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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes</title><author><name sortKey="Castera, Laurent" sort="Castera, Laurent" uniqKey="Castera L" first="Laurent" last="Castéra">Laurent Castéra</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Krieger, Sophie" sort="Krieger, Sophie" uniqKey="Krieger S" first="Sophie" last="Krieger">Sophie Krieger</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Department of Biochemistry and Toxicology, Caen University</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Rousselin, Antoine" sort="Rousselin, Antoine" uniqKey="Rousselin A" first="Antoine" last="Rousselin">Antoine Rousselin</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Legros, Angelina" sort="Legros, Angelina" uniqKey="Legros A" first="Angélina" last="Legros">Angélina Legros</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Baumann, Jean Jacques" sort="Baumann, Jean Jacques" uniqKey="Baumann J" first="Jean-Jacques" last="Baumann">Jean-Jacques Baumann</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Bruet, Olivia" sort="Bruet, Olivia" uniqKey="Bruet O" first="Olivia" last="Bruet">Olivia Bruet</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Brault, Baptiste" sort="Brault, Baptiste" uniqKey="Brault B" first="Baptiste" last="Brault">Baptiste Brault</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Fouillet, Robin" sort="Fouillet, Robin" uniqKey="Fouillet R" first="Robin" last="Fouillet">Robin Fouillet</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Goardon, Nicolas" sort="Goardon, Nicolas" uniqKey="Goardon N" first="Nicolas" last="Goardon">Nicolas Goardon</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Letac, Olivier" sort="Letac, Olivier" uniqKey="Letac O" first="Olivier" last="Letac">Olivier Letac</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Baert Desurmont, Stephanie" sort="Baert Desurmont, Stephanie" uniqKey="Baert Desurmont S" first="Stéphanie" last="Baert-Desurmont">Stéphanie Baert-Desurmont</name><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Department of Genetics, University Hospital</institution>, Rouen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Tinat, Julie" sort="Tinat, Julie" uniqKey="Tinat J" first="Julie" last="Tinat">Julie Tinat</name><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Department of Genetics, University Hospital</institution>, Rouen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Bera, Odile" sort="Bera, Odile" uniqKey="Bera O" first="Odile" last="Bera">Odile Bera</name><affiliation><nlm:aff id="aff5"><institution>Department of Genetics, University Hospital</institution>, Fort-de-France,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Dugast, Catherine" sort="Dugast, Catherine" uniqKey="Dugast C" first="Catherine" last="Dugast">Catherine Dugast</name><affiliation><nlm:aff id="aff6"><institution>Department of Genetics, University Hospital</institution>, Rennes,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Berthet, Pascaline" sort="Berthet, Pascaline" uniqKey="Berthet P" first="Pascaline" last="Berthet">Pascaline Berthet</name><affiliation><nlm:aff id="aff7"><institution>Department of Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Polycarpe, Florence" sort="Polycarpe, Florence" uniqKey="Polycarpe F" first="Florence" last="Polycarpe">Florence Polycarpe</name><affiliation><nlm:aff id="aff7"><institution>Department of Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Layet, Valerie" sort="Layet, Valerie" uniqKey="Layet V" first="Valérie" last="Layet">Valérie Layet</name><affiliation><nlm:aff id="aff8"><institution>Department of Genetics, Jacques Monod Hospital</institution>, Le Havre,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Hardouin, Agnes" sort="Hardouin, Agnes" uniqKey="Hardouin A" first="Agnes" last="Hardouin">Agnes Hardouin</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Frebourg, Thierry" sort="Frebourg, Thierry" uniqKey="Frebourg T" first="Thierry" last="Frébourg">Thierry Frébourg</name><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Department of Genetics, University Hospital</institution>, Rouen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"><institution>Rouen University, IRIB</institution>, Rouen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Vaur, Dominique" sort="Vaur, Dominique" uniqKey="Vaur D" first="Dominique" last="Vaur">Dominique Vaur</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24549055</idno><idno type="pmc">4200427</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200427</idno><idno type="RBID">PMC:4200427</idno><idno type="doi">10.1038/ejhg.2014.16</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000000</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes</title><author><name sortKey="Castera, Laurent" sort="Castera, Laurent" uniqKey="Castera L" first="Laurent" last="Castéra">Laurent Castéra</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Krieger, Sophie" sort="Krieger, Sophie" uniqKey="Krieger S" first="Sophie" last="Krieger">Sophie Krieger</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Department of Biochemistry and Toxicology, Caen University</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Rousselin, Antoine" sort="Rousselin, Antoine" uniqKey="Rousselin A" first="Antoine" last="Rousselin">Antoine Rousselin</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Legros, Angelina" sort="Legros, Angelina" uniqKey="Legros A" first="Angélina" last="Legros">Angélina Legros</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Baumann, Jean Jacques" sort="Baumann, Jean Jacques" uniqKey="Baumann J" first="Jean-Jacques" last="Baumann">Jean-Jacques Baumann</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Bruet, Olivia" sort="Bruet, Olivia" uniqKey="Bruet O" first="Olivia" last="Bruet">Olivia Bruet</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Brault, Baptiste" sort="Brault, Baptiste" uniqKey="Brault B" first="Baptiste" last="Brault">Baptiste Brault</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Fouillet, Robin" sort="Fouillet, Robin" uniqKey="Fouillet R" first="Robin" last="Fouillet">Robin Fouillet</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Goardon, Nicolas" sort="Goardon, Nicolas" uniqKey="Goardon N" first="Nicolas" last="Goardon">Nicolas Goardon</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Letac, Olivier" sort="Letac, Olivier" uniqKey="Letac O" first="Olivier" last="Letac">Olivier Letac</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Baert Desurmont, Stephanie" sort="Baert Desurmont, Stephanie" uniqKey="Baert Desurmont S" first="Stéphanie" last="Baert-Desurmont">Stéphanie Baert-Desurmont</name><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Department of Genetics, University Hospital</institution>, Rouen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Tinat, Julie" sort="Tinat, Julie" uniqKey="Tinat J" first="Julie" last="Tinat">Julie Tinat</name><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Department of Genetics, University Hospital</institution>, Rouen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Bera, Odile" sort="Bera, Odile" uniqKey="Bera O" first="Odile" last="Bera">Odile Bera</name><affiliation><nlm:aff id="aff5"><institution>Department of Genetics, University Hospital</institution>, Fort-de-France,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Dugast, Catherine" sort="Dugast, Catherine" uniqKey="Dugast C" first="Catherine" last="Dugast">Catherine Dugast</name><affiliation><nlm:aff id="aff6"><institution>Department of Genetics, University Hospital</institution>, Rennes,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Berthet, Pascaline" sort="Berthet, Pascaline" uniqKey="Berthet P" first="Pascaline" last="Berthet">Pascaline Berthet</name><affiliation><nlm:aff id="aff7"><institution>Department of Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Polycarpe, Florence" sort="Polycarpe, Florence" uniqKey="Polycarpe F" first="Florence" last="Polycarpe">Florence Polycarpe</name><affiliation><nlm:aff id="aff7"><institution>Department of Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Layet, Valerie" sort="Layet, Valerie" uniqKey="Layet V" first="Valérie" last="Layet">Valérie Layet</name><affiliation><nlm:aff id="aff8"><institution>Department of Genetics, Jacques Monod Hospital</institution>, Le Havre,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Hardouin, Agnes" sort="Hardouin, Agnes" uniqKey="Hardouin A" first="Agnes" last="Hardouin">Agnes Hardouin</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Frebourg, Thierry" sort="Frebourg, Thierry" uniqKey="Frebourg T" first="Thierry" last="Frébourg">Thierry Frébourg</name><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Department of Genetics, University Hospital</institution>, Rouen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"><institution>Rouen University, IRIB</institution>, Rouen,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Vaur, Dominique" sort="Vaur, Dominique" uniqKey="Vaur D" first="Dominique" last="Vaur">Dominique Vaur</name><affiliation><nlm:aff id="aff1"><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Inserm U1079</institution>, Rouen,<country>France</country></nlm:aff></affiliation></author></analytic><series><title level="j">European Journal of Human Genetics</title><idno type="ISSN">1018-4813</idno><idno type="eISSN">1476-5438</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>To optimize the molecular diagnosis of hereditary breast and ovarian cancer (HBOC), we developed a next-generation sequencing (NGS)-based screening based on the capture of a panel of genes involved, or suspected to be involved in HBOC, on pooling of indexed DNA and on paired-end sequencing in an Illumina GAIIx platform, followed by confirmation by Sanger sequencing or MLPA/QMPSF. The bioinformatic pipeline included CASAVA, NextGENe, CNVseq and Alamut-HT. We validated this procedure by the analysis of 59 patients' DNAs harbouring SNVs, indels or large genomic rearrangements of <italic>BRCA1</italic> or <italic>BRCA2</italic>. We also conducted a blind study in 168 patients comparing NGS <italic>versus</italic> Sanger sequencing or MLPA analyses of <italic>BRCA1</italic> and <italic>BRCA2</italic>. All mutations detected by conventional procedures were detected by NGS. We then screened, using three different versions of the capture set, a large series of 708 consecutive patients. We detected in these patients 69 germline deleterious alterations within <italic>BRCA1</italic> and <italic>BRCA2</italic>, and 4 <italic>TP53</italic> mutations in 468 patients also tested for this gene. We also found 36 variations inducing either a premature codon stop or a splicing defect among other genes: 5/708 in <italic>CHEK2,</italic> 3/708 in <italic>RAD51C</italic>, 1/708 in <italic>RAD50,</italic> 7/708 in <italic>PALB2</italic>, 3/708 in <italic>MRE11A</italic>, 5/708 in <italic>ATM</italic>, 3/708 in <italic>NBS1</italic>, 1/708 in <italic>CDH1</italic>, 3/468 in <italic>MSH2</italic>, 2/468 in <italic>PMS2</italic>, 1/708 in <italic>BARD1</italic>, 1/468 in <italic>PMS1</italic> and 1/468 in <italic>MLH3</italic>. These results demonstrate the efficiency of NGS in performing molecular diagnosis of HBOC. Detection of mutations within other genes than <italic>BRCA1</italic> and <italic>BRCA2</italic> highlights the genetic heterogeneity of HBOC.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Eur J Hum Genet</journal-id><journal-id journal-id-type="iso-abbrev">Eur. J. Hum. Genet</journal-id><journal-title-group><journal-title>European Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">1018-4813</issn><issn pub-type="epub">1476-5438</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24549055</article-id><article-id pub-id-type="pmc">4200427</article-id><article-id pub-id-type="pii">ejhg201416</article-id><article-id pub-id-type="doi">10.1038/ejhg.2014.16</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes</article-title><alt-title alt-title-type="running">NGS diagnosis of HBOC</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Castéra</surname><given-names>Laurent</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Krieger</surname><given-names>Sophie</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Rousselin</surname><given-names>Antoine</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Legros</surname><given-names>Angélina</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Baumann</surname><given-names>Jean-Jacques</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Bruet</surname><given-names>Olivia</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Brault</surname><given-names>Baptiste</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Fouillet</surname><given-names>Robin</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Goardon</surname><given-names>Nicolas</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Letac</surname><given-names>Olivier</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Baert-Desurmont</surname><given-names>Stéphanie</given-names></name><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Tinat</surname><given-names>Julie</given-names></name><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Bera</surname><given-names>Odile</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Dugast</surname><given-names>Catherine</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Berthet</surname><given-names>Pascaline</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Polycarpe</surname><given-names>Florence</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Layet</surname><given-names>Valérie</given-names></name><xref ref-type="aff" rid="aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Hardouin</surname><given-names>Agnes</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Frébourg</surname><given-names>Thierry</given-names></name><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff4">4</xref><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Vaur</surname><given-names>Dominique</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="corresp" rid="caf1">*</xref></contrib><aff id="aff1"><label>1</label><institution>Department of Cancer Biology and Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></aff><aff id="aff2"><label>2</label><institution>Inserm U1079</institution>, Rouen,<country>France</country></aff><aff id="aff3"><label>3</label><institution>Department of Biochemistry and Toxicology, Caen University</institution>, Caen,<country>France</country></aff><aff id="aff4"><label>4</label><institution>Department of Genetics, University Hospital</institution>, Rouen,<country>France</country></aff><aff id="aff5"><label>5</label><institution>Department of Genetics, University Hospital</institution>, Fort-de-France,<country>France</country></aff><aff id="aff6"><label>6</label><institution>Department of Genetics, University Hospital</institution>, Rennes,<country>France</country></aff><aff id="aff7"><label>7</label><institution>Department of Genetics, CLCC François Baclesse</institution>, Caen,<country>France</country></aff><aff id="aff8"><label>8</label><institution>Department of Genetics, Jacques Monod Hospital</institution>, Le Havre,<country>France</country></aff><aff id="aff9"><label>9</label><institution>Rouen University, IRIB</institution>, Rouen,<country>France</country></aff></contrib-group><author-notes><corresp id="caf1"><label>*</label><institution>Centre François Baclesse, Laboratoire de Biologie et de Génétique du Cancer; 3, avenue du général Harris</institution>, Caen 14076 Cedex 05, <country>France</country>. Tel: +33 231 45 50 54; Fax: +33 2 31 45 50 53; E-mail: <email>d.vaur@baclesse.fr</email></corresp></author-notes><pub-date pub-type="ppub"><month>11</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>19</day><month>02</month><year>2014</year></pub-date><volume>22</volume><issue>11</issue><fpage>1305</fpage><lpage>1313</lpage><history><date date-type="received"><day>07</day><month>10</month><year>2013</year></date><date date-type="rev-recd"><day>15</day><month>01</month><year>2014</year></date><date date-type="accepted"><day>16</day><month>01</month><year>2014</year></date></history><permissions><copyright-statement>Copyright © 2014 Macmillan Publishers Limited</copyright-statement><copyright-year>2014</copyright-year><copyright-holder>Macmillan Publishers Limited</copyright-holder></permissions><abstract><p>To optimize the molecular diagnosis of hereditary breast and ovarian cancer (HBOC), we developed a next-generation sequencing (NGS)-based screening based on the capture of a panel of genes involved, or suspected to be involved in HBOC, on pooling of indexed DNA and on paired-end sequencing in an Illumina GAIIx platform, followed by confirmation by Sanger sequencing or MLPA/QMPSF. The bioinformatic pipeline included CASAVA, NextGENe, CNVseq and Alamut-HT. We validated this procedure by the analysis of 59 patients' DNAs harbouring SNVs, indels or large genomic rearrangements of <italic>BRCA1</italic> or <italic>BRCA2</italic>. We also conducted a blind study in 168 patients comparing NGS <italic>versus</italic> Sanger sequencing or MLPA analyses of <italic>BRCA1</italic> and <italic>BRCA2</italic>. All mutations detected by conventional procedures were detected by NGS. We then screened, using three different versions of the capture set, a large series of 708 consecutive patients. We detected in these patients 69 germline deleterious alterations within <italic>BRCA1</italic> and <italic>BRCA2</italic>, and 4 <italic>TP53</italic> mutations in 468 patients also tested for this gene. We also found 36 variations inducing either a premature codon stop or a splicing defect among other genes: 5/708 in <italic>CHEK2,</italic> 3/708 in <italic>RAD51C</italic>, 1/708 in <italic>RAD50,</italic> 7/708 in <italic>PALB2</italic>, 3/708 in <italic>MRE11A</italic>, 5/708 in <italic>ATM</italic>, 3/708 in <italic>NBS1</italic>, 1/708 in <italic>CDH1</italic>, 3/468 in <italic>MSH2</italic>, 2/468 in <italic>PMS2</italic>, 1/708 in <italic>BARD1</italic>, 1/468 in <italic>PMS1</italic> and 1/468 in <italic>MLH3</italic>. These results demonstrate the efficiency of NGS in performing molecular diagnosis of HBOC. Detection of mutations within other genes than <italic>BRCA1</italic> and <italic>BRCA2</italic> highlights the genetic heterogeneity of HBOC.</p></abstract><kwd-group><kwd>NGS</kwd><kwd>breast</kwd><kwd>ovary</kwd><kwd>cancer</kwd><kwd><italic>BRCA1</italic></kwd><kwd><italic>BRCA2</italic></kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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