent Store at 4˚C for three months and -20˚C, stable for up to one year. As with all antibodies STORAGE CONDITIONS: care should be taken to avoid repeated freeze thaw cycles. Antibodies should not be exposed to
    [Show full text]
  • Anti-RUVBL1 / Pontin Antibody [1D6] (ARG57073)
    Product datasheet [email protected] ARG57073 Package: 50 μl anti-RUVBL1 / Pontin antibody [1D6] Store at: -20°C Summary Product Description Mouse Monoclonal antibody [1D6] recognizes RUVBL1 / Pontin Tested Reactivity Hu Tested Application ICC/IF, WB Host Mouse Clonality Monoclonal Clone 1D6 Isotype IgG2a, kappa Target Name RUVBL1 / Pontin Antigen Species Human Immunogen Recombinant fragment around aa. 1-456 of Human RUVBL1 / Pontin. Conjugation Un-conjugated Alternate Names ECP-54; Pontin 52; 49 kDa TATA box-binding protein-interacting protein; ECP54; TIP49A; NMP238; EC 3.6.4.12; RuvB-like 1; TIH1; TIP49a; TIP60-associated protein 54-alpha; NMP 238; PONTIN; INO80 complex subunit H; Nuclear matrix protein 238; RVB1; INO80H; 54 kDa erythrocyte cytosolic protein; 49 kDa TBP-interacting protein; Pontin52; TIP49; TAP54-alpha Application Instructions Application table Application Dilution ICC/IF Assay-dependent WB Assay-dependent Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Calculated Mw 50 kDa Properties Form Liquid Purification Purification with Protein A. Buffer PBS (pH 7.4), 0.02% Sodium azide and 10% Glycerol. Preservative 0.02% Sodium azide Stabilizer 10% Glycerol Concentration 1 mg/ml Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw www.arigobio.com 1/3 cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. Note For laboratory research only, not for drug, diagnostic or other use.
    [Show full text]
  • Supplementary Material and Methods
    Supplementary Material and Methods Patients, controls and tissue handling Fresh frozen lymphoma biopsies were obtained from100 newly diagnosed cases of DLBCL. The diagnoses were based on standard histology and immunphenotyping according to the 2008 WHO lymphoma classification.1 The fraction of tumor cells was scored, and samples with more than 50% and 80% tumor cells were selected for DNA and RNA extraction, respectively. Peripheral blood B-lymphocytes (PBL-B) were obtained from random, anonymous donors and isolated using CD19+ selection kit on a RoboSep Device (Stemcell). Genomic DNA was isolated after proteinase K digestion using the Purescript DNA Isolation Kit (Gentra Systems). Paraffin- embedded tissue from the same patient with no morphological signs of DLBCL (“normal control tissue”) was used as control material. The allelic frequencies of the lymphoma associated sequence variants were analysed in 500 other alleles from the Danish population. Clinical data were obtained from the patient files and from the Danish lymphoma registry LYFO. All patients were treated with antracyclin containing regimens, however only 21 patients received immunotherapy with Rituximab. Approval of this study was obtained from the regional ethical committee. Cell lines Diffuse large B-cell derived lymphoma cell lines: Farage, DB1, HT, RL, and Toledo were purchased from the American Type Culture Collection (ATCC). The cells were cultured in RPMI 1640 medium with Glutamax supplemented with 10% fetal calf serum. Mutation detection 1 Detection of TET2 mutations The melting characteristics of each exonic region were calculated and appropriate GC- and AT- clamps were included in the PCR primers to modulate the melting properties into a two-domain profile.2 For TET2 sequences, PCR was performed in 15- L reactions containing 10 mM Tris- HCl (pH 9.0), 50 mM KCl, 1.5 mM MgCl2, 0.2 mM cresol red, 12% sucrose, 10 pmol of each primer, 100 µM each dNTP, 10 ng of genomic DNA, and 0.8 units of hot-star Taq polymerase.
    [Show full text]
  • Modeling Cancer Driver Events in Vitro Using Barrier Bypass-Clonal Expansion Assays and Massively Parallel Sequencing
    OPEN Oncogene (2017) 36, 6041–6048 www.nature.com/onc ORIGINAL ARTICLE Modeling cancer driver events in vitro using barrier bypass-clonal expansion assays and massively parallel sequencing H Huskova1,2, M Ardin1, A Weninger3, K Vargova4, S Barrin5, S Villar1, M Olivier1, T Stopka2, Z Herceg6, M Hollstein1,3,7, J Zavadil1 and M Korenjak1 The information on candidate cancer driver alterations available from public databases is often descriptive and of limited mechanistic insight, which poses difficulties for reliable distinction between true driver and passenger events. To address this challenge, we performed in-depth analysis of whole-exome sequencing data from cell lines generated by a barrier bypass-clonal expansion (BBCE) protocol. The employed strategy is based on carcinogen-driven immortalization of primary mouse embryonic fibroblasts and recapitulates early steps of cell transformation. Among the mutated genes were almost 200 COSMIC Cancer Gene Census genes, many of which were recurrently affected in the set of 25 immortalized cell lines. The alterations affected pathways regulating DNA damage response and repair, transcription and chromatin structure, cell cycle and cell death, as well as developmental pathways. The functional impact of the mutations was strongly supported by the manifestation of several known cancer hotspot mutations among the identified alterations. We identified a new set of genes encoding subunits of the BAF chromatin remodeling complex that exhibited Ras-mediated dependence on PRC2 histone methyltransferase activity, a finding that is similar to what has been observed for other BAF subunits in cancer cells. Among the affected BAF complex subunits, we determined Smarcd2 and Smarcc1 as putative driver candidates not yet fully identified by large- scalecancergenomesequencingprojects.Inaddition,Ep400 displayed characteristics of a driver gene in that it showed a mutually exclusive mutation pattern when compared with mutations in the Trrap subunit of the TIP60 complex, both in the cell line panel and in a human tumor data set.
    [Show full text]
  • Function and Regulation of the Tip60-P400 Complex in Embryonic Stem Cells: a Dissertation
    University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2015-08-13 Function and Regulation of the Tip60-p400 Complex in Embryonic Stem Cells: A Dissertation Poshen B. Chen University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Cell Biology Commons, Developmental Biology Commons, and the Genetics and Genomics Commons Repository Citation Chen PB. (2015). Function and Regulation of the Tip60-p400 Complex in Embryonic Stem Cells: A Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/M2SW20. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/785 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. i Function and regulation of the Tip60-p400 complex in embryonic stem cells A Dissertation Presented By Poshen Chen Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY August 13, 2015 INTERDISCIPLINARY GRADUATE PROGRAM ii A Dissertation Presented By POSHEN CHEN The signatures of the Dissertation Defense Committee signify completion and approval as to style and content of the Dissertation Thomas Fazzio Ph.D., Thesis Advisor Jennifer Benanti Ph.D., Member of Committee Paul Kaufman Ph.D., Member of Committee Erica Larschan Ph.D., Member of Committee Craig Peterson Ph.D., Member of Committee The signature of the Chair of the Committee signifies that the written dissertation meets the requirements of the Dissertation Committee Oliver Rando M.D.
    [Show full text]
  • Pan-Cancer Multi-Omics Analysis and Orthogonal Experimental Assessment of Epigenetic Driver Genes
    Downloaded from genome.cshlp.org on October 9, 2021 - Published by Cold Spring Harbor Laboratory Press Resource Pan-cancer multi-omics analysis and orthogonal experimental assessment of epigenetic driver genes Andrea Halaburkova, Vincent Cahais, Alexei Novoloaca, Mariana Gomes da Silva Araujo, Rita Khoueiry,1 Akram Ghantous,1 and Zdenko Herceg1 Epigenetics Group, International Agency for Research on Cancer (IARC), 69008 Lyon, France The recent identification of recurrently mutated epigenetic regulator genes (ERGs) supports their critical role in tumorigen- esis. We conducted a pan-cancer analysis integrating (epi)genome, transcriptome, and DNA methylome alterations in a cu- rated list of 426 ERGs across 33 cancer types, comprising 10,845 tumor and 730 normal tissues. We found that, in addition to mutations, copy number alterations in ERGs were more frequent than previously anticipated and tightly linked to ex- pression aberrations. Novel bioinformatics approaches, integrating the strengths of various driver prediction and multi- omics algorithms, and an orthogonal in vitro screen (CRISPR-Cas9) targeting all ERGs revealed genes with driver roles with- in and across malignancies and shared driver mechanisms operating across multiple cancer types and hallmarks. This is the largest and most comprehensive analysis thus far; it is also the first experimental effort to specifically identify ERG drivers (epidrivers) and characterize their deregulation and functional impact in oncogenic processes. [Supplemental material is available for this article.] Although it has long been known that human cancers harbor both gression, potentially acting as oncogenes or tumor suppressors genetic and epigenetic changes, with an intricate interplay be- (Plass et al. 2013; Vogelstein et al. 2013).
    [Show full text]
  • Anti-TIP49 / RUVBL1 Antibody (Aa1-268) Rabbit Anti Human Polyclonal Antibody Catalog # ALS17399
    10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 Anti-TIP49 / RUVBL1 Antibody (aa1-268) Rabbit Anti Human Polyclonal Antibody Catalog # ALS17399 Specification Anti-TIP49 / RUVBL1 Antibody (aa1-268) - Product Information Application WB, IHC-P Primary Accession Q9Y265 Predicted Human Host Rabbit Clonality Polyclonal Calculated MW 50228 Anti-TIP49 / RUVBL1 Antibody (aa1-268) - Additional Information Gene ID 8607 Alias Symbol RUVBL1 Other Names RUVBL1, 49 kDa TBP-interacting protein, ECP54, INO80 complex subunit H, INO80H, Nuclear matrix protein 238, Pontin52, RuvB-like 1, TIH1, TAP54-alpha, TIP49, NMP 238, PONTIN, RuvB (E coli homolog)-like 1, RuvB-like 1 (E. coli), ECP-54, NMP238, Pontin ... Target/Specificity Human TIP49 / RUVBL1 Reconstitution & Storage PBS, 0.05% sodium azide. Store at 4°C short term. Aliquot and store at -20°C long term. Avoid freeze-thaw cycles. Precautions Anti-TIP49 / RUVBL1 Antibody (aa1-268) is for research use only and not for use in diagnostic or therapeutic procedures. Anti-TIP49 / RUVBL1 Antibody (aa1-268) - Protein Information Name RUVBL1 (HGNC:10474) Function Possesses single-stranded DNA-stimulated ATPase and ATP- dependent DNA helicase Page 1/4 10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 (3' to 5') activity; hexamerization is thought to be critical for ATP hydrolysis and adjacent subunits in the ring- like structure contribute to the ATPase activity (PubMed:<a href="http://www.uniprot.org/c itations/17157868" target="_blank">17157868</a>). Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A (PubMed:<a href="htt p://www.uniprot.org/citations/14966270" target="_blank">14966270</a>).
    [Show full text]