DOCSLIB.ORG

Molecular Classification of Renal Tumors by Gene Expression Profiling

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Molecular Classification of Renal Tumors by Gene Expression Profiling Journal of Molecular Diagnostics, Vol. 7, No. 2, May 2005 Copyright © American Society for Investigative Pathology and the Association for Molecular Pathology Molecular Classification of Renal Tumors by Gene Expression Profiling Audrey N. Schuetz,* Qiqin Yin-Goen,*† Renal cell carcinoma (RCC) is the most common malig- Mahul B. Amin,*‡§ Carlos S. Moreno,*‡ nancy of the adult kidney, comprising 3% of all human 1 Cynthia Cohen,* Christopher D. Hornsby,* cancers. Localized tumors can be detected by abdom- 2 Wen Li Yang,*† John A. Petros,*†‡§ inal imaging and cured by surgery. However, 25 to 40% of cases present with extrarenal growth or metastases,3 Muta M. Issa,†§ John G. Pattaras,§ § § and one-third of apparently localized lesions develop Kenneth Ogan, Fray F. Marshall, and metastases during the postoperative course.4,5 Ad- † Andrew N. Young* vanced RCC responds poorly to systemic therapy and From the Departments of Pathology and Laboratory Medicine* has a 5-year survival rate of less than 10%.6,7 and Urology,§ and the Winship Cancer Institute,‡ Emory Important predictors of outcome for RCC include tumor University School of Medicine, Atlanta; and the Atlanta Veterans stage, Fuhrman nuclear grade, histopathological classi- 3,8–10 Affairs Medical Center,† Decatur, Georgia fication, and perioperative thrombocytosis. The cur- rent renal tumor classification system is based on mor- phology, as well as underlying genetic differences.3,11,12 More than 90% of clinically significant lesions can be diagnosed as one of the common subtypes of renal ep- Renal tumor classification is important because his- ithelial tumor: clear cell (conventional) RCC, papillary topathological subtypes are associated with distinct RCC, chromophobe RCC, and renal oncocytoma. Mes- clinical behavior. However, diagnosis is difficult be- enchymal renal tumors are more rare and include angio- cause tumor subtypes have overlapping microscopic myolipoma. Recent clinicopathological surveys have in- characteristics. Therefore, ancillary methods are dicated that clear cell RCC has the highest rate of needed to optimize classification. We used oligonucle- metastasis and poorest survival among common renal otide microarrays to analyze 31 adult renal tumors, malignancies.3 Papillary and chromophobe carcinomas including clear cell renal cell carcinoma (RCC), pap- are relatively indolent but exhibit potential for metastasis illary RCC, chromophobe RCC, oncocytoma, and an- and transformation to high-grade, sarcomatoid tumors. In giomyolipoma. Expression profiles correlated with contrast, typical oncocytomas and angiomyolipomas are histopathology; unsupervised algorithms clustered 30 considered benign neoplasms. of 31 tumors according to appropriate diagnostic sub- Renal tumor subtypes exhibit several common mor- types while supervised analyses identified significant, phological characteristics, making diagnosis difficult and subtype-specific expression markers. Clear cell RCC subjective in many cases. For instance, eosinophilic vari- overexpressed proximal nephron, angiogenic, and ants of clear cell and chromophobe RCC can closely immune response genes, chromophobe RCC oncocy- resemble the benign oncocytoma histologically. There- toma overexpressed distal nephron and oxidative fore, ancillary molecular methods are needed for optimal phosphorylation genes, papillary RCC overexpressed diagnosis and clinical management. In several types of serine protease inhibitors, and extracellular matrix human cancer, gene expression microarrays have products, and angiomyolipoma overexpressed mus- proved to be effective tools for classifying tumors and cle developmental, lipid biosynthetic, melanocytic, identifying novel molecular biomarkers.13–16 Previously, and distinct angiogenic factors. Quantitative reverse we used microarrays to profile gene expression in clear transcriptase-polymerase chain reaction and immu- cell RCC, papillary RCC, chromophobe RCC, and onco- nohistochemistry of formalin-fixed renal tumors con- firmed overexpression of proximal nephron markers (megalin/low-density lipoprotein-related protein 2, Supported by a Veterans Affairs merit review grant (to A.N.Y.). ␣ -methylacyl CoA racemase) in clear cell and papil- A.N.S. and Q.Y.-G. contributed equally to this study. ␤ lary RCC and distal nephron markers ( -defensin 1, Accepted for publication November 17, 2004. claudin 7) in chromophobe RCC/oncocytoma. In Supplementary material for this article can be found at http://jmd. summary, renal tumor subtypes were classified by amjpathol.org. distinct gene expression profiles, illustrating tumor Address reprint requests to Andrew N. Young, M.D., Ph.D., Department pathobiology and translating into novel molecular of Pathology and Laboratory Medicine, Emory University/Atlanta VA Med- bioassays using fixed tissue. (J Mol Diagn 2005, ical Center, 1670 Clairmont Rd., Decatur, GA 30033. E-mail: andrew. 7:206–218) [email protected]. 206 Molecular Classification of Renal Tumors 207 JMD May 2005, Vol. 7, No. 2 cytoma; based on distinct expression patterns, we devel- CA) according to the manufacturer’s recommendations. oped a novel immunohistochemical panel for renal tumor RNA was quantified and assessed for integrity using a subtyping.17,18 Other groups have confirmed these find- 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA). ings in larger studies.5,19–21 We extended our observa- Expression profiles of all specimens were compared to a tions in the current experiments, using oligonucleotide commercial universal reference RNA (Clontech, Palo microarrays to profile the expression of several thousand Alto, CA). Probe synthesis and microarray hybridization genes in a cohort of clear cell RCC, papillary RCC, chro- were performed according to standard Affymetrix proto- mophobe RCC, oncocytoma, and angiomyolipoma. We cols, described in detail at the Internet site http://www. validated the microarray data for selected, differentially affymetrix.com/community/academic/grant.affx. Briefly, to- expressed gene products in an independent cohort of tal RNA (5 ␮g per specimen) was reverse-transcribed fixed tissues, using quantitative reverse transcriptase- into double-stranded cDNA, and biotin-labeled cRNA polymerase chain reaction (RT-PCR) and immunohisto- was produced by in vitro transcription. Labeled cRNA chemistry, and thereby confirmed these gene products was fragmented and digested by DNase I before hybrid- as potential expression markers for renal tumor ization. Hybridization cocktails were prepared by com- classification. bining fragmented targets, probe array controls, bovine serum albumin, and herring sperm DNA. Cocktails were applied to HG Focus oligonucleotide microarrays (Af- Materials and Methods fymetrix, Santa Clara, CA) for 16 hours, followed by au- tomated washing and staining on an Affymetrix worksta- Experimental Specimens tion. After staining, microarrays were scanned and analyzed with Affymetrix Microarray Suite 5.0 software, to Microarray experiments were performed on frozen spec- define probe cells, compute signal intensities in each imens from 13 clear cell RCC, 5 papillary RCC, 4 chro- cell, and calculate signal log expression ratios for each mophobe RCC, 3 oncocytoma, and 6 angiomyolipoma. 2 gene in tumor versus reference specimens. The HG Fo- Clinicopathological characteristics of this tumor cohort cus arrays produced data for 8746 genes. All hybridiza- are described in Supplementary Table 1 at http://jmd. tion experiments met the following quality control criteria: amjpathol.org. Quantitative RT-PCR experiments were average background, Ͻ100 U; noise, Ͻ5U;3Ј:5Ј ratio of performed on formalin-fixed paraffin-embedded tissue control genes, Ͻ3; and RNA spikes present with appro- from an independent cohort of 10 clear cell RCC, 6 priate signal intensities. Scaling factors and transcript papillary RCC, 5 chromophobe RCC, and 7 renal onco- presence rates varied less than 20% among tumor cytoma. Immunohistochemistry was performed on a fixed samples. tissue microarray that included 33 clear cell RCC, 19 papillary RCC, 6 chromophobe RCC, and 6 oncocytoma. The Emory University and Atlanta Veterans Affairs Medi- cal Center Departments of Pathology and Laboratory Data Analysis Medicine diagnosed tumors using published criteria:3 Affymetrix data sets were normalized with a robust mul- clear cell RCC– neoplastic clear cells with an anastomos- tiarray algorithm22 accounting for GC sequence informa- ing vascular network; papillary RCC– circumscription tion (GCRMA algorithm), encoded in GeneTraffic soft- with a fibrous capsule, papillary growth pattern, foam ware (Iobion Informatics, La Jolla, CA). Expression cells, and necrosis; chromophobe RCC– broad alveolar profiles were filtered to exclude genes with fewer than or nested growth pattern, neoplastic cells with irregular two observations of absolute value log ratio Ͼ2, or with nuclei and perinuclear halos, clear flocculent or granular 2 mean log ratio range (maximum Ϫ minimum) Ͻ 2. This eosinophilic cytoplasm; renal oncocytoma– circumscrip- 2 procedure selected 4030 differentially expressed genes tion with a central scar, nested or tubulocystic growth from the total of 8746. To compare global expression pattern, and neoplastic oncocytes with small round nuclei patterns among renal tumor subtypes, the filtered expres- and granular eosinophilic cytoplasm; angiomyolipoma– sion profiles were analyzed by unsupervised hierarchical mesenchymal tumor containing mature adipose, spindle, average linkage clustering, using Pearson correlation
Load more

Recommended publications
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Identification of Isobutyryl-Coa Dehydrogenase and Its Deficiency
    Molecular Genetics and Metabolism 77 (2002) 68–79 www.academicpress.com Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans Tien V. Nguyen,a Brage S. Andresen,b,c Thomas J. Corydon,b Sandro Ghisla,d Nasser Abd-El Razik,d Al-Walid A. Mohsen,a Stephen D. Cederbaum,e Diane S. Roe,f Charles R. Roe,f Nicolas J. Lench,g and Jerry Vockleya,* a Department of Medical Genetics, Mayo Clinic, Rochester, MN 55905, USA b Institute for Human Genetics, Aarhus University, Aarhus, Denmark c Research Unit for Molecular Medicine, Skejby Sygehus and Aarhus University, Aarhus, Denmark d Faculty of Biology, University of Konstanz, Konstanz, Germany e Department of Pediatrics, UCLA Medical Center, Los Angeles, CA, USA f Institute of Metabolic Disease, Baylor University, Dallas, TX, USA g Molecular Medicine Unit, University of Leeds, St. JamesÕ University Hospital, Leeds, UK Received 19 July 2002; received in revised form 31 July 2002; accepted 1 August 2002 Abstract The acyl-CoA dehydrogenases (ACDs) are a family of related enzymes that catalyze the a,b-dehydrogenation of acyl-CoA esters. Two homologues active in branched chain amino acid metabolism have previously been identified. We have used expression in Escherichia coli to produce a previously uncharacterized ACD-like sequence (ACAD8) and define its substrate specificity. Purified À1 À1 recombinant enzyme had a kcat=Km of 0.8, 0.23, and 0.04 (lM s ) with isobutyryl-CoA, (S) 2-methylbutyryl-CoA, and n-propionyl- CoA, respectively, as substrates. Thus, this enzyme is an isobutyryl-CoA dehydrogenase. A single patient has previously been described whose fibroblasts exhibit a specific deficit in the oxidation of valine.
    [Show full text]
  • The Role of GRHL2 and Epigenetic Remodeling in Epithelial–Mesenchymal Plasticity in Ovarian Cancer Cells
    ARTICLE https://doi.org/10.1038/s42003-019-0506-3 OPEN The role of GRHL2 and epigenetic remodeling in epithelial–mesenchymal plasticity in ovarian cancer cells Vin Yee Chung 1, Tuan Zea Tan 1, Jieru Ye1, Rui-Lan Huang2, Hung-Cheng Lai2, Dennis Kappei 1,3, 1234567890():,; Heike Wollmann4, Ernesto Guccione4 & Ruby Yun-Ju Huang1,5 Cancer cells exhibit phenotypic plasticity during epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) involving intermediate states. To study genome-wide epigenetic remodeling associated with EMT plasticity, we integrate the ana- lyses of DNA methylation, ChIP-sequencing of five histone marks (H3K4me1, H3K4me3, H3K27Ac, H3K27me3 and H3K9me3) and transcriptome profiling performed on ovarian cancer cells with different epithelial/mesenchymal states and on a knockdown model of EMT suppressor Grainyhead-like 2 (GRHL2). We have identified differentially methylated CpG sites associated with EMT, found at promoters of epithelial genes and GRHL2 binding sites. GRHL2 knockdown results in CpG methylation gain and nucleosomal remodeling (reduction in permissive marks H3K4me3 and H3K27ac; elevated repressive mark H3K27me3), resembling the changes observed across progressive EMT states. Epigenetic-modifying agents such as 5-azacitidine, GSK126 and mocetinostat further reveal cell state-dependent plasticity upon GRHL2 overexpression. Overall, we demonstrate that epithelial genes are subject to epigenetic control during intermediate phases of EMT/MET involving GRHL2. 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. 2 Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, 11031 Taipei, Taiwan. 3 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore.
    [Show full text]
  • Establishment and Characterisation of a New Breast Cancer Xenograft Obtained from a Woman Carrying a Germline BRCA2 Mutation
    British Journal of Cancer (2010) 103, 1192 – 1200 & 2010 Cancer Research UK All rights reserved 0007 – 0920/10 www.bjcancer.com Establishment and characterisation of a new breast cancer xenograft obtained from a woman carrying a germline BRCA2 mutation 1 ´ 2 1 1 1 2 2,3 L de Plater , A Lauge , C Guyader , M-F Poupon , F Assayag , P de Cremoux , A Vincent-Salomon , 2,3,4 2 5 6 6 6 1,7 D Stoppa-Lyonnet , B Sigal-Zafrani , J-J Fontaine , R Brough , CJ Lord , A Ashworth , P Cottu , 1,7 *,1 D Decaudin and E Marangoni 1 Preclinical Investigation Unit, Institut Curie – Translational Research Department, Hoˆpital St Louis, Quadrilate`re historique, Porte 13, 1, Ave Claude 2 3 4 Vellefaux, Paris 75010, France; Department of Tumor Biology, Institut Curie, Paris, France; INSERM U830, Institut Curie, Paris, France; University Paris Translational Therapeutics 5 6 Descartes, Paris, France; National Veterinary School of Maisons Alfort, Maisons-Alfort, France; Gene Function Laboratory, The Breakthrough Breast 7 Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK; Department of Medical Oncology, Institut Curie, Paris, France BACKGROUND: The BRCA2 gene is responsible for a high number of hereditary breast and ovarian cancers, and studies of the BRCA2 biological functions are limited by the lack of models that resemble the patient’s tumour features. The aim of this study was to establish and characterise a new human breast carcinoma xenograft obtained from a woman carrying a germline BRCA2 mutation. METHODS: A transplantable xenograft was obtained by grafting a breast cancer sample into nude mice.
    [Show full text]
  • Chromosome Instability Drives Phenotypic Switching to Metastasis
    Chromosome instability drives phenotypic switching to metastasis ChongFeng Gaoa,1, Yanli Sua, Julie Koemanb, Elizabeth Haaka, Karl Dykemab, Curt Essenberga, Eric Hudsonb, David Petilloc, Sok Kean Khood, and George F. Vande Woudea,1 aLaboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503; bCore Technologies and Services, Van Andel Research Institute, Grand Rapids, MI 49503; cLaboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI 49503; and dDepartment of Cell and Molecular Biology, Grand Valley State University, Grand Rapids, MI 49503 Contributed by George F. Vande Woude, November 3, 2016 (sent for review October 5, 2016; reviewed by Webster K. Cavenee and Peter K. Vogt) Chromosome instability (CIN) is the most striking feature of human successively isolating mesenchymal variants from clonal epithelial cancers. However, how CIN drives tumor progression to metastasis populations, and then isolating epithelial revertants of the mesen- remains elusive. Here we studied the role of chromosome content chymal variants. We have shown that generation of mesenchymal changes in generating the phenotypic dynamics that are required variants associated with loss of chromosome contents harbors genes for metastasis. We isolated epithelial and mesenchymal clones from encoding IJ protein, whereas generation of epithelial variants was human carcinoma cell lines and showed that the epithelial clones frequently caused by Zeb1 (zinc-finger E-box–binding homeobox 1) were able to generate mesenchymal variants, which had the haploinsufficiency through 10p loss. potential to further produce epithelial revertants autonomously. The successive acquisition of invasive mesenchymal and then Result and Discussion epithelial phenotypes recapitulated the steps in tumor progression OVCAR5 (OV5-P) cells growing in a Petri dish exhibited a het- to metastasis.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2016/0002733 A1 Chu (43) Pub
    US 2016.0002733A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0002733 A1 Chu (43) Pub. Date: Jan. 7, 2016 (54) ASSESSING RISK FORENCEPHALOPATHY Related U.S. Application Data INDUCED BYS-FLUOROURACL, OR (60) Provisional application No. 61/772,949, filed on Mar. CAPECTABINE 5, 2013. Publication Classification (71) Applicant: THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNOR (51) Int. C. UNIVERSITY, Palo Alto, CA (US) CI2O I/68 (2006.01) (52) U.S. C. (72) Inventor: Gilbert Chu, Stanford, CA (US) CPC ........ CI2O I/6886 (2013.01); C12O 2600/156 (2013.01); C12O 2600/106 (2013.01); C12O (21) Appl. No.: 14/769,961 2600/142 (2013.01) (22) PCT Fled: Feb. 26, 2014 (57) ABSTRACT Methods and systems are provided for determining Suscepti (86) PCT NO.: PCT/US14/18739 bility to 5-fluorouracil (5-FU) or capecitabine toxicity. Meth ods are provided for treating a human Subject based on a S371 (c)(1), determined susceptibility to 5-fluorouracil (5-FU) or capecit (2) Date: Aug. 24, 2015 abine toxicity. Patent Application Publication Jan. 7, 2016 Sheet 1 of 17 US 2016/0002733 A1 Figure 1A urea cycle pyrimidine synthesis -- - - - - - - - - - - - Glin / WPA H al-NAGS NH 3. NH3CPSIDcarbamoyl-P Glu->NAG->|CPS Ca rbamyl-Asp: carbamoyl-P OHO : P. Orotate ornithine citruline s --AlORNT - Y - - - OMPwY Ornithine citruline UDP am UMP as UTP RR urea { UDP in OSuccinat A. 5-FUTP arginine 8 gypsuccina e CUMP i. cycleRECTS-5-FdUMP4-5-FU dTMP Figure IB /a-ketoglutarate pyruvate Asp PD PC 4-acetyl-CoA Glu oxaloacetate malate isocitrate Krebs cycle NH3 fumarate a-ketoglutarate Glu succinate succinyl-CoA methylmalonyl-CoA r a fatty acid proponyi-UOE.
    [Show full text]
  • Heterozygous Deletion of Chromosome 17P Renders Prostate Cancer Vulnerable to Inhibition of RNA Polymerase II
    ARTICLE DOI: 10.1038/s41467-018-06811-z OPEN Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II Yujing Li1,2,3, Yunhua Liu 2,3,4, Hanchen Xu1,2,3, Guanglong Jiang3, Kevin Van der Jeught 2,3, Yuanzhang Fang2,3, Zhuolong Zhou3, Lu Zhang2,3, Michael Frieden3, Lifei Wang3, Zhenhua Luo5, Milan Radovich4,6, Bryan P. Schneider7, Yibin Deng8, Yunlong Liu3, Kun Huang7, Bin He9, Jin Wang 10, Xiaoming He 11,12, Xinna Zhang3,4, Guang Ji 1 & Xiongbin Lu2,3,4 1234567890():,; Heterozygous deletion of chromosome 17p (17p) is one of the most frequent genomic events in human cancers. Beyond the tumor suppressor TP53, the POLR2A gene encoding the cat- alytic subunit of RNA polymerase II (RNAP2) is also included in a ~20-megabase deletion region of 17p in 63% of metastatic castration-resistant prostate cancer (CRPC). Using a focused CRISPR-Cas9 screen, we discovered that heterozygous loss of 17p confers a selective dependence of CRPC cells on the ubiquitin E3 ligase Ring-Box 1 (RBX1). RBX1 activates POLR2A by the K63-linked ubiquitination and thus elevates the RNAP2-mediated mRNA synthesis. Combined inhibition of RNAP2 and RBX1 profoundly suppress the growth of CRPC in a synergistic manner, which potentiates the therapeutic effectivity of the RNAP2 inhibitor, α-amanitin-based antibody drug conjugate (ADC). Given the limited therapeutic options for CRPC, our findings identify RBX1 as a potentially therapeutic target for treating human CRPC harboring heterozygous deletion of 17p. 1 Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 200032 Shanghai, China.
    [Show full text]
  • Met Synergizes with P53 Loss to Induce Mammary Tumors That Possess
    Met synergizes with p53 loss to induce mammary PNAS PLUS tumors that possess features of claudin-low breast cancer Jennifer F. Knighta,1, Robert Lesurfa,b,1, Hong Zhaoa, Dushanthi Pinnaduwagec, Ryan R. Davisd, Sadiq M. I. Saleha,b, Dongmei Zuoa, Monica A. Naujokasa, Naila Chughtaia, Jason I. Herschkowitze, Aleix Pratf,g, Anna Marie Mulliganh,i, William J. Mullera,b, Robert D. Cardiffd, Jeff P. Greggd, Irene L. Andrulisc,h,i,j, Michael T. Halletta, and Morag Parka,b,k,2 aGoodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3; bDepartment of Biochemistry, McGill University, Montreal, QC, Canada H2W 1S6; cSamuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5; dCenter for Comparative Medicine, University of California, Davis, CA 95616; eDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; fLineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27514; gVall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; hDepartment of Laboratory Medicine, St. Michael’s Hospital, Toronto, ON, Canada M5B 1W8; iDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A1; jDepartment of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8; and kDepartment of Oncology, McGill University, Montreal, QC, Canada H2W 1S6 Edited by Tak W. Mak, The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute at Princess Margaret Hospital, University Health Network, Toronto, ON, Canada, and approved February 13, 2013 (received for review June 18, 2012) Triple-negative breast cancer (TNBC) accounts for ∼20% of cases Claudin-low tumors were originally distinguished from other and contributes to basal and claudin-low molecular subclasses of subtypes on the basis of gene expression profiling (3) and have the disease.
    [Show full text]
  • A Meta-Analysis of the Effects of High-LET Ionizing Radiations in Human Gene Expression
    Supplementary Materials A Meta-Analysis of the Effects of High-LET Ionizing Radiations in Human Gene Expression Table S1. Statistically significant DEGs (Adj. p-value < 0.01) derived from meta-analysis for samples irradiated with high doses of HZE particles, collected 6-24 h post-IR not common with any other meta- analysis group. This meta-analysis group consists of 3 DEG lists obtained from DGEA, using a total of 11 control and 11 irradiated samples [Data Series: E-MTAB-5761 and E-MTAB-5754]. Ensembl ID Gene Symbol Gene Description Up-Regulated Genes ↑ (2425) ENSG00000000938 FGR FGR proto-oncogene, Src family tyrosine kinase ENSG00000001036 FUCA2 alpha-L-fucosidase 2 ENSG00000001084 GCLC glutamate-cysteine ligase catalytic subunit ENSG00000001631 KRIT1 KRIT1 ankyrin repeat containing ENSG00000002079 MYH16 myosin heavy chain 16 pseudogene ENSG00000002587 HS3ST1 heparan sulfate-glucosamine 3-sulfotransferase 1 ENSG00000003056 M6PR mannose-6-phosphate receptor, cation dependent ENSG00000004059 ARF5 ADP ribosylation factor 5 ENSG00000004777 ARHGAP33 Rho GTPase activating protein 33 ENSG00000004799 PDK4 pyruvate dehydrogenase kinase 4 ENSG00000004848 ARX aristaless related homeobox ENSG00000005022 SLC25A5 solute carrier family 25 member 5 ENSG00000005108 THSD7A thrombospondin type 1 domain containing 7A ENSG00000005194 CIAPIN1 cytokine induced apoptosis inhibitor 1 ENSG00000005381 MPO myeloperoxidase ENSG00000005486 RHBDD2 rhomboid domain containing 2 ENSG00000005884 ITGA3 integrin subunit alpha 3 ENSG00000006016 CRLF1 cytokine receptor like
    [Show full text]
  • Table S1. 103 Ferroptosis-Related Genes Retrieved from the Genecards
    Table S1. 103 ferroptosis-related genes retrieved from the GeneCards. Gene Symbol Description Category GPX4 Glutathione Peroxidase 4 Protein Coding AIFM2 Apoptosis Inducing Factor Mitochondria Associated 2 Protein Coding TP53 Tumor Protein P53 Protein Coding ACSL4 Acyl-CoA Synthetase Long Chain Family Member 4 Protein Coding SLC7A11 Solute Carrier Family 7 Member 11 Protein Coding VDAC2 Voltage Dependent Anion Channel 2 Protein Coding VDAC3 Voltage Dependent Anion Channel 3 Protein Coding ATG5 Autophagy Related 5 Protein Coding ATG7 Autophagy Related 7 Protein Coding NCOA4 Nuclear Receptor Coactivator 4 Protein Coding HMOX1 Heme Oxygenase 1 Protein Coding SLC3A2 Solute Carrier Family 3 Member 2 Protein Coding ALOX15 Arachidonate 15-Lipoxygenase Protein Coding BECN1 Beclin 1 Protein Coding PRKAA1 Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 Protein Coding SAT1 Spermidine/Spermine N1-Acetyltransferase 1 Protein Coding NF2 Neurofibromin 2 Protein Coding YAP1 Yes1 Associated Transcriptional Regulator Protein Coding FTH1 Ferritin Heavy Chain 1 Protein Coding TF Transferrin Protein Coding TFRC Transferrin Receptor Protein Coding FTL Ferritin Light Chain Protein Coding CYBB Cytochrome B-245 Beta Chain Protein Coding GSS Glutathione Synthetase Protein Coding CP Ceruloplasmin Protein Coding PRNP Prion Protein Protein Coding SLC11A2 Solute Carrier Family 11 Member 2 Protein Coding SLC40A1 Solute Carrier Family 40 Member 1 Protein Coding STEAP3 STEAP3 Metalloreductase Protein Coding ACSL1 Acyl-CoA Synthetase Long Chain Family Member 1 Protein
    [Show full text]
  • Novel and Highly Recurrent Chromosomal Alterations in Se´Zary Syndrome
    Research Article Novel and Highly Recurrent Chromosomal Alterations in Se´zary Syndrome Maarten H. Vermeer,1 Remco van Doorn,1 Remco Dijkman,1 Xin Mao,3 Sean Whittaker,3 Pieter C. van Voorst Vader,4 Marie-Jeanne P. Gerritsen,5 Marie-Louise Geerts,6 Sylke Gellrich,7 Ola So¨derberg,8 Karl-Johan Leuchowius,8 Ulf Landegren,8 Jacoba J. Out-Luiting,1 Jeroen Knijnenburg,2 Marije IJszenga,2 Karoly Szuhai,2 Rein Willemze,1 and Cornelis P. Tensen1 Departments of 1Dermatology and 2Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands; 3Department of Dermatology, St Thomas’ Hospital, King’s College, London, United Kingdom; 4Department of Dermatology, University Medical Center Groningen, Groningen, the Netherlands; 5Department of Dermatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; 6Department of Dermatology, Gent University Hospital, Gent, Belgium; 7Department of Dermatology, Charite, Berlin, Germany; and 8Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden Abstract Introduction This study was designed to identify highly recurrent genetic Se´zary syndrome (Sz) is an aggressive type of cutaneous T-cell alterations typical of Se´zary syndrome (Sz), an aggressive lymphoma/leukemia of skin-homing, CD4+ memory T cells and is cutaneous T-cell lymphoma/leukemia, possibly revealing characterized by erythroderma, generalized lymphadenopathy, and pathogenetic mechanisms and novel therapeutic targets. the presence of neoplastic T cells (Se´zary cells) in the skin, lymph High-resolution array-based comparative genomic hybridiza- nodes, and peripheral blood (1). Sz has a poor prognosis, with a tion was done on malignant T cells from 20 patients. disease-specific 5-year survival of f24% (1).
    [Show full text]
  • Development of a Newborn Screening Follow-Up Algorithm for The
    article February 2007 ⅐ Vol. 9 ⅐ No. 2 Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency Devin Oglesbee, PhD1, Miao He, PhD4, Nilanjana Majumder4, Jerry Vockley, MD, PhD4, Ayesha Ahmad, MD5, Brad Angle, MD6, Barbara Burton, MD6, Joel Charrow, MD6, Regina Ensenauer, MD1,7, Can H. Ficicioglu, MD, PhD8, Laura Davis Keppen, MD9, Deborah Marsden, MD10, Silvia Tortorelli, MD, PhD1,2, Si Houn Hahn, MD, PhD1,2,3, and Dietrich Matern, MD1,2,3 Purpose: Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. We identified 13 isobutyryl-CoA dehydrogenase– deficient patients through newborn screening due to an elevation of C4-acylcarnitine in dried blood spots. Because C4-acylcarnitine represents both isobutyryl- and butyrylcarnitine, elevations are not specific for isobutyryl-CoA dehydrogenase deficiency but are also observed in short-chain acyl-CoA dehydrogenase deficiency. To delineate the correct diagnosis, we have developed a follow-up algorithm for abnormal C4-acylcarnitine newborn screening results based on the comparison of biomarkers for both conditions. Methods: Fibroblast cultures were established from infants with C4-acylcarnitine elevations, and the analysis of in vitro acylcarnitine profiles provided confirmation of either isobutyryl-CoA dehydrogenase or short-chain acyl-CoA dehydrogenase deficiency. Isobutyryl-CoA dehydro- genase deficiency was further confirmed by molecular genetic analysis of the gene encoding isobutyryl-CoA dehydrogenase (ACAD8). Plasma acylcarnitines, urine acylglycines, organic acids, and urine acylcarnitine results were compared between isobutyryl-CoA dehydrogenase– and short-chain acyl-CoA dehydrogenase–deficient pa- tients.
    [Show full text]