Epstein-Barr virus from Burkitt Lymphoma biopsies from Africa and South America share novel LMP-1 promoter and gene variations
Identifieur interne : 000061 ( Pmc/Curation ); précédent : 000060; suivant : 000062Epstein-Barr virus from Burkitt Lymphoma biopsies from Africa and South America share novel LMP-1 promoter and gene variations
Auteurs : Haiyan Lei ; Tianwei Li ; Bingjie Li ; Shien Tsai ; Robert J. Biggar ; Francis Nkrumah [Ghana] ; Janet Neequaye [Ghana] ; Marina Gutierrez [Argentine] ; Sidnei Epelman [Brésil] ; Sam M. Mbulaiteye ; Kishor Bhatia ; Shyh-Ching LoSource :
- Scientific Reports [ 2045-2322 ] ; 2015.
Abstract
Epstein Barr virus (EBV) sequence variation is thought to contribute to Burkitt lymphoma (BL), but lack of data from primary BL tumors hampers efforts to test this hypothesis. We directly sequenced EBV from 12 BL biopsies from Ghana, Brazil, and Argentina, aligned the obtained reads to the wild-type (WT) EBV reference sequence, and compared them with 100 published EBV genomes from normal and diseased people from around the world. The 12 BL EBVs were Type 1. Eleven clustered close to each other and to EBV from Raji BL cell line, but away from 12 EBVs reported from other BL-derived cell lines and away from EBV from NPC and healthy people from Asia. We discovered 23 shared novel nucleotide-base changes in the latent membrane protein (LMP)-1 promoter and gene (associated with 9 novel amino acid changes in the LMP-1 protein) of the 11 BL EBVs. Alignment of this region for the 112 EBV genomes revealed four distinct patterns, tentatively termed patterns A to D. The distribution of BL EBVs was 48%, 8%, 24% and 20% for patterns A to D, respectively; the NPC EBV’s were Pattern B, and EBV-WT was pattern D. Further work is needed to investigate the association between EBV LMP-1 patterns with BL.
Url:
DOI: 10.1038/srep16706
PubMed: 26593963
PubMed Central: 4655394
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Haiyan Lei<affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation><affiliation><nlm:aff id="a2"><institution>Bethesda Maryland</institution>, formerly<country>NCI</country></nlm:aff><wicri:noCountry code="nlm country">NCI</wicri:noCountry></affiliation><affiliation><nlm:aff id="a7"><institution>Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health</institution>, Rockville,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation><affiliation><nlm:aff id="a7"><institution>Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health</institution>, Rockville,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation>Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Epstein-Barr virus from Burkitt Lymphoma biopsies from Africa and South America share novel LMP-1 promoter and gene variations</title><author><name sortKey="Lei, Haiyan" sort="Lei, Haiyan" uniqKey="Lei H" first="Haiyan" last="Lei">Haiyan Lei</name><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Li, Tianwei" sort="Li, Tianwei" uniqKey="Li T" first="Tianwei" last="Li">Tianwei Li</name><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Li, Bingjie" sort="Li, Bingjie" uniqKey="Li B" first="Bingjie" last="Li">Bingjie Li</name><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Tsai, Shien" sort="Tsai, Shien" uniqKey="Tsai S" first="Shien" last="Tsai">Shien Tsai</name><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Biggar, Robert J" sort="Biggar, Robert J" uniqKey="Biggar R" first="Robert J." last="Biggar">Robert J. Biggar</name><affiliation><nlm:aff id="a2"><institution>Bethesda Maryland</institution>, formerly<country>NCI</country></nlm:aff><wicri:noCountry code="nlm country">NCI</wicri:noCountry></affiliation></author><author><name sortKey="Nkrumah, Francis" sort="Nkrumah, Francis" uniqKey="Nkrumah F" first="Francis" last="Nkrumah">Francis Nkrumah</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Noguchi Memorial Institute</institution>, Accra,<country>Ghana</country></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Neequaye, Janet" sort="Neequaye, Janet" uniqKey="Neequaye J" first="Janet" last="Neequaye">Janet Neequaye</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Child Health, University of Ghana</institution>, Accra,<country>Ghana</country></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gutierrez, Marina" sort="Gutierrez, Marina" uniqKey="Gutierrez M" first="Marina" last="Gutierrez">Marina Gutierrez</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Laboratorio Stamboulian, Buenos Aires</institution>,<country>Argentina</country></nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Epelman, Sidnei" sort="Epelman, Sidnei" uniqKey="Epelman S" first="Sidnei" last="Epelman">Sidnei Epelman</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Department of Pediatric Oncology, St Marcelina Hospital</institution>, Sao Paolo,<country>Brazil</country></nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mbulaiteye, Sam M" sort="Mbulaiteye, Sam M" uniqKey="Mbulaiteye S" first="Sam M." last="Mbulaiteye">Sam M. Mbulaiteye</name><affiliation><nlm:aff id="a7"><institution>Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health</institution>, Rockville,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Bhatia, Kishor" sort="Bhatia, Kishor" uniqKey="Bhatia K" first="Kishor" last="Bhatia">Kishor Bhatia</name><affiliation><nlm:aff id="a7"><institution>Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health</institution>, Rockville,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Lo, Shyh Ching" sort="Lo, Shyh Ching" uniqKey="Lo S" first="Shyh-Ching" last="Lo">Shyh-Ching Lo</name><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26593963</idno><idno type="pmc">4655394</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655394</idno><idno type="RBID">PMC:4655394</idno><idno type="doi">10.1038/srep16706</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000061</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000061</idno><idno type="wicri:Area/Pmc/Curation">000061</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000061</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Epstein-Barr virus from Burkitt Lymphoma biopsies from Africa and South America share novel LMP-1 promoter and gene variations</title><author><name sortKey="Lei, Haiyan" sort="Lei, Haiyan" uniqKey="Lei H" first="Haiyan" last="Lei">Haiyan Lei</name><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Li, Tianwei" sort="Li, Tianwei" uniqKey="Li T" first="Tianwei" last="Li">Tianwei Li</name><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Li, Bingjie" sort="Li, Bingjie" uniqKey="Li B" first="Bingjie" last="Li">Bingjie Li</name><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Tsai, Shien" sort="Tsai, Shien" uniqKey="Tsai S" first="Shien" last="Tsai">Shien Tsai</name><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Biggar, Robert J" sort="Biggar, Robert J" uniqKey="Biggar R" first="Robert J." last="Biggar">Robert J. Biggar</name><affiliation><nlm:aff id="a2"><institution>Bethesda Maryland</institution>, formerly<country>NCI</country></nlm:aff><wicri:noCountry code="nlm country">NCI</wicri:noCountry></affiliation></author><author><name sortKey="Nkrumah, Francis" sort="Nkrumah, Francis" uniqKey="Nkrumah F" first="Francis" last="Nkrumah">Francis Nkrumah</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Noguchi Memorial Institute</institution>, Accra,<country>Ghana</country></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Neequaye, Janet" sort="Neequaye, Janet" uniqKey="Neequaye J" first="Janet" last="Neequaye">Janet Neequaye</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Child Health, University of Ghana</institution>, Accra,<country>Ghana</country></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gutierrez, Marina" sort="Gutierrez, Marina" uniqKey="Gutierrez M" first="Marina" last="Gutierrez">Marina Gutierrez</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Laboratorio Stamboulian, Buenos Aires</institution>,<country>Argentina</country></nlm:aff><country xml:lang="fr">Argentine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Epelman, Sidnei" sort="Epelman, Sidnei" uniqKey="Epelman S" first="Sidnei" last="Epelman">Sidnei Epelman</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Department of Pediatric Oncology, St Marcelina Hospital</institution>, Sao Paolo,<country>Brazil</country></nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mbulaiteye, Sam M" sort="Mbulaiteye, Sam M" uniqKey="Mbulaiteye S" first="Sam M." last="Mbulaiteye">Sam M. Mbulaiteye</name><affiliation><nlm:aff id="a7"><institution>Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health</institution>, Rockville,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Bhatia, Kishor" sort="Bhatia, Kishor" uniqKey="Bhatia K" first="Kishor" last="Bhatia">Kishor Bhatia</name><affiliation><nlm:aff id="a7"><institution>Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health</institution>, Rockville,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author><author><name sortKey="Lo, Shyh Ching" sort="Lo, Shyh Ching" uniqKey="Lo S" first="Shyh-Ching" last="Lo">Shyh-Ching Lo</name><affiliation><nlm:aff id="a1"><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></nlm:aff><wicri:noCountry code="nlm country">Maryland</wicri:noCountry></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Epstein Barr virus (EBV) sequence variation is thought to contribute to Burkitt lymphoma (BL), but lack of data from primary BL tumors hampers efforts to test this hypothesis. We directly sequenced EBV from 12 BL biopsies from Ghana, Brazil, and Argentina, aligned the obtained reads to the wild-type (WT) EBV reference sequence, and compared them with 100 published EBV genomes from normal and diseased people from around the world. The 12 BL EBVs were Type 1. Eleven clustered close to each other and to EBV from Raji BL cell line, but away from 12 EBVs reported from other BL-derived cell lines and away from EBV from NPC and healthy people from Asia. We discovered 23 shared novel nucleotide-base changes in the latent membrane protein (LMP)-1 promoter and gene (associated with 9 novel amino acid changes in the LMP-1 protein) of the 11 BL EBVs. Alignment of this region for the 112 EBV genomes revealed four distinct patterns, tentatively termed patterns A to D. The distribution of BL EBVs was 48%, 8%, 24% and 20% for patterns A to D, respectively; the NPC EBV’s were Pattern B, and EBV-WT was pattern D. Further work is needed to investigate the association between EBV LMP-1 patterns with BL.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Epstein, M A" uniqKey="Epstein M">M. A. Epstein</name></author><author><name sortKey="Achong, B G" uniqKey="Achong B">B. G. Achong</name></author><author><name sortKey="Barr, Y M" uniqKey="Barr Y">Y. M. Barr</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hjalgrim, H" uniqKey="Hjalgrim H">H. Hjalgrim</name></author><author><name sortKey="Engels, E A" uniqKey="Engels E">E. A. Engels</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Harabuchi, Y" uniqKey="Harabuchi Y">Y. Harabuchi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De The, G" uniqKey="De The G">G. de The</name></author><author><name sortKey="Ablashi, D V" uniqKey="Ablashi D">D. V. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id><journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id><journal-title-group><journal-title>Scientific Reports</journal-title></journal-title-group><issn pub-type="epub">2045-2322</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26593963</article-id><article-id pub-id-type="pmc">4655394</article-id><article-id pub-id-type="pii">srep16706</article-id><article-id pub-id-type="doi">10.1038/srep16706</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Epstein-Barr virus from Burkitt Lymphoma biopsies from Africa and South America share novel LMP-1 promoter and gene variations</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lei</surname><given-names>Haiyan</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Tianwei</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Bingjie</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Tsai</surname><given-names>Shien</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Biggar</surname><given-names>Robert J.</given-names></name><xref ref-type="aff" rid="a2">2</xref></contrib><contrib contrib-type="author"><name><surname>Nkrumah</surname><given-names>Francis</given-names></name><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Neequaye</surname><given-names>Janet</given-names></name><xref ref-type="aff" rid="a4">4</xref></contrib><contrib contrib-type="author"><name><surname>Gutierrez</surname><given-names>Marina</given-names></name><xref ref-type="aff" rid="a5">5</xref></contrib><contrib contrib-type="author"><name><surname>Epelman</surname><given-names>Sidnei</given-names></name><xref ref-type="aff" rid="a6">6</xref></contrib><contrib contrib-type="author"><name><surname>Mbulaiteye</surname><given-names>Sam M.</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a7">7</xref></contrib><contrib contrib-type="author"><name><surname>Bhatia</surname><given-names>Kishor</given-names></name><xref ref-type="aff" rid="a7">7</xref></contrib><contrib contrib-type="author"><name><surname>Lo</surname><given-names>Shyh-Ching</given-names></name><xref ref-type="corresp" rid="c2">b</xref><xref ref-type="aff" rid="a1">1</xref></contrib><aff id="a1"><label>1</label><institution>Center for Biologics Evaluation and Research, Food and Drug Administration</institution>, Silver Spring,<country>Maryland</country></aff><aff id="a2"><label>2</label><institution>Bethesda Maryland</institution>, formerly<country>NCI</country></aff><aff id="a3"><label>3</label><institution>Noguchi Memorial Institute</institution>, Accra,<country>Ghana</country></aff><aff id="a4"><label>4</label><institution>Department of Child Health, University of Ghana</institution>, Accra,<country>Ghana</country></aff><aff id="a5"><label>5</label><institution>Laboratorio Stamboulian, Buenos Aires</institution>,<country>Argentina</country></aff><aff id="a6"><label>6</label><institution>Department of Pediatric Oncology, St Marcelina Hospital</institution>, Sao Paolo,<country>Brazil</country></aff><aff id="a7"><label>7</label><institution>Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health</institution>, Rockville,<country>Maryland</country></aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>mbulaits@mail.nih.gov</email></corresp><corresp id="c2"><label>b</label><email>ShyhChing.Lo@fda.hhs.gov</email></corresp></author-notes><pub-date pub-type="epub"><day>23</day><month>11</month><year>2015</year></pub-date><pub-date pub-type="collection"><year>2015</year></pub-date><volume>5</volume><elocation-id>16706</elocation-id><history><date date-type="received"><day>01</day><month>07</month><year>2015</year></date><date date-type="accepted"><day>19</day><month>10</month><year>2015</year></date></history><permissions><copyright-statement>Copyright © 2015, Macmillan Publishers Limited</copyright-statement><copyright-year>2015</copyright-year><copyright-holder>Macmillan Publishers Limited</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>Epstein Barr virus (EBV) sequence variation is thought to contribute to Burkitt lymphoma (BL), but lack of data from primary BL tumors hampers efforts to test this hypothesis. We directly sequenced EBV from 12 BL biopsies from Ghana, Brazil, and Argentina, aligned the obtained reads to the wild-type (WT) EBV reference sequence, and compared them with 100 published EBV genomes from normal and diseased people from around the world. The 12 BL EBVs were Type 1. Eleven clustered close to each other and to EBV from Raji BL cell line, but away from 12 EBVs reported from other BL-derived cell lines and away from EBV from NPC and healthy people from Asia. We discovered 23 shared novel nucleotide-base changes in the latent membrane protein (LMP)-1 promoter and gene (associated with 9 novel amino acid changes in the LMP-1 protein) of the 11 BL EBVs. Alignment of this region for the 112 EBV genomes revealed four distinct patterns, tentatively termed patterns A to D. The distribution of BL EBVs was 48%, 8%, 24% and 20% for patterns A to D, respectively; the NPC EBV’s were Pattern B, and EBV-WT was pattern D. Further work is needed to investigate the association between EBV LMP-1 patterns with BL.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><title>Phylogenetic analysis based on heterogeneity of EBV genome sequences (A), amino acid sequences of EBNA-1 (B) and amino acid sequences of LMP-1 (C).</title><p>The 12 BL-EBVs genomes sequenced from BL tumors in our study are marked with three red stars. The 13 BL-EBV genomes previously sequenced from BL cell lines are marked with two blue stars. Type 2 EBVs are boxed in red rectangle(s). EBV genomes are classified into Pattern A (yellow), Pattern B (pink), Pattern C (blue) and Pattern D (no color) for the variations/mutations identified in the promoter region and the N-terminus of LMP-1.</p></caption><graphic xlink:href="srep16706-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>Shared amino acid (aa) changes identified in EBVs from BL tumors. Positions of common aa changes due to non-synonymous SNVs identified in the 15 EBV genes with known or putative functions are marked by color arrows.</title><p>The positions of common aa changes shared by all 12 BL-EBVs studied are marked with red arrows, those shared by 11 of the 12 BL-EBVs, except VGO–EBV, are marked with purple arrows. Most of these aa changes (red arrows) are also observed in NPC-EBVs. Green arrow indicates the position with common aa change shared by 7 South America BL-EBVs. Blue arrows indicate the positions with common aa changes shared by 5 West Africa BL-EBVs. Transmembrane domain of LMP-1 protein is illustrated using light blue. Black bars mark the regions with specialized features of EBNA-1, and LMP-1.</p></caption><graphic xlink:href="srep16706-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>Amino acid (aa) sequence alignment (1-235 aa) for LMP-1 proteins (387 aa) deduced from genomes of BL-EBVs and EBVs available in NCBI database.</title><p>There are overall 22 common aa changes observed in LMP-1 protein from BL-EBVs. Positions of the 9 out of the 22 common aa changes uniquely shared by the similar 11 BL-EBVs studied, but not VGO, are marked with purple dots (E2D, H3L, S57A, I63V, I124V, I152L, H213N and E214Q). Positions of the 8 aa out of the 13 common aa changes in the N-terminus are marked as red dots in this figure: L25I, D46N, I85L, F106Y, L126F, M129I, L151I and G212S. These changes were also present in essentially all NPC-EBVs. The other 5 common aa changes observed in all 12 BL-EBVs and essentially all NPC-EBVs are not shown in the Figure: S309N, Q322N, Q334R, L338S and S366T.</p></caption><graphic xlink:href="srep16706-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title>Alignment of nt sequences in LMP-1 promoter region in ~220 nt upstream of its coding region.</title><p>The alignment is corresponding to 169239–168992 positions in the reference genome of WT-EBV including part of the LMP-1 coding region (25 nt shadowed with black) with marked ATG initiation codon (position 169017). The transcription starting site is marked as +1 (position 169058). The sequences recognized for functions associated with transcription factors (ref. <xref ref-type="bibr" rid="b27">27</xref>) are marked with pink or green shadow. The 5 common variations or mutations shared by 11 of the12 BL-EBVs, but not by VGO or any NPC-EBVs are T-172C, T-50A, A-39C (in CREB), G-12A and T+18G. In this particular region, there are additional 5 common variations or mutations, C-158T, T-114C, A-63C, G-44C and G+41C, shared by all 12 BL-EBVs and essentially all NPC-EBVs.</p></caption><graphic xlink:href="srep16706-f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><title>Alignment of nt sequences in LMP-1 promoter region -183 to -428 upstream of the transcribing region.</title><p>The alignment is corresponding to 169485 to169240 positions at the very end of WT-EBV reference genome, neighboring the terminal repeats (TR). The sequences recognized for functions associated with transcription factors (ref. <xref ref-type="bibr" rid="b27">27</xref>)) are marked with pink or green shadow. The region shadowed with black (from 169294–169448 in the WT-EBV) was identified as LMP-2B 1<sup>st</sup> exon (noncoding) (ref. <xref ref-type="bibr" rid="b23">23</xref> in the manuscript). The 7 common variations/mutations (G-426A, T-412G, C-410A, G-376A, A-354G, and A-184T) were shared by the 11 similar BL-EBVs, but not by VGO and any NPC-EBVs. One additional common mutation (G-227A) located in AML1 of LBF2 was shared by 9 BL-EBVs is, not present in VGO and any NPC-EBVs. There are 3 additional common variations or mutations, A-314G, C-272G and T-242C, shared by all 12 BL-EBVs and essentially all NPC-EBVs.</p></caption><graphic xlink:href="srep16706-f5"></graphic></fig><fig id="f6"><label>Figure 6</label><caption><title>Graphic depiction of aa changes in LMP-1 protein.</title><p>The positions of 9 common aa changes (resulted from10 nt changes in the coding region) uniquely shared by 11 of 12 BL-EBVs, except VGO, are marked purple. None of these 9 aa common changes are observed in NPC-EBVs. They are located in cytoplasmic domain (2 aa), intramembrane domain (5 aa) and CTAR1 (2 aa) of LMP-1 protein. The positions of 13 common aa changes shared by essentially all 12 BL-EBVs studied as well as NPC-EBVs in NCBI database are marked red. Positions of 10 common aa deletions found in NPC-EBVs are marked yellow. C-terminal activation regions 1–3 (CTAR1-3) of the protein are marked by rectangle.</p></caption><graphic xlink:href="srep16706-f6"></graphic></fig><table-wrap position="float" id="t1"><label>Table 1</label><caption><title>Characteristics of the BL tumor samples that were sequenced for Epstein-Barr virus.</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50">Sample ID (Subject ID)</th><th align="center" valign="top" charoff="50">GenBankaccessionnumber</th><th align="center" valign="top" charoff="50">Sex</th><th align="center" valign="top" charoff="50">Age,years</th><th align="center" valign="top" charoff="50">Tumor site</th><th align="center" valign="top" charoff="50">8;14abnormality</th></tr></thead><tbody valign="top"><tr><td colspan="6" align="left" valign="top" charoff="50"><bold>Brazil</bold></td></tr><tr><td align="left" valign="top" charoff="50"> CCH</td><td align="center" valign="top" charoff="50"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KP968257">KP968257</ext-link></td><td align="center" valign="top" charoff="50">M</td><td align="center" valign="top" charoff="50">4</td><td align="center" valign="top" charoff="50">Abdomen, CNS</td><td align="center" valign="top" charoff="50">Far 5’; NSμ</td></tr><tr><td align="left" valign="top" charoff="50"> MP</td><td align="center" valign="top" charoff="50"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KP968258">KP968258</ext-link></td><td align="center" valign="top" charoff="50">M</td><td align="center" valign="top" charoff="50">4</td><td align="center" valign="top" charoff="50">Abdomen</td><td align="center" valign="top" charoff="50"><italic>H3-Pst</italic>; Sμ</td></tr><tr><td align="left" valign="top" charoff="50"> SCL</td><td align="center" valign="top" charoff="50"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KP968259">KP968259</ext-link></td><td align="center" valign="top" charoff="50">F</td><td align="center" valign="top" charoff="50">6</td><td align="center" valign="top" charoff="50">Abdomen</td><td align="center" valign="top" charoff="50"><italic>Sma-Pvu</italic>- Sμ</td></tr><tr><td align="left" valign="top" charoff="50"> VGO</td><td align="center" valign="top" charoff="50"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KP968260">KP968260</ext-link></td><td align="center" valign="top" charoff="50">M</td><td align="center" valign="top" charoff="50">5</td><td align="center" valign="top" charoff="50">Abdomen</td><td align="center" valign="top" charoff="50"><italic>H3-Pst</italic>; Sμ</td></tr><tr><td align="left" valign="top" charoff="50"> RPF</td><td align="center" valign="top" charoff="50"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KR063344">KR063344</ext-link></td><td align="center" valign="top" charoff="50">M</td><td align="center" valign="top" charoff="50">11</td><td align="center" valign="top" charoff="50">Abdomen</td><td align="center" valign="top" charoff="50">Far 5’; NSμ</td></tr><tr><td align="left" valign="top" charoff="50"> FNR</td><td align="center" valign="top" charoff="50"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KR063345">KR063345</ext-link></td><td align="center" valign="top" charoff="50">M</td><td align="center" valign="top" charoff="50">6</td><td align="center" valign="top" charoff="50">Abdomen</td><td align="center" valign="top" charoff="50">Far 5’+; NSμ</td></tr><tr><td colspan="6" align="left" valign="top" charoff="50"><bold>Argentina</bold></td></tr><tr><td align="left" valign="top" charoff="50"> CV-ARG</td><td align="center" valign="top" charoff="50"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KR063343">KR063343</ext-link></td><td align="center" valign="top" charoff="50">F</td><td align="center" valign="top" charoff="50">7</td><td align="center" valign="top" charoff="50">Abdomen</td><td align="center" valign="top" charoff="50">Far 5’+; NSμJ<sub>H</sub></td></tr><tr><td colspan="6" align="left" valign="top" charoff="50"><bold>Ghana</bold></td></tr><tr><td align="left" valign="top" charoff="50"> HU11393 (K00091800)<xref ref-type="fn" rid="t1-fn1">*</xref></td><td align="center" valign="top" charoff="50"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KP968261">KP968261</ext-link></td><td align="center" valign="top" charoff="50">M</td><td align="center" valign="top" charoff="50">7.23</td><td align="center" valign="top" charoff="50">Intestine</td><td align="center" valign="top" charoff="50">Not done</td></tr><tr><td align="left" valign="top" charoff="50"> H03753A (K00091800)<xref ref-type="fn" rid="t1-fn1">*</xref></td><td align="center" valign="top" charoff="50"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KR063342">KR063342</ext-link></td><td align="center" valign="top" charoff="50">M</td><td align="center" valign="top" charoff="50">7.23</td><td align="center" valign="top" charoff="50">Intestine</td><td align="center" valign="top" charoff="50">Not done</td></tr><tr><td align="left" valign="top" charoff="50"> H018436D (K00062500)</td><td align="center" valign="top" charoff="50"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KP968262">KP968262</ext-link></td><td align="center" valign="top" charoff="50">M</td><td align="center" valign="top" charoff="50">5.06</td><td align="center" valign="top" charoff="50">Colon</td><td align="center" valign="top" charoff="50">Not done</td></tr><tr><td align="left" valign="top" charoff="50"> H058015C (K00126500)</td><td align="center" valign="top" charoff="50"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KP968263">KP968263</ext-link></td><td align="center" valign="top" charoff="50">F</td><td align="center" valign="top" charoff="50">12.1</td><td align="center" valign="top" charoff="50">Abdomen</td><td align="center" valign="top" charoff="50">Not done</td></tr><tr><td align="left" valign="top" charoff="50"> H002213 (K00094200)</td><td align="center" valign="top" charoff="50"><ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="KP968264">KP968264</ext-link></td><td align="center" valign="top" charoff="50">M</td><td align="center" valign="top" charoff="50">7.6 1</td><td align="center" valign="top" charoff="50">Spleen</td><td align="center" valign="top" charoff="50">Not done</td></tr></tbody></table><table-wrap-foot><fn id="t1-fn1"><p>*These samples were from the same subject, but different tumor sites.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t2"><label>Table 2</label><caption><title>EBV genomes with the same or a highly similar pattern of nucleotide variations or mutations and imputed amino acid changes in the LMP-1 promoter and the coding regions.</title></caption><graphic xlink:href="srep16706-t2"></graphic><table-wrap-foot><fn id="t2-fn1"><p>Samples written in red font are EBV genomes sequenced directly form BL tumors in this study. **The eight BL cases are: 1) KP968258**(MP), 2) KP968259**(SCL), 3) KP968257**(CCH), 4) KP968262**(H018436D), 5) KP968263**(H058015C), 6) KP968261**(HU11393), 7) KR063342**(H03753A) and 8) KP968264**(H002213).</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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