Whole-exome sequencing and clinical interpretation of formalin-fixed, paraffin-embedded tumor samples to guide precision cancer medicine.
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.
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.
Eliezer M
EM
Van Allen
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.
Nikhil
N
Wagle
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.
Petar
P
Stojanov
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Danielle L
DL
Perrin
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Kristian
K
Cibulskis
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.
Sara
S
Marlow
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.
Judit
J
Jane-Valbuena
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Dennis C
DC
Friedrich
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Gregory
G
Kryukov
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Scott L
SL
Carter
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Aaron
A
McKenna
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Andrey
A
Sivachenko
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Mara
M
Rosenberg
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Adam
0000000266341073
A
Kiezun
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Douglas
D
Voet
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Michael
M
Lawrence
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Lee T
LT
Lichtenstein
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Jeff G
JG
Gentry
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.
Franklin W
FW
Huang
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Jennifer
J
Fostel
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Deborah
D
Farlow
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
David
D
Barbie
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Leena
L
Gandhi
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Eric S
ES
Lander
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Stacy W
SW
Gray
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Children's Hospital Boston, Boston, Massachusetts, USA.
Steven
0000000206677384
S
Joffe
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Pasi
P
Janne
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Judy
J
Garber
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.
Laura
L
MacConaill
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.
Neal
N
Lindeman
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Barrett
B
Rollins
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Philip
P
Kantoff
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Sheila A
SA
Fisher
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] [3].
Stacey
S
Gabriel
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].
Gad
G
Getz
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].
Levi A
LA
Garraway
D000465:Algorithms; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D059472:Exome / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008404:Massachusetts; D016297:Mutagenesis, Site-Directed; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D057285:Precision Medicine / Q000379:methods* / Q000639:trends; D017422:Sequence Analysis, DNA / Q000379:methods*; D018709:Statistics, Nonparametric