CRX Is a Diagnostic Marker of Retinal and Pineal Lineage Tumors
Publication Date
November 20, 2009
Journal
PLOS ONE
Authors
Sandro Santagata, Cecile L. Maire, Ahmed Idbaih, Lars Geffers, et al
Volume
4
Issue
11
Pages
e7932
DOI
https://dx.plos.org/10.1371/journal.pone.0007932
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0007932
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/19936203
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775954
Europe PMC
http://europepmc.org/abstract/MED/19936203
Web of Science
000272004800013
Scopus
70949098077
Mendeley
http://www.mendeley.com/research/crx-diagnostic-marker-retinal-pineal-lineage-tumors
Events
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Mendeley | Further Information

{"title"=>"CRX is a diagnostic marker of retinal and pineal lineage tumors", "type"=>"journal", "authors"=>[{"first_name"=>"Sandro", "last_name"=>"Santagata", "scopus_author_id"=>"6701622288"}, {"first_name"=>"Cecile L.", "last_name"=>"Maire", "scopus_author_id"=>"6603788850"}, {"first_name"=>"Ahmed", "last_name"=>"Idbaih", "scopus_author_id"=>"22134879200"}, {"first_name"=>"Lars", "last_name"=>"Geffers", "scopus_author_id"=>"6507892725"}, {"first_name"=>"Mick", "last_name"=>"Correll", "scopus_author_id"=>"57194642775"}, {"first_name"=>"Kristina", "last_name"=>"Holton", "scopus_author_id"=>"35321121100"}, {"first_name"=>"John", "last_name"=>"Quackenbush", "scopus_author_id"=>"7004974520"}, {"first_name"=>"Keith L.", "last_name"=>"Ligon", "scopus_author_id"=>"26643307700"}], "year"=>2009, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"355732646", "sgr"=>"70949098077", "pmid"=>"19936203", "scopus"=>"2-s2.0-70949098077", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "doi"=>"10.1371/journal.pone.0007932", "issn"=>"19326203"}, "id"=>"23157953-8930-3cb5-99c4-2700aa317956", "abstract"=>"BACKGROUND: CRX is a homeobox transcription factor whose expression and function is critical to maintain retinal and pineal lineage cells and their progenitors. To determine the biologic and diagnostic potential of CRX in human tumors of the retina and pineal, we examined its expression in multiple settings.\n\nMETHODOLOGY/PRINCIPAL FINDINGS: Using situ hybridization and immunohistochemistry we show that Crx RNA and protein expression are exquisitely lineage restricted to retinal and pineal cells during normal mouse and human development. Gene expression profiling analysis of a wide range of human cancers and cancer cell lines also supports that CRX RNA is highly lineage restricted in cancer. Immunohistochemical analysis of 22 retinoblastomas and 13 pineal parenchymal tumors demonstrated strong expression of CRX in over 95% of these tumors. Importantly, CRX was not detected in the majority of tumors considered in the differential diagnosis of pineal region tumors (n = 78). The notable exception was medulloblastoma, 40% of which exhibited CRX expression in a heterogeneous pattern readily distinguished from that seen in retino-pineal tumors.\n\nCONCLUSIONS/SIGNIFICANCE: These findings describe new potential roles for CRX in human cancers and highlight the general utility of lineage restricted transcription factors in cancer biology. They also identify CRX as a sensitive and specific clinical marker and a potential lineage dependent therapeutic target in retinoblastoma and pineoblastoma.", "link"=>"http://www.mendeley.com/research/crx-diagnostic-marker-retinal-pineal-lineage-tumors", "reader_count"=>23, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>5, "Student > Master"=>1, "Other"=>1, "Student > Bachelor"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>5, "Student > Master"=>1, "Other"=>1, "Student > Bachelor"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>7, "Medicine and Dentistry"=>8, "Neuroscience"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>8}, "Neuroscience"=>{"Neuroscience"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>7}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>2}}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/875949"], "description"=>"<p>Antibody Panel Used In This Study.</p>", "links"=>[], "tags"=>["developmental biology/neurodevelopment", "neurological disorders/neuroendocrinology and pituitary", "neurological disorders/neuro-oncology", "oncology/neuro-oncology", "oncology/pediatric oncology", "pathology/neuropathology"], "article_id"=>546400, "categories"=>["Neuroscience", "Cancer", "Developmental Biology", "Medicine"], "users"=>["Sandro Santagata", "Cecile L. Maire", "Ahmed Idbaih", "Lars Geffers", "Mick Correll", "Kristina Holton", "John Quackenbush", "Keith L. Ligon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007932.t001", "stats"=>{"downloads"=>3, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Antibody_Panel_Used_In_This_Study_/546400", "title"=>"Antibody Panel Used In This Study.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-11-20 01:46:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/875369"], "description"=>"<p>Human enucleation specimen with retinoblastoma (rb) abutting and infiltrating a portion of optic nerve (A, opt), immunohistochemical staining for CRX demonstrates robust expression in the nuclei of most all tumor cells and an absence of CRX expression in cells of the optic nerve (B). 100x original magnification. A higher magnification view of human retinoblastoma demonstrating distinct Flexner-Wintersteiner rosettes (C, D arrows) also reveals strong expression of CRX in tumor nuclei particularly in rosettes (D). Original magnification 400x.</p>", "links"=>[], "tags"=>["developmental biology/neurodevelopment", "neurological disorders/neuroendocrinology and pituitary", "neurological disorders/neuro-oncology", "oncology/neuro-oncology", "oncology/pediatric oncology", "pathology/neuropathology"], "article_id"=>545809, "categories"=>["Neuroscience", "Cancer", "Developmental Biology", "Medicine"], "users"=>["Sandro Santagata", "Cecile L. Maire", "Ahmed Idbaih", "Lars Geffers", "Mick Correll", "Kristina Holton", "John Quackenbush", "Keith L. Ligon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007932.g004", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CRX_is_a_sensitive_marker_for_retinoblastoma_/545809", "title"=>"CRX is a sensitive marker for retinoblastoma.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-11-20 01:36:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/875985"], "description"=>"<p><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007932#pone-0007932-t002\" target=\"_blank\">Table 2</a> Legend:</p><p>0 indicates no staining; 1+, <5% tumor cells reactive; 2+, 5% to 25% tumor cells reactive; 3+, 26% to 50% tumor cells reactive; 4+, 51% to 75% tumor cells.</p><p>reactive; 5+, >75% tumor cells reactive. GFAP, Glial Fibrillary Acid Protein; Pineal Parenchymal Tumor of Intermediate Differentiation (PPTID).</p>", "links"=>[], "tags"=>["staining", "pineal", "parenchymal"], "article_id"=>546435, "categories"=>["Neuroscience", "Cancer", "Developmental Biology", "Medicine"], "users"=>["Sandro Santagata", "Cecile L. Maire", "Ahmed Idbaih", "Lars Geffers", "Mick Correll", "Kristina Holton", "John Quackenbush", "Keith L. Ligon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007932.t002", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Immunohistochemical_Staining_Results_on_Pineal_Parenchymal_Tumors_/546435", "title"=>"Immunohistochemical Staining Results on Pineal Parenchymal Tumors.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-11-20 01:47:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/875477"], "description"=>"<p>Immunohistochemistry reveals robust intranuclear expression of CRX in the nuclei of various tumors of pineal lineage: pineocytoma (A, B), pineal parenchymal tumor of intermediate differentiation (C, D) and a pineoblastoma (E, F). Original magnification, 400x.</p>", "links"=>[], "tags"=>["tumors", "pineal"], "article_id"=>545937, "categories"=>["Neuroscience", "Cancer", "Developmental Biology", "Medicine"], "users"=>["Sandro Santagata", "Cecile L. Maire", "Ahmed Idbaih", "Lars Geffers", "Mick Correll", "Kristina Holton", "John Quackenbush", "Keith L. Ligon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007932.g005", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CRX_is_a_sensitive_marker_for_tumors_of_pineal_lineage_/545937", "title"=>"CRX is a sensitive marker for tumors of pineal lineage.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-11-20 01:38:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/875598"], "description"=>"<p>Immunohistochemistry for CRX in tumors frequently considered in the differential diagnosis of pineoblastoma including atypical teratoid rhabdoid tumor (ATRT) (A, B), CNS germinoma (C, D) and primitive neuroectodermal tumor (PNET) (E, F) reveals an absence of staining. Immunostaining for CRX in classic medulloblastoma reveals heterogeneous intranuclear staining in scattered cells in a subset of tumors (G, H). Original magnification, 400x.</p>", "links"=>[], "tags"=>["tumors", "retinal", "pineal"], "article_id"=>546050, "categories"=>["Neuroscience", "Cancer", "Developmental Biology", "Medicine"], "users"=>["Sandro Santagata", "Cecile L. Maire", "Ahmed Idbaih", "Lars Geffers", "Mick Correll", "Kristina Holton", "John Quackenbush", "Keith L. Ligon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007932.g006", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CRX_is_a_specific_marker_for_tumors_of_retinal_and_pineal_lineage_/546050", "title"=>"CRX is a specific marker for tumors of retinal and pineal lineage.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-11-20 01:40:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/434087", "https://ndownloader.figshare.com/files/434110", "https://ndownloader.figshare.com/files/434138", "https://ndownloader.figshare.com/files/434149"], "description"=>"<div><h3>Background</h3><p>CRX is a homeobox transcription factor whose expression and function is critical to maintain retinal and pineal lineage cells and their progenitors. To determine the biologic and diagnostic potential of CRX in human tumors of the retina and pineal, we examined its expression in multiple settings.</p><h3>Methodology/Principal Findings</h3><p>Using situ hybridization and immunohistochemistry we show that Crx RNA and protein expression are exquisitely lineage restricted to retinal and pineal cells during normal mouse and human development. Gene expression profiling analysis of a wide range of human cancers and cancer cell lines also supports that <em>CRX</em> RNA is highly lineage restricted in cancer. Immunohistochemical analysis of 22 retinoblastomas and 13 pineal parenchymal tumors demonstrated strong expression of CRX in over 95% of these tumors. Importantly, CRX was not detected in the majority of tumors considered in the differential diagnosis of pineal region tumors (n = 78). The notable exception was medulloblastoma, 40% of which exhibited CRX expression in a heterogeneous pattern readily distinguished from that seen in retino-pineal tumors.</p><h3>Conclusions/Significance</h3><p>These findings describe new potential roles for CRX in human cancers and highlight the general utility of lineage restricted transcription factors in cancer biology. They also identify CRX as a sensitive and specific clinical marker and a potential lineage dependent therapeutic target in retinoblastoma and pineoblastoma.</p></div>", "links"=>[], "tags"=>["crx", "diagnostic", "retinal", "pineal", "lineage", "tumors"], "article_id"=>145649, "categories"=>["Neuroscience", "Cancer", "Developmental Biology", "Medicine"], "users"=>["Sandro Santagata", "Cecile L. Maire", "Ahmed Idbaih", "Lars Geffers", "Mick Correll", "Kristina Holton", "John Quackenbush", "Keith L. Ligon"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0007932.s001", "https://dx.doi.org/10.1371/journal.pone.0007932.s002", "https://dx.doi.org/10.1371/journal.pone.0007932.s003", "https://dx.doi.org/10.1371/journal.pone.0007932.s004"], "stats"=>{"downloads"=>9, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/CRX_Is_a_Diagnostic_Marker_of_Retinal_and_Pineal_Lineage_Tumors/145649", "title"=>"CRX Is a Diagnostic Marker of Retinal and Pineal Lineage Tumors", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2009-11-20 01:34:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/875246"], "description"=>"<p>Immunohistochemical analysis of CRX expression demonstrates robust expression in the nuclei of cones and rod cells in the outer nuclear layer (onl) as well as much weaker expression in a subset of nuclei in the inner nuclear layer (inl) that abut the outer plexiform layer (opl) of the adult human retina (A, B). This region is populated predominantly by horizontal and bipolar cells. The ganglion cell layer does not express CRX. Expression of CRX in the pinealocytes of a surgically resected normal pineal gland (C, D) and pineal cyst (E, F arrows). Gliotic regions composing the cyst wall do not express CRX (lower left corner of E, F). Optic fiber layer (ofl), ganglion cell layer (gcl), inner plexiform layer (ipl), inner segment (is), outer segment (os), pineal cyst (pc). Original magnification 200x (A, B, E, F) and 400x (C, D).</p>", "links"=>[], "tags"=>["retina"], "article_id"=>545701, "categories"=>["Neuroscience", "Cancer", "Developmental Biology", "Medicine"], "users"=>["Sandro Santagata", "Cecile L. Maire", "Ahmed Idbaih", "Lars Geffers", "Mick Correll", "Kristina Holton", "John Quackenbush", "Keith L. Ligon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007932.g003", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CRX_protein_is_highly_expressed_in_the_normal_adult_human_retina_and_pineal_/545701", "title"=>"CRX protein is highly expressed in the normal adult human retina and pineal.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-11-20 01:35:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/874947"], "description"=>"<p>RNA <i>in situ</i> hybridization using antisense riboprobes for <i>Crx</i> at developmental stage E14.5 in NMRI mouse embryos (Genepaint Set ID DA117) demonstrates strong expression in the ventricular zone of the retina (A, B) and in the developing pineal which appears as a diverticulum in the diencephalic roof of the third ventricle (C, D). <i>Crx</i> in the brain of a P7 C57BL/6 mouse (Genepaint Set ID MH1082) demonstrates strong expression restricted to the pineal primordium (E, F)<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007932#pone.0007932-Visel1\" target=\"_blank\">[40]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007932#pone.0007932-Yaylaoglu1\" target=\"_blank\">[41]</a>.</p>", "links"=>[], "tags"=>["mrna", "restricted", "retina", "pineal", "murine"], "article_id"=>545398, "categories"=>["Neuroscience", "Cancer", "Developmental Biology", "Medicine"], "users"=>["Sandro Santagata", "Cecile L. Maire", "Ahmed Idbaih", "Lars Geffers", "Mick Correll", "Kristina Holton", "John Quackenbush", "Keith L. Ligon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007932.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Strong_expression_of_Crx_mRNA_is_highly_restricted_to_the_retina_and_pineal_during_normal_murine_development_/545398", "title"=>"Strong expression of <i>Crx</i> mRNA is highly restricted to the retina and pineal during normal murine development.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-11-20 01:29:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/875094"], "description"=>"<p>Sequence alignment (Smith-Waterman) of human CRX immunogen (amino acids 166 to 285) with OTX1 and OTX2 (A) demonstrates low identity for the relevant epitope (<40%). Residue number 1 correpsonds with residue 166 of CRX. AMAS conservation scores are listed below the alignment. Immunoblot of native, non-denatured GST-Crx, GST alone and with the unrelated protein GST-Cry1 demonstrates robust specificity of the H120 antibody for native Crx (B). Immunohistochemical analysis using the H120 anti-Crx antibody demonstrates strong reactivity in the developing retina of E14.5 mice, which are heterozygous for Crx (<i>Crx</i> +/−), while the signal is absent in the retina of <i>Crx</i> knockout mice (<i>Crx</i> −/−) (C). Competition assays with CRX protein on tissue sections of human retina and retinoblastoma (cells at top of image) demonstrate the immunoreactivity of the H120 anti-Crx antibody is specifically competed away with 1∶1 molar amounts of purified GST-Crx protein in normal and tumor cells.</p>", "links"=>[], "tags"=>["antibody"], "article_id"=>545555, "categories"=>["Neuroscience", "Cancer", "Developmental Biology", "Medicine"], "users"=>["Sandro Santagata", "Cecile L. Maire", "Ahmed Idbaih", "Lars Geffers", "Mick Correll", "Kristina Holton", "John Quackenbush", "Keith L. Ligon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007932.g002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Validation_of_antibody_specificity_/545555", "title"=>"Validation of antibody specificity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-11-20 01:32:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/875709"], "description"=>"<p>Examination of H&E stained sections of a pineal tumor reveals high-grade histologic features somewhat suggestive of glioblastoma (A). Immunohistochemistry showed nuclear CRX in normal pineocytes (red arrow) that are infiltrated by the invasive tumor which is negative for CRX (black arrow) (B). The germ cell marker OCT4 is absent in neoplastic cells and in pineocytes (C). However, robust expression of OLIG2 is evident in neoplastic cells but absent in infiltrated pineocytes (arrow) (D). Original magnification 400x.</p>", "links"=>[], "tags"=>["lineage-specific", "transcription", "glioblastoma", "pineal"], "article_id"=>546162, "categories"=>["Neuroscience", "Cancer", "Developmental Biology", "Medicine"], "users"=>["Sandro Santagata", "Cecile L. Maire", "Ahmed Idbaih", "Lars Geffers", "Mick Correll", "Kristina Holton", "John Quackenbush", "Keith L. Ligon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007932.g007", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Diagnostic_use_of_lineage_specific_transcription_factor_8220_code_8221_in_evaluation_of_a_glioblastoma_of_the_pineal_region_/546162", "title"=>"Diagnostic use of lineage-specific transcription factor “code” in evaluation of a glioblastoma of the pineal region.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-11-20 01:42:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/875824"], "description"=>"<p>Analysis of <i>CRX</i> mRNA expression was assessed using publically available expression profiling data from over 1900 primary tumor samples and demonstrates elevated expression of <i>CRX</i> predominantly in medulloblastoma samples (A). Pineal parenchymal tumor data is not available. Oncomine data from 316 human cancer cell lines demonstrates 26 lines with significant expression of <i>CRX</i> relative to other lines as demonstrated in a scatter plot (B). All expression levels are relative to the total dataset. The highest relative expression level was present in the sole retinoblastoma cell line (Y79) within the dataset (C). High level expression was also noted in the only two medulloblastoma cell lines present in the dataset (D341 and D283). Other CNS tumor cell lines showed no significant increase in <i>CRX</i> expression (8 astrocytoma, 1 PNET). Additional validation using same independent normalization methods as for tissues produced similar results (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007932#pone.0007932.s002\" target=\"_blank\">Fig. S2</a>). Data utilized in construction of plots is provided as <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007932#pone.0007932.s003\" target=\"_blank\">Table S1</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007932#pone.0007932.s004\" target=\"_blank\">S2</a>.</p>", "links"=>[], "tags"=>["profiling", "demonstrates", "lineage-restricted", "cancer", "tissues"], "article_id"=>546271, "categories"=>["Neuroscience", "Cancer", "Developmental Biology", "Medicine"], "users"=>["Sandro Santagata", "Cecile L. Maire", "Ahmed Idbaih", "Lars Geffers", "Mick Correll", "Kristina Holton", "John Quackenbush", "Keith L. Ligon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007932.g008", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_profiling_analysis_demonstrates_CRX_expression_is_highly_lineage_restricted_across_a_broad_range_of_cancer_tissues_and_cell_lines_/546271", "title"=>"Expression profiling analysis demonstrates <i>CRX</i> expression is highly lineage-restricted across a broad range of cancer tissues and cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-11-20 01:44:31"}

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Relative Metric

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