DOCSLIB.ORG

Pathways Impacted by Genomic Alterations in Pulmonary Carcinoid Tumors Michael K

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Published OnlineFirst January 19, 2018; DOI: 10.1158/1078-0432.CCR-17-0252 Cancer Therapy: Preclinical Clinical Cancer Research Pathways Impacted by Genomic Alterations in Pulmonary Carcinoid Tumors Michael K. Asiedu1, Charles F. Thomas Jr2, Jie Dong1, Sandra C. Schulte1, Prasidda Khadka1, Zhifu Sun3, Farhad Kosari3, Jin Jen3, Julian Molina4, George Vasmatzis3, Ray Kuang5, Marie Christine Aubry3, Ping Yang3, and Dennis A.Wigle1 Abstract Purpose: Pulmonary carcinoid tumors account for up to 5% of RAB38, NF1, RAD51C, TAF1L, EPHB2, POLR3B,andAGFG1. all lung malignancies in adults, comprise 30% of all carcinoid The mutated genes are involved in biological processes includ- malignancies, and are defined histologically as typical carcinoid ing cellular metabolism, cell division cycle, cell death, (TC) and atypical carcinoid (AC) tumors. The role of specific apoptosis, and immune regulation. The top most significantly genomic alterations in the pathogenesis of pulmonary carcinoid mutated genes were TMEM41B, DEFB127, WDYHV1, and tumors remains poorly understood. We sought to identify geno- TBPL1. Pathway analysis of significantly mutated and cancer mic alterations and pathways that are deregulated in these tumors driver genes implicated MAPK/ERK and amyloid beta precur- to find novel therapeutic targets for pulmonary carcinoid tumors. sor protein (APP) pathways whereas analysis of CNV and Experimental Design: We performed integrated genomic anal- gene expression data suggested deregulation of the NF-kBand ysis of carcinoid tumors comprising whole genome and exome MAPK/ERK pathways. The mutation signature was predomi- sequencing, mRNA expression profiling and SNP genotyping of nantly C>T and T>C transitions with a minor contribution of specimens from normal lung, TC and AC, and small cell lung T>G transversions. carcinoma (SCLC) to fully represent the lung neuroendocrine Conclusions: This study identified mutated genes affecting tumor spectrum. cancer relevant pathways and biological processes that could Results: Analysis of sequencing data found recurrent muta- provide opportunities for developing targeted therapies for pul- tions in cancer genes including ATP1A2, CNNM1, MACF1, monary carcinoid tumors. Clin Cancer Res; 1–14. Ó2018 AACR. Introduction behavior, prognosis, and treatment response within the spectrum of pulmonary NETs (4). Unfortunately, an immense scientific gap Pulmonary neuroendocrine tumors (NET) include a spectrum exists in understanding the biology of these tumors, in part due to of tumors, classified as typical carcinoid (TC) tumors, atypical the lack of genomic information and suitable reagents such as cell carcinoid (AC) tumors, large-cell neuroendocrine carcinoma lines and tumor xenograft models. As a consequence, there have (LCNEC), and small-cell lung cancer (SCLC; ref. 1). Pulmonary been no major advances in the treatment and prognosis for these carcinoid tumors account for up to 5% of all lung cancers, and for cancers (2, 3, 5, 6). Currently, the only effective treatment to unclear reasons have shown the greatest increase in incidence achieve cure is complete surgical excision, which may be unat- compared with NETs from other sites from 1973 to 2005 accord- tainable depending upon the location and extent of the tumor. ing to epidemiological data from the SEER database (2, 3). Both chemotherapy and radiation therapy have limited success in Despite similarities in their morphology, structure, and immu- treating these tumors and therefore the outcome for patients with nohistochemistry, there are dramatic differences in clinical metastatic disease is poor. A recent study advancing the field by Fernandez-Cuesta and colleagues, examining genomic alterations 1 in pulmonary carcinoids using copy number analysis, exome/ Division of General Thoracic Surgery, Department of Surgery, Mayo Clinic fi College of Medicine, Rochester, Minnesota. 2Thoracic Diseases Research Unit, genome, and transcriptome sequencing identi ed recurrent muta- Division of Pulmonary, Critical Care, and Internal Medicine, Mayo Clinic College of tions in chromatin remodeling genes. The study found that 40% Medicine, Rochester, Minnesota. 3Department of Laboratory Medicine and of the cases studied harbored mutations in histone modifier genes Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota. 4Department such as MEN1, PSIP1, and ARID1A, and 20% of cases had 5 of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota. University mutations in the components of the SWI/SNF complex (7). The of Minnesota, Minneapolis, Minnesota. study found MEN1, ARID1A, and EIF1AX to be significantly Note: Supplementary data for this article are available at Clinical Cancer mutated (q < 0.2; ref. 7). These results remain to be confirmed Research Online (http://clincancerres.aacrjournals.org/). in further studies. Corresponding Authors: Michael K. Asiedu, Mayo Clinic, 200 First Street SW We analyzed genomic alterations in pulmonary carcinoid Rochester, 228 Medical Science Building, MN 55905. Phone: 507-284-3482; Fax: tumors using a variety of approaches, including mRNA expres- 507-266-1163; E-mail: [email protected]; and Dennis A. Wigle, Phone: sion, SNP genotyping, and a combination of exome, and whole 507-284-8462; Fax: 507-284-0058; E-mail: [email protected] genome sequencing. Hierarchical clustering of differentially doi: 10.1158/1078-0432.CCR-17-0252 expressed genes clearly segregated histologies of normal lung, Ó2018 American Association for Cancer Research. carcinoid, and SCLC from each other. Despite this, relatively little www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst January 19, 2018; DOI: 10.1158/1078-0432.CCR-17-0252 Asiedu et al. mutated genes. Pathway analysis of differentially expressed genes Translational Relevance with CNV changes identified the involvement of NF-kB and Pulmonary neuroendocrine tumors are classified into typ- MAPK/ERK signaling pathways. These results suggest several ical carcinoid tumors, atypical carcinoid tumors, small-cell potential opportunities for development of new therapeutic lung cancers, and large-cell neuroendocrine carcinoma. Com- approaches to treat pulmonary carcinoid tumors. plete surgical resection of the tumor remains the treatment of choice for cure in patients able to tolerate surgery. For patients Materials and Methods with tumors not amenable to surgical resection, there are This study was reviewed and approved by the Mayo Clinic currently no targeted therapies available and chemotherapeu- Institutional Review Board and the Biospecimen Protocol tic options have low response rates of 20% or less. There is Review Group. Informed consent was obtained prior to speci- therefore the need to identify genomic alterations and signal- men collection and medical chart review for each patient. ing pathways deregulated in these tumors to aid the develop- Prospectively collected samples of surgically resected TC tumors ment of alternative therapies. We performed integrated geno- n ¼ n ¼ n ¼ fi ( 39), AC tumors ( 12), SCLC ( 12), and corresponding mic analysis and identi ed recurrent mutated genes including n ¼ ATP1A2, CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, normal lung tissue ( 26) were obtained from the Mayo Clinic Lung Tissue Registry. Patient demographics, clinical, surgical EPHB2, POLR3B, and AGFG1. Pathway analysis of mutated and pathologic data, including tumor recurrence, tumor metas- genes implicated MAPK/ERK and APP signaling pathways tasis, and patient survival were extracted from medical records. whereas analysis of CNV and gene expression data identified The tumor stage was adjusted according to the seventh edition of deregulation of the NF-B and MAPK/ERK pathways. Targeting the TNM classification of malignant tumors (6, 8, 9). A summary recurrent mutated genes as well as ERK and NF-B pathways of the patient characteristics is provided in Table 1 and Supple- might represent therapeutic options for pulmonary carcinoid mentary Table S1. tumors. Sample acquisition and preparation The specimens utilized in this study were snap frozen in liquid nitrogen in the frozen section pathology laboratory within 30 separation was found between the 31 TC and 11 AC tumors in the minutes of resection and then transferred to À80C for permanent cohort. We also sequenced the exomes of 20 tumor–normal pairs storage in the Mayo Clinic Lung Tissue Registry. Prior to proces- and performed whole genome sequencing on a subset of 5 sing, the histology of the tumor specimens and the nonneoplastic tumor–normal pairs and found 126 functional and disease- histology of the matched surrounding normal lung tissue were causing mutations in 114 genes with known biological or clinical confirmed by a dedicated lung pathologist (M.C. Aubry). RNA significance. The overall number of genomic rearrangements and DNA extraction from macrodissected specimens was con- identified from whole genome sequencing showed a relatively ducted through the institutional Biospecimen Accessioning and low frequency of genomic rearrangements compared with that Processing (BAP) Shared Resource. present in lung adenocarcinoma from either smoker or non- smoker patients. Recurrent mutations were identified in ATP1A2, Gene expression profiling CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, EPHB2, RNA for gene expression analysis was extracted using the POLR3B, and AGFG1. RNeasy Mini Kit and TissueLyser (Qiagen) according to the We identified cancer relevant
Recommended publications
  • Epigenome-Wide Association Study of Wellbeing

    Epigenome-Wide Association Study of Wellbeing

    Twin Research and Human Genetics Volume 18 Number 6 pp. 710–719 C The Author(s) 2015 doi:10.1017/thg.2015.85 Epigenome-Wide Association Study of Wellbeing Bart M. L. Baselmans,1,2 Jenny van Dongen,1,2 Michel G. Nivard,1 Bochao D. Lin,1 BIOS Consortium,3 Nuno R. Zilhao,˜ 1 Dorret I. Boomsma,1,2,4 and Meike Bartels1,2,4 1Department of Biological Psychology, VU University, Amsterdam, the Netherlands 2EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands 3The Biobank-Based Integrative Omics Study (BIOS) Consortium 4Neuroscience Campus Amsterdam, Amsterdam, the Netherlands Wellbeing (WB) is a major topic of research across several scientific disciplines, partly driven by its strong association with psychological and mental health. Twin-family studies have found that both genotype and environment play an important role in explaining the variance in WB. Epigenetic mechanisms, such as DNA methylation, regulate gene expression, and may mediate genetic and environmental effects on WB. Here, for the first time, we apply an epigenome-wide association study (EWAS) approach to identify differentially methylated sites associated with individual differences in WB. Subjects were part of the longitudinal survey studies of the Netherlands Twin Register (NTR) and participated in the NTR biobank project between 2002 and 2011. WB was assessed by a short inventory that measures satisfaction with life (SAT). DNA methylation was measured in whole blood by the Illumina Infinium HumanMethylation450 BeadChip (HM450k array) and the association between WB and DNA methylation level was tested at 411,169 autosomal sites. Two sites (cg10845147, p = 1.51 ∗ 10-8 and cg01940273, p = 2.34 ∗ 10-8) reached genome-wide significance following Bonferonni correction.
  • A Misplaced Lncrna Causes Brachydactyly in Humans

    A Misplaced Lncrna Causes Brachydactyly in Humans

    A misplaced lncRNA causes brachydactyly in humans Philipp G. Maass, … , Friedrich C. Luft, Sylvia Bähring J Clin Invest. 2012;122(11):3990-4002. https://doi.org/10.1172/JCI65508. Research Article Translocations are chromosomal rearrangements that are frequently associated with a variety of disease states and developmental disorders. We identified 2 families with brachydactyly type E (BDE) resulting from different translocations affecting chromosome 12p. Both translocations caused downregulation of the parathyroid hormone-like hormone (PTHLH) gene by disrupting the cis-regulatory landscape. Using chromosome conformation capturing, we identified a regulator on chromosome 12q that interacts in cis with PTHLH over a 24.4-megabase distance and in trans with the sex- determining region Y-box 9 (SOX9) gene on chromosome 17q. The element also harbored a long noncoding RNA (lncRNA). Silencing of the lncRNA, PTHLH, or SOX9 revealed a feedback mechanism involving an expression-dependent network in humans. In the BDE patients, the human lncRNA was upregulated by the disrupted chromosomal association. Moreover, the lncRNA occupancy at the PTHLH locus was reduced. Our results document what we believe to be a novel in cis– and in trans–acting DNA and lncRNA regulatory feedback element that is reciprocally regulated by coding genes. Furthermore, our findings provide a systematic and combinatorial view of how enhancers encoding lncRNAs may affect gene expression in normal development. Find the latest version: https://jci.me/65508/pdf Research article Related Commentary, page 3837 A misplaced lncRNA causes brachydactyly in humans Philipp G. Maass,1,2 Andreas Rump,3 Herbert Schulz,2 Sigmar Stricker,4 Lisanne Schulze,1,2 Konrad Platzer,3 Atakan Aydin,1,2 Sigrid Tinschert,3 Mary B.
  • Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights Into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle

    Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights Into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle

    animals Article Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle Masoumeh Naserkheil 1 , Abolfazl Bahrami 1 , Deukhwan Lee 2,* and Hossein Mehrban 3 1 Department of Animal Science, University College of Agriculture and Natural Resources, University of Tehran, Karaj 77871-31587, Iran; [email protected] (M.N.); [email protected] (A.B.) 2 Department of Animal Life and Environment Sciences, Hankyong National University, Jungang-ro 327, Anseong-si, Gyeonggi-do 17579, Korea 3 Department of Animal Science, Shahrekord University, Shahrekord 88186-34141, Iran; [email protected] * Correspondence: [email protected]; Tel.: +82-31-670-5091 Received: 25 August 2020; Accepted: 6 October 2020; Published: 9 October 2020 Simple Summary: Hanwoo is an indigenous cattle breed in Korea and popular for meat production owing to its rapid growth and high-quality meat. Its yearling weight and carcass traits (backfat thickness, carcass weight, eye muscle area, and marbling score) are economically important for the selection of young and proven bulls. In recent decades, the advent of high throughput genotyping technologies has made it possible to perform genome-wide association studies (GWAS) for the detection of genomic regions associated with traits of economic interest in different species. In this study, we conducted a weighted single-step genome-wide association study which combines all genotypes, phenotypes and pedigree data in one step (ssGBLUP). It allows for the use of all SNPs simultaneously along with all phenotypes from genotyped and ungenotyped animals. Our results revealed 33 relevant genomic regions related to the traits of interest.
  • Anti-ALPPL2 Antibody (ARG58232)

    Anti-ALPPL2 Antibody (ARG58232)

    Product datasheet [email protected] ARG58232 Package: 100 μl anti-ALPPL2 antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes ALPPL2 Tested Reactivity Hu, Ms Tested Application WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name ALPPL2 Antigen Species Human Immunogen Recombinant fusion protein corresponding to aa. 20-280 of Human ALPPL2 (NP_112603.2). Conjugation Un-conjugated Alternate Names Alkaline phosphatase, placental-like; Placental alkaline phosphatase-like; PLAP-like; EC 3.1.3.1; Germ cell alkaline phosphatase; ALPG; Alkaline phosphatase Nagao isozyme; ALP-1; ALPPL; GCAP Application Instructions Application table Application Dilution WB 1:500 - 1:2000 Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Positive Control HeLa Calculated Mw 57 kDa Observed Size 70 kDa Properties Form Liquid Purification Affinity purified. Buffer PBS (pH 7.3), 0.02% Sodium azide and 50% Glycerol. Preservative 0.02% Sodium azide Stabilizer 50% Glycerol 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 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. www.arigobio.com 1/2 Bioinformation Gene Symbol ALPPL2 Gene Full Name alkaline phosphatase, placental-like 2 Background There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue non-specific).
  • Myopia Genetics Report

    Myopia Genetics Report

    Special Issue IMI – Myopia Genetics Report Milly S. Tedja,1,2 Annechien E. G. Haarman,1,2 Magda A. Meester-Smoor,1,2 Jaakko Kaprio,3,4 David A. Mackey,5–7 Jeremy A. Guggenheim,8 Christopher J. Hammond,9 Virginie J. M. Verhoeven,1,2,10 and Caroline C. W. Klaver1,2,11; for the CREAM Consortium 1Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands 2Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands 3Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland 4Department of Public Health, University of Helsinki, Helsinki, Finland 5Centre for Eye Research Australia, Ophthalmology, Department of Surgery, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia 6Department of Ophthalmology, Menzies Institute of Medical Research, University of Tasmania, Hobart, Tasmania, Australia 7Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia 8School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom 9Section of Academic Ophthalmology, School of Life Course Sciences, King’s College London, London, United Kingdom 10Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands 11Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands Correspondence: Caroline C. W. The knowledge on the genetic background of refractive error and myopia has expanded Klaver, Erasmus Medical Center, dramatically in the past few years. This white paper aims to provide a concise summary of Room Na-2808, P.O. Box 2040, 3000 current genetic findings and defines the direction where development is needed. CA, Rotterdam, the Netherlands; [email protected]. We performed an extensive literature search and conducted informal discussions with key MST and AEGH contributed equally to stakeholders.
  • Noelia Díaz Blanco

    Noelia Díaz Blanco

    Effects of environmental factors on the gonadal transcriptome of European sea bass (Dicentrarchus labrax), juvenile growth and sex ratios Noelia Díaz Blanco Ph.D. thesis 2014 Submitted in partial fulfillment of the requirements for the Ph.D. degree from the Universitat Pompeu Fabra (UPF). This work has been carried out at the Group of Biology of Reproduction (GBR), at the Department of Renewable Marine Resources of the Institute of Marine Sciences (ICM-CSIC). Thesis supervisor: Dr. Francesc Piferrer Professor d’Investigació Institut de Ciències del Mar (ICM-CSIC) i ii A mis padres A Xavi iii iv Acknowledgements This thesis has been made possible by the support of many people who in one way or another, many times unknowingly, gave me the strength to overcome this "long and winding road". First of all, I would like to thank my supervisor, Dr. Francesc Piferrer, for his patience, guidance and wise advice throughout all this Ph.D. experience. But above all, for the trust he placed on me almost seven years ago when he offered me the opportunity to be part of his team. Thanks also for teaching me how to question always everything, for sharing with me your enthusiasm for science and for giving me the opportunity of learning from you by participating in many projects, collaborations and scientific meetings. I am also thankful to my colleagues (former and present Group of Biology of Reproduction members) for your support and encouragement throughout this journey. To the “exGBRs”, thanks for helping me with my first steps into this world. Working as an undergrad with you Dr.
  • Fine-Mapping of 150 Breast Cancer Risk Regions Identifies 178 High Confidence Target Genes

    Fine-Mapping of 150 Breast Cancer Risk Regions Identifies 178 High Confidence Target Genes

    bioRxiv preprint doi: https://doi.org/10.1101/521054; this version posted January 15, 2019. 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. Fine-mapping of 150 breast cancer risk regions identifies 178 high confidence target genes Laura Fachal1, Hugues Aschard2-4,275, Jonathan Beesley5,275, Daniel R. Barnes6, Jamie Allen6, Siddhartha Kar1, Karen A. Pooley6, Joe Dennis6, Kyriaki Michailidou6, 7, Constance Turman4, Penny Soucy8, Audrey Lemaçon8, Michael Lush6, Jonathan P. Tyrer1, Maya Ghoussaini1, Mahdi Moradi Marjaneh5, Xia Jiang3, Simona Agata9, Kristiina Aittomäki10, M. Rosario Alonso11, Irene L. Andrulis12, 13, Hoda Anton-Culver14, Natalia N. Antonenkova15, Adalgeir Arason16, 17, Volker Arndt18, Kristan J. Aronson19, Banu K. Arun20, Bernd Auber21, Paul L. Auer22, 23, Jacopo Azzollini24, Judith Balmaña25, Rosa B. Barkardottir16, 17, Daniel Barrowdale6, Alicia Beeghly-Fadiel26, Javier Benitez27, 28, Marina Bermisheva29, Katarzyna Białkowska30, Amie M. Blanco31, Carl Blomqvist32, 33, William Blot26, 34, Natalia V. Bogdanova15, 35, 36, Stig E. Bojesen37- 39, Manjeet K. Bolla6, Bernardo Bonanni40, Ake Borg41, Kristin Bosse42, Hiltrud Brauch43-45, Hermann Brenner18, 45, 46, Ignacio Briceno47, 48, Ian W. Brock49, Angela Brooks-Wilson50, 51, Thomas Brüning52, Barbara Burwinkel53, 54, Saundra S. Buys55, Qiuyin Cai26, Trinidad Caldés56, Maria A. Caligo57, Nicola J. Camp58, Ian Campbell59, 60, Federico Canzian61, Jason S. Carroll62, Brian D. Carter63, Jose E. Castelao64, Jocelyne Chiquette65, Hans Christiansen35, Wendy K. Chung66, Kathleen B.M. Claes67, Christine L. Clarke68, GEMO Study Collaborators69-71, EMBRACE Collaborators6, J.
  • (P -Value&lt;0.05, Fold Change≥1.4), 4 Vs. 0 Gy Irradiation

    (P -Value<0.05, Fold Change≥1.4), 4 Vs. 0 Gy Irradiation

    Table S1: Significant differentially expressed genes (P -Value<0.05, Fold Change≥1.4), 4 vs. 0 Gy irradiation Genbank Fold Change P -Value Gene Symbol Description Accession Q9F8M7_CARHY (Q9F8M7) DTDP-glucose 4,6-dehydratase (Fragment), partial (9%) 6.70 0.017399678 THC2699065 [THC2719287] 5.53 0.003379195 BC013657 BC013657 Homo sapiens cDNA clone IMAGE:4152983, partial cds. [BC013657] 5.10 0.024641735 THC2750781 Ciliary dynein heavy chain 5 (Axonemal beta dynein heavy chain 5) (HL1). 4.07 0.04353262 DNAH5 [Source:Uniprot/SWISSPROT;Acc:Q8TE73] [ENST00000382416] 3.81 0.002855909 NM_145263 SPATA18 Homo sapiens spermatogenesis associated 18 homolog (rat) (SPATA18), mRNA [NM_145263] AA418814 zw01a02.s1 Soares_NhHMPu_S1 Homo sapiens cDNA clone IMAGE:767978 3', 3.69 0.03203913 AA418814 AA418814 mRNA sequence [AA418814] AL356953 leucine-rich repeat-containing G protein-coupled receptor 6 {Homo sapiens} (exp=0; 3.63 0.0277936 THC2705989 wgp=1; cg=0), partial (4%) [THC2752981] AA484677 ne64a07.s1 NCI_CGAP_Alv1 Homo sapiens cDNA clone IMAGE:909012, mRNA 3.63 0.027098073 AA484677 AA484677 sequence [AA484677] oe06h09.s1 NCI_CGAP_Ov2 Homo sapiens cDNA clone IMAGE:1385153, mRNA sequence 3.48 0.04468495 AA837799 AA837799 [AA837799] Homo sapiens hypothetical protein LOC340109, mRNA (cDNA clone IMAGE:5578073), partial 3.27 0.031178378 BC039509 LOC643401 cds. [BC039509] Homo sapiens Fas (TNF receptor superfamily, member 6) (FAS), transcript variant 1, mRNA 3.24 0.022156298 NM_000043 FAS [NM_000043] 3.20 0.021043295 A_32_P125056 BF803942 CM2-CI0135-021100-477-g08 CI0135 Homo sapiens cDNA, mRNA sequence 3.04 0.043389246 BF803942 BF803942 [BF803942] 3.03 0.002430239 NM_015920 RPS27L Homo sapiens ribosomal protein S27-like (RPS27L), mRNA [NM_015920] Homo sapiens tumor necrosis factor receptor superfamily, member 10c, decoy without an 2.98 0.021202829 NM_003841 TNFRSF10C intracellular domain (TNFRSF10C), mRNA [NM_003841] 2.97 0.03243901 AB002384 C6orf32 Homo sapiens mRNA for KIAA0386 gene, partial cds.
  • (12) United States Patent (10) Patent No.: US 7.873,482 B2 Stefanon Et Al

    (12) United States Patent (10) Patent No.: US 7.873,482 B2 Stefanon Et Al

    US007873482B2 (12) United States Patent (10) Patent No.: US 7.873,482 B2 Stefanon et al. (45) Date of Patent: Jan. 18, 2011 (54) DIAGNOSTIC SYSTEM FOR SELECTING 6,358,546 B1 3/2002 Bebiak et al. NUTRITION AND PHARMACOLOGICAL 6,493,641 B1 12/2002 Singh et al. PRODUCTS FOR ANIMALS 6,537,213 B2 3/2003 Dodds (76) Inventors: Bruno Stefanon, via Zilli, 51/A/3, Martignacco (IT) 33035: W. Jean Dodds, 938 Stanford St., Santa Monica, (Continued) CA (US) 90403 FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 WO WO99-67642 A2 12/1999 U.S.C. 154(b) by 158 days. (21)21) Appl. NoNo.: 12/316,8249 (Continued) (65) Prior Publication Data Swanson, et al., “Nutritional Genomics: Implication for Companion Animals'. The American Society for Nutritional Sciences, (2003).J. US 2010/O15301.6 A1 Jun. 17, 2010 Nutr. 133:3033-3040 (18 pages). (51) Int. Cl. (Continued) G06F 9/00 (2006.01) (52) U.S. Cl. ........................................................ 702/19 Primary Examiner—Edward Raymond (58) Field of Classification Search ................... 702/19 (74) Attorney, Agent, or Firm Greenberg Traurig, LLP 702/23, 182–185 See application file for complete search history. (57) ABSTRACT (56) References Cited An analysis of the profile of a non-human animal comprises: U.S. PATENT DOCUMENTS a) providing a genotypic database to the species of the non 3,995,019 A 1 1/1976 Jerome human animal Subject or a selected group of the species; b) 5,691,157 A 1 1/1997 Gong et al.
  • Supplementary Table 1 Genes Tested in Qrt-PCR in Nfpas

    Supplementary Table 1 Genes Tested in Qrt-PCR in Nfpas

    Supplementary Table 1 Genes tested in qRT-PCR in NFPAs Gene Bank accession Gene Description number ABI assay ID a disintegrin-like and metalloprotease with thrombospondin type 1 motif 7 ADAMTS7 NM_014272.3 Hs00276223_m1 Rho guanine nucleotide exchange factor (GEF) 3 ARHGEF3 NM_019555.1 Hs00219609_m1 BCL2-associated X protein BAX NM_004324 House design Bcl-2 binding component 3 BBC3 NM_014417.2 Hs00248075_m1 B-cell CLL/lymphoma 2 BCL2 NM_000633 House design Bone morphogenetic protein 7 BMP7 NM_001719.1 Hs00233476_m1 CCAAT/enhancer binding protein (C/EBP), alpha CEBPA NM_004364.2 Hs00269972_s1 coxsackie virus and adenovirus receptor CXADR NM_001338.3 Hs00154661_m1 Homo sapiens Dicer1, Dcr-1 homolog (Drosophila) (DICER1) DICER1 NM_177438.1 Hs00229023_m1 Homo sapiens dystonin DST NM_015548.2 Hs00156137_m1 fms-related tyrosine kinase 3 FLT3 NM_004119.1 Hs00174690_m1 glutamate receptor, ionotropic, N-methyl D-aspartate 1 GRIN1 NM_000832.4 Hs00609557_m1 high-mobility group box 1 HMGB1 NM_002128.3 Hs01923466_g1 heterogeneous nuclear ribonucleoprotein U HNRPU NM_004501.3 Hs00244919_m1 insulin-like growth factor binding protein 5 IGFBP5 NM_000599.2 Hs00181213_m1 latent transforming growth factor beta binding protein 4 LTBP4 NM_001042544.1 Hs00186025_m1 microtubule-associated protein 1 light chain 3 beta MAP1LC3B NM_022818.3 Hs00797944_s1 matrix metallopeptidase 17 MMP17 NM_016155.4 Hs01108847_m1 myosin VA MYO5A NM_000259.1 Hs00165309_m1 Homo sapiens nuclear factor (erythroid-derived 2)-like 1 NFE2L1 NM_003204.1 Hs00231457_m1 oxoglutarate (alpha-ketoglutarate)
  • Single Cell Derived Clonal Analysis of Human Glioblastoma Links

    Single Cell Derived Clonal Analysis of Human Glioblastoma Links

    SUPPLEMENTARY INFORMATION: Single cell derived clonal analysis of human glioblastoma links functional and genomic heterogeneity ! Mona Meyer*, Jüri Reimand*, Xiaoyang Lan, Renee Head, Xueming Zhu, Michelle Kushida, Jane Bayani, Jessica C. Pressey, Anath Lionel, Ian D. Clarke, Michael Cusimano, Jeremy Squire, Stephen Scherer, Mark Bernstein, Melanie A. Woodin, Gary D. Bader**, and Peter B. Dirks**! ! * These authors contributed equally to this work.! ** Correspondence: [email protected] or [email protected]! ! Supplementary information - Meyer, Reimand et al. Supplementary methods" 4" Patient samples and fluorescence activated cell sorting (FACS)! 4! Differentiation! 4! Immunocytochemistry and EdU Imaging! 4! Proliferation! 5! Western blotting ! 5! Temozolomide treatment! 5! NCI drug library screen! 6! Orthotopic injections! 6! Immunohistochemistry on tumor sections! 6! Promoter methylation of MGMT! 6! Fluorescence in situ Hybridization (FISH)! 7! SNP6 microarray analysis and genome segmentation! 7! Calling copy number alterations! 8! Mapping altered genome segments to genes! 8! Recurrently altered genes with clonal variability! 9! Global analyses of copy number alterations! 9! Phylogenetic analysis of copy number alterations! 10! Microarray analysis! 10! Gene expression differences of TMZ resistant and sensitive clones of GBM-482! 10! Reverse transcription-PCR analyses! 11! Tumor subtype analysis of TMZ-sensitive and resistant clones! 11! Pathway analysis of gene expression in the TMZ-sensitive clone of GBM-482! 11! Supplementary figures and tables" 13" "2 Supplementary information - Meyer, Reimand et al. Table S1: Individual clones from all patient tumors are tumorigenic. ! 14! Fig. S1: clonal tumorigenicity.! 15! Fig. S2: clonal heterogeneity of EGFR and PTEN expression.! 20! Fig. S3: clonal heterogeneity of proliferation.! 21! Fig.
  • Fine-Mapping of 150 Breast Cancer Risk Regions Identifies 191 Likely Target Genes

    Fine-Mapping of 150 Breast Cancer Risk Regions Identifies 191 Likely Target Genes

    Europe PMC Funders Group Author Manuscript Nat Genet. Author manuscript; available in PMC 2020 July 07. Published in final edited form as: Nat Genet. 2020 January ; 52(1): 56–73. doi:10.1038/s41588-019-0537-1. Europe PMC Funders Author Manuscripts Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes A full list of authors and affiliations appears at the end of the article. # These authors contributed equally to this work. Abstract Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms *Correspondence: [email protected] (PK), [email protected] (AMD). 280Senior author. Europe PMC Funders Author Manuscripts Data Availablity The credible set of causal variants (determined by either multinomial stepwise regression and PAINTOR) is provided in Supplementary Table S2C.