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PMID: 24836576 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Whole-exome sequencing and clinical interpretation of formalin-fixed, paraffin-embedded tumor samples to guide precision cancer medicine.

Nature medicine ·Vol. 20 ·No. 6 ·2014-06-00 ·Pages 682-8

Van Allen EM, Wagle N, Stojanov P, Perrin DL, Cibulskis K, Marlow S, Jane-Valbuena J, Friedrich DC, Kryukov G, Carter SL, McKenna A, Sivachenko A, Rosenberg M, Kiezun A, Voet D, Lawrence M, Lichtenstein LT, Gentry JG, Huang FW, Fostel J, Farlow D, Barbie D, Gandhi L, Lander ES, Gray SW, Joffe S, Janne P, Garber J, MacConaill L, Lindeman N, Rollins B, Kantoff P, Fisher SA, Gabriel S, Getz G, Garraway LA

Abstract

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.

MeSH Terms
Algorithms Computational Biology/methods Databases, Genetic Exome/genetics HEK293 Cells Humans Massachusetts Mutagenesis, Site-Directed Neoplasms/genetics,pathology Precision Medicine/methods,trends Sequence Analysis, DNA/methods Statistics, Nonparametric
Authors & Affiliations
36 authors, click to expand affiliations / ORCID
Van Allen Eliezer M
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Wagle Nikhil
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Stojanov Petar
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Perrin Danielle L
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Cibulskis Kristian
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Marlow Sara
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Jane-Valbuena Judit
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Friedrich Dennis C
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Kryukov Gregory
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Carter Scott L
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
McKenna Aaron
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Sivachenko Andrey
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Rosenberg Mara
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Kiezun Adam ORCID
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Voet Douglas
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Lawrence Michael
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Lichtenstein Lee T
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Gentry Jeff G
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Huang Franklin W
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Fostel Jennifer
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Farlow Deborah
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Barbie David
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Gandhi Leena
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Lander Eric S
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Gray Stacy W
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Joffe Steven ORCID
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Children's Hospital Boston, Boston, Massachusetts, USA.
Janne Pasi
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Garber Judy
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
MacConaill Laura
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Lindeman Neal
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Rollins Barrett
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Kantoff Philip
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Fisher Sheila A
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Gabriel Stacey
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] [3].
Getz Gad
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [4] [5].
Garraway Levi A
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] [4].
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.3559
Published
2014-06-00
Epub
2014-00-18
Pages
682-8
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC4048335
Subset
IM
Grants
NHGRI NIH HHS · U54 HG003067 · United States
NCI NIH HHS · T32 CA009172 · United States
NHGRI NIH HHS · 1U01HG006492 · United States
NCI NIH HHS · U24CA143845 · United States
NHGRI NIH HHS · U01 HG006492 · United States
NCI NIH HHS · P30 CA014051 · United States
NCI NIH HHS · U24 CA143845 · United States
NCI NIH HHS · 1U24CA126546 · United States
NCI NIH HHS · R33 CA155554 · United States
External Links
PubMed source DOI: 10.1038/nm.3559 PMC Full Text View journal details
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