DOCSLIB.ORG

Interesting Cases in Surgical Pathology a Malignant Neoplasm in the Brain

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Interesting Cases in Surgical Pathology a Malignant Neoplasm in the Brain Interesting cases in surgical pathology A malignant neoplasm in the brain Ashley Cimino‐Mathews, MD Assistant Professor of Pathology and Oncology The Johns Hopkins Hospital 24 March 2013 Case Presentation A 54 year‐old female presented to the emergency department with mental status changes and was found to have a large dural‐ based brain mass. The patient had a reported history of melanoma and breast cancer (ER 1%, PR‐, Her2‐). The patient underwent resection of the brain tumor. Brain lesion Brain lesion Brain lesion Brain lesion Brain lesion Brain lesion: Sox10 Positive Brain lesion: GATA3 negative (lymphocytes are positive internal control) Is this a metastatic melanoma? Metastatic melanoma? • Diffuse Sox10 immunoreactivity is typically used to support a diagnosis of melanoma or a nerve sheath tumor. • The morphology of this brain lesion in keeping with malignant melanoma. However…diffuse Sox10 immunoreactivity has also been documented in other neoplasms: primary brain tumors (most often astrocytomas), salivary gland neoplasms, and breast carcinoma. The patient’s prior lumpectomy slides were retrieved and additional immunostains performed Breast tumor Breast tumor Breast tumor Breast tumor: CK7 positive Breast tumor: HMB45 negative Breast tumor: Sox10 positive Additional immunostains were performed on the brain lesion Brain lesion Brain lesion: CK7 positive Brain lesion: ER focally positive Final diagnosis: Metastatic breast carcinoma to the brain Case lessons learned 1. Sox10 can be expressed in primary breast carcinomas, primarily triple‐negative carcinomas 2. Sox10 can be expressed in metastatic breast carcinomas – Potential diagnostic utility as triple negative breast carcinomas may not label for traditional markers of mammary differentiation 3. Sox10 labeling in breast carcinomas is a potential diagnostic pitfall for metastatic melanoma Case lessons learned 1. Sox10 can be expressed in primary breast carcinomas, primarily basal‐like carcinomas 2. Sox10 can be expressed in metastatic breast carcinomas – Potential diagnostic utility as triple negative breast carcinomas may not label for traditional markers of mammary differentiation 3. Sox10 labeling in breast carcinomas is a potential diagnostic pitfall for metastatic melanoma What is Sox10? What is Sox10? • Sox10 is a transcription factor in the Sox (Sry‐related HMG box) gene family, which have HMG DNA‐binding domains and play a role in many developmental processes including the development of the immune, nervous and skeletal systems. • Sox10 has a role in the survival, maturation and differentiation of neural‐crest derived melanocytes and glial cells. • In the breast, Sox10 is required for Notch4‐PBP mediated cell growth of mammary epithelial cells in in vitro mouse models. Sox10 Immunohistochemistry: initial utility in neural‐crest derived tissues • Normal tissues that demonstrated Sox10+ labeling: – Schwann cells, melanocytes and the myoepithelial cells of the salivary glands, bronchial mucosa, and breast. • Neoplastic tissues that demonstrated Sox10+ labeling: – 97% of melanomas, 100% of schwannomas and neurofibromas, 100% of salivary gland myoepitheliomas, as well as a subset of malignant peripheral nerve sheath tumors, paragangliomas, carcinoids and astrocytomas. • In this study, none of the 25 epithelial tumors (including 8 breast carcinomas) labeled for Sox10. Nonaka D, et al. Am J Surg Pathol. 2008;32:1291‐1298. Sox10 Immunohistochemistry: initial utility in neural‐crest derived tissues • Normal tissues that demonstrated Sox10+ labeling: – Schwann cells, melanocytes and the myoepithelial cells of the salivary glands, bronchial mucosa, and breast. • Neoplastic tissues that demonstrated Sox10+ labeling: – 97% of melanomas, 100% of schwannomas and neurofibromas, 100% of salivary gland myoepitheliomas, as well as a subset of malignant peripheral nerve sheath tumors, paragangliomas, carcinoids and astrocytomas. • In this study, none of the 25 epithelial tumors (including 8 breast carcinomas) labeled for Sox10. Nonaka D, et al. Am J Surg Pathol. 2008;32:1291‐1298. Sox10 Immunohistochemistry: initial utility in neural‐crest derived tissues • Normal tissues that demonstrated Sox10+ labeling: – Schwann cells, melanocytes and the myoepithelial cells of the salivary glands, bronchial mucosa, and breast. • Neoplastic tissues that demonstrated Sox10+ labeling: – 97% of melanomas, 100% of schwannomas and neurofibromas, 100% of salivary gland myoepitheliomas, as well as a subset of malignant peripheral nerve sheath tumors, paragangliomas, carcinoids and astrocytomas. • In this study, none of the 25 epithelial tumors (including 8 breast carcinomas) labeled for Sox10. Nonaka D, et al. Am J Surg Pathol. 2008;32:1291‐1298. Sox10 Immunohistochemistry: initial utility in neural‐crest derived tissues • Normal tissues that demonstrated Sox10+ labeling: – Schwann cells, melanocytes and the myoepithelial cells of the salivary glands, bronchial mucosa, and breast. • Neoplastic tissues that demonstrated Sox10+ labeling: – 97% of melanomas, 100% of schwannomas and neurofibromas, 100% of salivary gland myoepitheliomas, as well as a subset of malignant peripheral nerve sheath tumors, paragangliomas, carcinoids and astrocytomas. • In this study, none of the 25 epithelial tumors (including 8 breast carcinomas) labeled for Sox10. Nonaka D, et al. Am J Surg Pathol. 2008;32:1291‐1298. Melanocytes: Sox10+ Melanoma: Sox10+ Peripheral nerve Schwann cells: Sox10+ Nerve sheath‐derived granular cell tumor: Sox10+ Breast lobule: myoepithelial and luminal cells Sox10+ Breast ductule: myoepithelial and luminal cells Sox10+ Sox10 labels a subset of breast carcinomas • We first reported Sox10 positivity in breast carcinomas: – Overall, 40% of primary invasive breast ductal carcinomas – Specifically 66% of all triple negative carcinomas • 69% of basal‐like triple negative carcinomas • 45% metaplastic carcinomas – In contrast, 5% of estrogen receptor (ER)‐positive or Her2‐positive carcinomas labeled for Sox10 – Focal labeling in ER‐negative ductal carcinoma in situ. Cimino‐Mathews A, et al. Hum Pathol. 2013;44:959‐965. Sox10 labels a subset of breast carcinomas • We reported Sox10 positivity in breast carcinomas: – Overall, 40% of primary invasive breast ductal carcinomas – Specifically 66% of all triple negative carcinomas • 69% of basal‐like triple negative carcinomas • 45% metaplastic carcinomas – In contrast, 5% of estrogen receptor (ER)‐positive or Her2‐positive carcinomas labeled for Sox10 – Focal labeling in ER‐negative ductal carcinoma in situ. Cimino‐Mathews A, et al. Hum Pathol. 2013;44:959‐965. Basal‐like triple negative breast carcinoma (ER‐/PR‐/Her2‐ and CK5/6+) Basal‐like triple negative breast carcinoma: Sox10+ Metaplastic Carcinoma: 45% are Sox10 positive ER+ Ductal Carcinoma: Sox10 negative Sox10 positivity in breast ductal carcinomas has been confirmed in subsequent studies • 12%‐17% breast carcinomas are Sox10+ in subsequent studies; if reported, the majority are ER negative or basal‐like in phenotype • Gene expression profiling data has also identified overlapping Sox10 gene signatures in breast basal‐like breast carcinoma and salivary adenoid cystic carcinoma Mohamed, et al. Appl Immunohistochem Mol Morphol. 2013;21:506‐51. Ivanov SV, et al. Br J Cancer. 2013;109:444‐451. Tacha, et al. Arch Pathol Lab Med. 2014. [Epub ahead of print]. Miettinen, et al. Am J Surg Pathol. 2015 Feb 25. [Epub ahead of print]. Sox10 positivity in breast ductal carcinomas has been confirmed in subsequent studies • 12%‐17% breast carcinomas are Sox10+ in subsequent studies; if reported, the majority are ER negative or basal‐like in phenotype • Gene expression profiling data has also identified overlapping Sox10 gene signatures in breast basal‐like carcinoma and salivary gland adenoid cystic carcinoma Mohamed, et al. Appl Immunohistochem Mol Morphol. 2013;21:506‐51. Ivanov SV, et al. Br J Cancer. 2013;109:444‐451. Tacha, et al. Arch Pathol Lab Med. 2014. [Epub ahead of print]. Miettinen, et al. Am J Surg Pathol. 2015 Feb 25. [Epub ahead of print]. What other epithelial neoplasms label for Sox10? *Asch‐Kendrick, et al. Mod Pathol. 2015.28(S2):14A. (USCAP 2015 Poster Wednesday 1pm) What other epithelial neoplasms label for Sox10? • Salivary gland neoplasms (adenoid cystic carcinoma, acinic cell carcinoma, epithelial‐myoepithelial carcinoma, myoepitheliomas, myoepithelial carcinoma, pleomorphic adenoma) • Breast adenoid cystic carcinoma* • Skin adnexal neoplasms (eccrine spiradenoma/ cylindroma) • Soft tissue myoepitheliomas and carcinomas • Rarely: – embryonal carcinoma (25%) – pulmonary small cell carcinoma (7%) – lung or head and neck squamous cell carcinoma (5%) – pulmonary adenocarcinoma (fetal type) (1%) – Miettinen, et al. Am J Surg Pathol. 2015 Feb 25. [Epub ahead of print]. *Asch‐Kendrick, et al. A broad survey of neural crest transcription factor Sox10 in benign and neoplastic tissues. Mod Pathol. 2015.28(S2):14A. (USCAP 2015 Poster Wednesday 1pm) What other epithelial neoplasms label for Sox10? • Salivary gland neoplasms (adenoid cystic carcinoma, acinic cell carcinoma, epithelial‐myoepithelial carcinoma, myoepitheliomas, myoepithelial carcinoma, pleomorphic adenoma) • Breast adenoid cystic carcinoma* • Skin adnexal neoplasms (eccrine spiradenoma/ cylindroma) • Soft tissue myoepitheliomas and carcinomas • Rarely: – embryonal carcinoma (25%) – pulmonary small cell carcinoma (7%) – lung or head and neck squamous cell carcinoma (5%) – pulmonary adenocarcinoma (fetal type) (1%) – Miettinen, et al.
Load more

Recommended publications
  • Integrated and Functional Genomic Approaches to Elucidate Differential Genetic Dependencies in Melanoma
    Integrated and Functional Genomic Approaches to Elucidate Differential Genetic Dependencies in Melanoma The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Wong, Terence. 2018. Integrated and Functional Genomic Approaches to Elucidate Differential Genetic Dependencies in Melanoma. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:42014990 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Integrated and Functional Genomic Approaches to Elucidate Differential Genetic Dependencies in Melanoma A dissertation presented by Terence Cheng Wong to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Biological and Biomedical Sciences Harvard University Cambridge, Massachusetts November 2017 © 2017 Terence Cheng Wong All rights reserved. Dissertation Advisor: Levi Garraway Terence Cheng Wong Integrated and Functional Genomic Approaches to Elucidate Differential Genetic Dependencies in Melanoma ABSTRACT Genomic characterization of human cancers over the past decade has generated comprehensive catalogues of genetic alterations in cancer genomes. Many of these genetic events result in molecular or cellular changes that drive cancer cell phenotypes. In melanoma, a majority of tumors harbor mutations in the BRAF gene, leading to activation of the MAPK pathway and tumor initiation. The development and use of drugs that target the mutant BRAF protein and the MAPK pathway have produced significant clinical benefit in melanoma patients.
    [Show full text]
  • Olig1 and Sox10 Interact Synergistically to Drivemyelin Basic
    The Journal of Neuroscience, December 26, 2007 • 27(52):14375–14382 • 14375 Cellular/Molecular Olig1 and Sox10 Interact Synergistically to Drive Myelin Basic Protein Transcription in Oligodendrocytes Huiliang Li,1 Yan Lu,2 Hazel K. Smith,1 and William D. Richardson1 1Wolfson Institute for Biomedical Research and Department of Biology, University College London, London WC1E 6BT, United Kingdom, and 2Medical Research Council, Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom The oligodendrocyte lineage genes (Olig1/2), encoding basic helix-loop-helix transcription factors, were first identified in screens for master regulators of oligodendrocyte development. OLIG1 is important for differentiation of oligodendrocyte precursors into myelin- forming oligodendrocytes during development and is thought to play a crucial role in remyelination during multiple sclerosis. However, itisstillunclearhowOLIG1interactswithitstranscriptionalcofactorsandDNAtargets.OLIG1wasreportedlyrestrictedtomammals,but we demonstrate here that zebrafish and other teleosts also possess an OLIG1 homolog. In zebrafish, as in mammals, Olig1 is expressed in the oligodendrocyte lineage. Olig1 associates physically with another myelin-associated transcription factor, Sox10, and the Olig1/Sox10 complex activates mbp (myelin basic protein) transcription via conserved DNA sequence motifs in the mbp promoter region. In contrast, Olig2 does not bind to Sox10 in zebrafish, although both OLIG1 and OLIG2 bind SOX10 in mouse. Key words: Olig1; Olig2; Sox10; Mbp; oligodendrocyte; myelin; zebrafish; mouse; evolution; development Introduction directly regulates Mbp transcription (Stolt et al., 2002), and over- Myelin, the multilayered glial sheath around axons, is one of the expression of SOX10 alone is sufficient to induce myelin gene defining features of jawed vertebrates (gnathostomes). It is expression in embryonic chick spinal cord (Liu et al., 2007).
    [Show full text]
  • SUPPLEMENTARY MATERIAL Bone Morphogenetic Protein 4 Promotes
    www.intjdevbiol.com doi: 10.1387/ijdb.160040mk SUPPLEMENTARY MATERIAL corresponding to: Bone morphogenetic protein 4 promotes craniofacial neural crest induction from human pluripotent stem cells SUMIYO MIMURA, MIKA SUGA, KAORI OKADA, MASAKI KINEHARA, HIROKI NIKAWA and MIHO K. FURUE* *Address correspondence to: Miho Kusuda Furue. Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. Tel: 81-72-641-9819. Fax: 81-72-641-9812. E-mail: [email protected] Full text for this paper is available at: http://dx.doi.org/10.1387/ijdb.160040mk TABLE S1 PRIMER LIST FOR QRT-PCR Gene forward reverse AP2α AATTTCTCAACCGACAACATT ATCTGTTTTGTAGCCAGGAGC CDX2 CTGGAGCTGGAGAAGGAGTTTC ATTTTAACCTGCCTCTCAGAGAGC DLX1 AGTTTGCAGTTGCAGGCTTT CCCTGCTTCATCAGCTTCTT FOXD3 CAGCGGTTCGGCGGGAGG TGAGTGAGAGGTTGTGGCGGATG GAPDH CAAAGTTGTCATGGATGACC CCATGGAGAAGGCTGGGG MSX1 GGATCAGACTTCGGAGAGTGAACT GCCTTCCCTTTAACCCTCACA NANOG TGAACCTCAGCTACAAACAG TGGTGGTAGGAAGAGTAAAG OCT4 GACAGGGGGAGGGGAGGAGCTAGG CTTCCCTCCAACCAGTTGCCCCAAA PAX3 TTGCAATGGCCTCTCAC AGGGGAGAGCGCGTAATC PAX6 GTCCATCTTTGCTTGGGAAA TAGCCAGGTTGCGAAGAACT p75 TCATCCCTGTCTATTGCTCCA TGTTCTGCTTGCAGCTGTTC SOX9 AATGGAGCAGCGAAATCAAC CAGAGAGATTTAGCACACTGATC SOX10 GACCAGTACCCGCACCTG CGCTTGTCACTTTCGTTCAG Suppl. Fig. S1. Comparison of the gene expression profiles of the ES cells and the cells induced by NC and NC-B condition. Scatter plots compares the normalized expression of every gene on the array (refer to Table S3). The central line
    [Show full text]
  • Birth Defects Caused by Mutations in Human GLI3 and Mouse Gli3 Genescga
    doi:10.1111/j.1741-4520.2009.00266.x Congenital Anomalies 2010; 50, 1–7 1 REVIEW ARTICLE Birth defects caused by mutations in human GLI3 and mouse Gli3 genescga_ 266 1..71..7 Ichiro Naruse1, Etsuko Ueta1, Yoshiki Sumino1, Masaya Ogawa1, and Satoshi Ishikiriyama2 1School of Health Science, Faculty of Medicine, Tottori University, Yonago, and 2Division of Clinical Genetics and Cytogenetics, Shizuoka Children’s Hospital, Shizuoka, Japan ABSTRACT GLI3 is the gene responsible for Greig cepha- type-A (PAP-A) and preaxial polydactyly type-IV (PPD-IV). A lopolysyndactyly syndrome (GCPS), Pallister–Hall syndrome mimic phenomenon is observed in mice. Investigation of human (PHS) and Postaxial polydactyly type-A (PAP-A). Genetic poly- GLI3 and Gli3 genes has progressed using the knowledge of dactyly mice such as Pdn/Pdn (Polydactyly Nagoya), XtH/XtH Cubitus interruptus (Ci) in Drosophila, a homologous gene of GLI3 (Extra toes) and XtJ/XtJ (Extra toes Jackson) are the mouse and Gli3 genes. These genes have been highly conserved in the homolog of GCPS, and Gli3tmlUrtt/Gli3tmlUrt is produced as the animal kingdom throughout evolution. Now, a lot of mutant mice of mouse homolog of PHS. In the present review, relationships Gli3 gene have been known and knockout mice have been pro- between mutation points of GLI3 and Gli3, and resulting phe- duced. It is expected that the knowledge obtained from mutant and notypes in humans and mice are described. It has been con- knockout mice will be extrapolated to the manifestation mecha- firmed that mutation in the upstream or within the zinc finger nisms in human diseases to understand the diseases caused by the domain of the GLI3 gene induces GCPS; that in the post-zinc mutations in GLI3 gene.
    [Show full text]
  • Identifying Isl1 Genetic Lineage in the Developing Olfactory System and in Gnrh-1 Neurons 2 3 Ed Zandro M
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.31.276360; this version posted August 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Identifying Isl1 genetic lineage in the developing olfactory system and in GnRH-1 neurons 2 3 Ed Zandro M. Taroc1, Raghu Ram Katreddi1 and Paolo E. Forni1*. 4 5 1Department of Biological Sciences; The RNA Institute, and the Center for Neuroscience 6 Research; University at Albany, State University of New York, Albany, NY 12222, USA. 7 8 * Corresponding Author 9 [email protected] 10 11 12 Keywords: Olfactory neurons, vomeronasal sensory neurons, GnRH neurons, Islet-1/Isl1, Isl1 13 Conditional knock-out; genetic lineage tracing, olfactory placode, neural crest. 14 15 Abstract (299, at 245 after editing) 16 During embryonic development, symmetric ectodermal thickenings (olfactory placodes) give rise 17 to several cell types that comprise the olfactory system, such as those that form the terminal nerve 18 ganglion (TN), gonadotropin releasing hormone-1 (GnRH-1) neurons and other migratory 19 neurons in rodents. Even though the genetic heterogeneity among these cell types are 20 documented, unidentified cell populations arising from the olfactory placode remain. One 21 candidate to identify placodal derived neurons in the developing nasal area is the transcription 22 factor Isl1, which was recently identified in GnRH-3 neurons of the terminal nerve in fish, as well 23 as expression in neurons of the nasal migratory mass. Here, we analyzed the Isl1 genetic lineage 24 in chemosensory neuronal populations in the nasal area and migratory GnRH-1 neurons in mice 25 using in-situ hybridization, immunolabeling a Tamoxifen inducible Isl1CreERT and a constitutive 26 Isl1Cre knock-in mouse lines.
    [Show full text]
  • Ablation of Ezh2 in Neural Crest Cells Leads to Hirschsprung's Disease-Like Phenotype in Mice
    bioRxiv preprint doi: https://doi.org/10.1101/265868; this version posted February 15, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Ablation of Ezh2 in neural crest cells leads to Hirschsprung’s disease-like phenotype in mice Hana Kim, Ingeborg M. Langohr, Mohammad Faisal, Margaret McNulty, Caitlin Thorn, Joomyeong Kim* Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA. Correspondence should be forwarded to: [email protected], 225-578-7692(ph), or 225-578-2597(fax) Running title: Function of Ezh2 in enteric neural crest cell development 1 bioRxiv preprint doi: https://doi.org/10.1101/265868; this version posted February 15, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract In the current study, we examined the role of Ezh2 as an epigenetic modifier for the enteric neural crest cell development through H3K27me3. Ezh2 conditional null mice were viable up to birth, but died within the first hour of life. In addition to craniofacial defects, Ezh2 conditional null mice displayed reduced number of ganglion cells in the enteric nervous system. RT-PCR and ChIP assays indicated aberrant up-regulation of Zic1, Pax3, and Sox10 and loss of H3K27me3 marks in the promoter regions of these genes in the myenteric plexus. Overall, these results suggest that Ezh2 is an important epigenetic modifier for the enteric neural crest cell development through repression of Zic1, Pax3, and Sox10.
    [Show full text]
  • To Proliferate Or to Die: Role of Id3 in Cell Cycle Progression and Survival of Neural Crest Progenitors
    Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press To proliferate or to die: role of Id3 in cell cycle progression and survival of neural crest progenitors Yun Kee and Marianne Bronner-Fraser1 Division of Biology, California Institute of Technology, Pasadena, California 91125, USA The neural crest is a unique population of mitotically active, multipotent progenitors that arise at the vertebrate neural plate border. Here, we show that the helix–loop–helix transcriptional regulator Id3 has a novel role in cell cycle progression and survival of neural crest progenitors in Xenopus. Id3 is localized at the neural plate border during gastrulation and neurulation, overlapping the domain of neural crest induction. Morpholino oligonucleotide-mediated depletion of Id3 results in the absence of neural crest precursors and a resultant loss of neural crest derivatives. This appears to be mediated by cell cycle inhibition followed by cell death of the neural crest progenitor pool, rather than a cell fate switch. Conversely, overexpression of Id3 increases cell proliferation and results in expansion of the neural crest domain. Our data suggest that Id3 functions by a novel mechanism, independent of cell fate determination, to mediate the decision of neural crest precursors to proliferate or die. [Keywords: Xenopus; Id3; neural crest; cell cycle; survival] Received September 1, 2004; revised version accepted January 19, 2005. The neural crest is an embryonic cell population that origi- et al. 2003), c-Myc (Bellmeyer et al. 2003), and Msx1 nates from the lateral edges of the neural plate during (Tribulo et al. 2003) have been identified in Xenopus nervous system formation.
    [Show full text]
  • A Combination of GATA3 and SOX10 Is Useful for the Diagnosis of Metastatic Triple-Negative Breast Cancer☆ Gary H
    Human Pathology (2019) 85,221–227 www.elsevier.com/locate/humpath Original contribution A combination of GATA3 and SOX10 is useful for the diagnosis of metastatic triple-negative breast cancer☆ Gary H. Tozbikian MD⁎, Debra L. Zynger MD Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA Received 9 July 2018; revised 2 November 2018; accepted 7 November 2018 Keywords: Summary In metastatic breast cancer (MBC), it can be difficult to establish the origin if the primary tumor is Triple negative; triple negative or if there is a loss of biomarker expression. SOX10 expression has been reported in primary Breast cancer; triple-negative breast cancer but is poorly studied in metastatic lesions. In this study, the diagnostic utility of SOX10; a panel of SOX10, GATA3, and androgen receptor (AR) in MBC negative for estrogen receptor, progester- GATA3; one receptor, and human epidermal growth factor receptor 2 was evaluated and compared with the expres- Metastatic; sion of these markers in the matched primary breast cancer. In a series of 57 triple-negative MBCs, 82% Primary were positive for GATA3, 58% for SOX10, and 25% for AR. Nearly all MBCs (95%) were positive for ei- ther GATA3 or SOX10, with 46% dual positive and 5% of cases negative for both markers. Most GATA3- negative MBC cases were SOX10 positive (70%). AR expression was only seen in GATA3-positive MBC (25%) and was significantly more frequent in SOX10-negative MBC (48%) versus SOX10-positive MBC (9%; P = .001). Concordance for GATA3, SOX10, and AR between the primary and metastasis was 89%, 88%, and 80%, respectively.
    [Show full text]
  • Spatial Distribution of Leading Pacemaker Sites in the Normal, Intact Rat Sinoa
    Supplementary Material Supplementary Figure 1: Spatial distribution of leading pacemaker sites in the normal, intact rat sinoatrial 5 nodes (SAN) plotted along a normalized y-axis between the superior vena cava (SVC) and inferior vena 6 cava (IVC) and a scaled x-axis in millimeters (n = 8). Colors correspond to treatment condition (black: 7 baseline, blue: 100 µM Acetylcholine (ACh), red: 500 nM Isoproterenol (ISO)). 1 Supplementary Figure 2: Spatial distribution of leading pacemaker sites before and after surgical 3 separation of the rat SAN (n = 5). Top: Intact SAN preparations with leading pacemaker sites plotted during 4 baseline conditions. Bottom: Surgically cut SAN preparations with leading pacemaker sites plotted during 5 baseline conditions (black) and exposure to pharmacological stimulation (blue: 100 µM ACh, red: 500 nM 6 ISO). 2 a &DUGLDFIoQChDQQHOV .FQM FOXVWHU &DFQDG &DFQDK *MD &DFQJ .FQLS .FQG .FQK .FQM &DFQDF &DFQE .FQM í $WSD .FQD .FQM í .FQN &DVT 5\U .FQM &DFQJ &DFQDG ,WSU 6FQD &DFQDG .FQQ &DFQDJ &DFQDG .FQD .FQT 6FQD 3OQ 6FQD +FQ *MD ,WSU 6FQE +FQ *MG .FQN .FQQ .FQN .FQD .FQE .FQQ +FQ &DFQDD &DFQE &DOP .FQM .FQD .FQN .FQG .FQN &DOP 6FQD .FQD 6FQE 6FQD 6FQD ,WSU +FQ 6FQD 5\U 6FQD 6FQE 6FQD .FQQ .FQH 6FQD &DFQE 6FQE .FQM FOXVWHU V6$1 L6$1 5$ /$ 3 b &DUGLDFReFHSWRUV $GUDF FOXVWHU $GUDD &DY &KUQE &KUP &KJD 0\O 3GHG &KUQD $GUE $GUDG &KUQE 5JV í 9LS $GUDE 7SP í 5JV 7QQF 3GHE 0\K $GUE *QDL $QN $GUDD $QN $QN &KUP $GUDE $NDS $WSE 5DPS &KUP 0\O &KUQD 6UF &KUQH $GUE &KUQD FOXVWHU V6$1 L6$1 5$ /$ 4 c 1HXURQDOPURWHLQV
    [Show full text]
  • Transcription Factor Gene Expression Profiling and Analysis of SOX Gene Family Transcription Factors in Human Limbal Epithelial
    Transcription factor gene expression profiling and analysis of SOX gene family transcription factors in human limbal epithelial progenitor cells Der Naturwissenschaftlichen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg zur Erlangung des Doktorgrades Dr. rer. nat. vorgelegt von Dr. med. Johannes Menzel-Severing aus Bonn Als Dissertation genehmigt von der Naturwissenschaftlichen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg Tag der mündlichen Prüfung: 7. Februar 2018 Vorsitzender des Promotionsorgans: Prof. Dr. Georg Kreimer Gutachter: Prof. Dr. Andreas Feigenspan Prof. Dr. Ursula Schlötzer-Schrehardt 1 INDEX 1. ABSTRACTS Page 1.1. Abstract in English 4 1.2. Zusammenfassung auf Deutsch 7 2. INTRODUCTION 2.1. Anatomy and histology of the cornea and the corneal surface 11 2.2. Homeostasis of corneal epithelium and the limbal stem cell paradigm 13 2.3. The limbal stem cell niche 15 2.4. Cell therapeutic strategies in ocular surface disease 17 2.5. Alternative cell sources for transplantation to the corneal surface 18 2.6. Transcription factors in cell differentiation and reprogramming 21 2.7. Transcription factors in limbal epithelial cells 22 2.8. Research question 25 3. MATERIALS AND METHODS 3.1. Human donor corneas 27 3.2. Laser Capture Microdissection (LCM) 28 3.3. RNA amplification and RT2 profiler PCR arrays 29 3.4. Real-time PCR analysis 33 3.5. Immunohistochemistry 34 3.6. Limbal epithelial cell culture 38 3.7. Transcription-factor knockdown/overexpression in vitro 39 3.8. Proliferation assay 40 3.9. Western blot 40 3.10. Statistical analysis 41 2 4. RESULTS 4.1. Quality control of LCM-isolated and amplified RNA 42 4.2.
    [Show full text]
  • Interspecies Difference in the Regulation of Melanocyte Development by SOX10 and MITF
    Interspecies difference in the regulation of melanocyte development by SOX10 and MITF Ling Hou*†, Heinz Arnheiter‡, and William J. Pavan*† *Genetic Disease Research Branch, National Human Genome Research Institute, and ‡Mammalian Development Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-4472 Communicated by Francis S. Collins, National Institutes of Health, Bethesda, MD, April 17, 2006 (received for review March 10, 2006) There is increasing indication that interspecific phenotypic differ- gous for a targeted mutation in Sox10 (12). In humans, SOX10 ences result from variations in gene-regulatory interactions. Here mutations are associated with Waardenburg–Hirschsprung dis- we provide evidence that mice differ from zebrafish in the way ease [Online Mendelian Inheritance in Man (OMIM) accession they use homologous key components to regulate pigment cell no. 277580] (13) and a complex neurocristopathy that combines differentiation. In both zebrafish and mice, one transcription peripheral demyelinating neuropathy, central leukodystrophy, factor, SOX10, controls the expression of another, MITF (microph- Waardenburg syndrome, and Hirschprung disease (PCWH, thalmia-associated transcription factor), which in turn regulates a OMIM accession no. 609136) (14). MITF, on the other hand, is set of genes critical for pigment cell development and pigmenta- a basic helix–loop–helix leucine zipper transcription factor tion. Mutations in either Sox10 or Mitf impair pigment cell devel- whose mutations lead to pigmentary abnormalities and, depend- opment. In Sox10-mutant zebrafish, experimentally induced ex- ing on the species, deafness and eye abnormalities but none of pression of Mitf fully rescues pigmentation. Using lineage-directed the intestinal or demyelinating and dysmyelinating symptoms gene transfer, we show that, in the mouse, Mitf can rescue seen with Sox10 mutations (6, 15).
    [Show full text]
  • Sox10 Has a Broad Expression Pattern in Gliomas and Enhances Platelet-Derived Growth Factor-B–Induced Gliomagenesis
    Sox10 Has a Broad Expression Pattern in Gliomas and Enhances Platelet-Derived Growth Factor-B–Induced Gliomagenesis Maria Ferletta, Lene Uhrbom, Tommie Olofsson, Fredrik Ponte´n, and Bengt Westermark Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden Abstract without any known intermediate stages of the tumor, whereas In a previously published insertional mutagenesis screen secondary glioblastoma arises by progression from a lower for candidate brain tumor genes in the mouse using a grade to a higher tumor grade. Common genetic alterations in Moloney mouse leukemia virus encodingplatelet-derived primary glioblastoma are amplification of EGFR and MDM2 growth factor (PDGF)-B, the Sox10 gene was tagged in and deletions of the INK4A gene (1, 2). During the progression five independent tumors. The proviral integrations of secondary glioblastoma, mutations accumulate over time suggest an enhancer effect on Sox10. All Moloney murine and more than 65% of the tumors have mutations in TRP53. leukemia virus/PDGFB tumors had a high protein Overexpression of the platelet-derived growth factor receptor-a expression of Sox10 independently of malignant grade (PDGFRA) and PDGFA are characteristic for secondary glio- or tumor type. To investigate the role of Sox10 in blastoma (3). Constitutive expression of growth factors and gliomagenesis, we used the RCAS/tv-a mouse model in their receptors has been shown to be necessary for the develop- which the expression of retroviral-encoded genes can be ment of brain tumors resulting in autocrine stimulation and directed to glial progenitor cells (Ntv-a mice). Both Ntv-a increased activity of downstream pathways (4). Inactivation transgenic mice, wild-type, and Ntv-a p19Arf null mice of the tumor suppressor gene phosphatase and tensin homo- were injected with RCAS-SOX10 alone or in combination logue (PTEN; refs.
    [Show full text]