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nature portfolio permissions reprints privacy policy advertising nature 486 nature 455 nature social media open platform autophagy-related molecular features jak-mutant myeloproliferative neoplasms dana-farber leadership council dana-farber cancer institute paraffin-embedded tumor tissue formaldehyde fixed-paraffin embedded fresh-frozen tissue specimens paraffin-embedded tumor samples precision cancer medicine integrative high-throughput sequencing report generation toolkit springerlink instant access permissions breast cancer subtypes copy-number alterations policy knowledge-based approach pilot study genomics-driven oncology generation sequence data nih u24ca143845 grant analytical output similar facilitating data deposition frozen tumor tissue privacy hypertension-related genes lung cancer biopsies prostate cancer foundation ret gene fusions crkl gene encoding generation sequencing data clinically important genes high-throughput detection data analysis pipelines systems biology approach wes data generally dna-mutation inventory enhance cancer treatment cancer reveal classes broad genomics platform clinical cancer settings

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      headline:Whole-exome sequencing and clinical interpretation of formalin-fixed, paraffin-embedded tumor samples to guide precision cancer medicine
      description:Whole-exome sequencing (WES) has emerged as a transformative technology for biological discovery, but technical difficulties have so far prevented its widespread clinical use. Here, Eliezer Van Allen and colleagues are able to perform production-scale WES on small amounts of clinically acquired formalin-fixed, paraffin-embedded tumor tissues. Using a newly created WES clinical interpretation algorithm, they apply the complete clinical WES framework prospectively to patients and demonstrate how it can be used to directly affect patient care. Translating whole-exome sequencing (WES) for prospective clinical use may have an impact on the care of patients with cancer; however, multiple innovations are necessary for clinical implementation. These include rapid and robust WES of DNA derived from formalin-fixed, paraffin-embedded tumor tissue, analytical output similar to data from frozen samples and clinical interpretation of WES data for prospective use. Here, we describe a prospective clinical WES platform for archival formalin-fixed, paraffin-embedded tumor samples. The platform employs computational methods for effective clinical analysis and interpretation of WES data. When applied retrospectively to 511 exomes, the interpretative framework revealed a 'long tail' of somatic alterations in clinically important genes. Prospective application of this approach identified clinically relevant alterations in 15 out of 16 patients. In one patient, previously undetected findings guided clinical trial enrollment, leading to an objective clinical response. Overall, this methodology may inform the widespread implementation of precision cancer medicine.
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            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
            name:University of Washington, Seattle, Washington, USA.
            address:
               name:Department of Genome Sciences, University of Washington, Seattle, Washington, USA.,
               type:PostalAddress
            type:Organization
      name:Andrey Sivachenko
      affiliation:
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Mara Rosenberg
      affiliation:
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Adam Kiezun
      url:http://orcid.org/0000-0002-6634-1073
      affiliation:
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Douglas Voet
      affiliation:
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Michael Lawrence
      affiliation:
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Lee T Lichtenstein
      affiliation:
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Jeff G Gentry
      affiliation:
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Franklin W Huang
      affiliation:
            name:Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Jennifer Fostel
      affiliation:
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Deborah Farlow
      affiliation:
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:David Barbie
      affiliation:
            name:Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Leena Gandhi
      affiliation:
            name:Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Eric S Lander
      affiliation:
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Stacy W Gray
      affiliation:
            name:Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Steven Joffe
      url:http://orcid.org/0000-0002-0667-7384
      affiliation:
            name:Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
            name:Children's Hospital Boston
            address:
               name:Children's Hospital Boston, Boston, USA
               type:PostalAddress
            type:Organization
      name:Pasi Janne
      affiliation:
            name:Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Judy Garber
      affiliation:
            name:Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Laura MacConaill
      affiliation:
            name:Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
            name:Brigham and Women's Hospital
            address:
               name:Department of Pathology, Brigham and Women's Hospital, Boston, USA
               type:PostalAddress
            type:Organization
      name:Neal Lindeman
      affiliation:
            name:Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
            name:Brigham and Women's Hospital
            address:
               name:Department of Pathology, Brigham and Women's Hospital, Boston, USA
               type:PostalAddress
            type:Organization
      name:Barrett Rollins
      affiliation:
            name:Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Philip Kantoff
      affiliation:
            name:Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Sheila A Fisher
      affiliation:
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Stacey Gabriel
      affiliation:
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      name:Gad Getz
      affiliation:
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
            name:Massachusetts General Hospital, Boston, Massachusetts, USA.
            address:
               name:Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
            name:Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
            address:
               name:Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Levi A Garraway
      affiliation:
            name:Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
            name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
            address:
               name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Department of Genome Sciences, University of Washington, Seattle, Washington, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Children's Hospital Boston, Boston, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Department of Pathology, Brigham and Women's Hospital, Boston, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Department of Pathology, Brigham and Women's Hospital, Boston, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
      name:Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.,
      name:Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.,
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,
      name:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,
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