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Nat Med DOI:10.1038/nm.3559

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

Publication TypeJournal Article
Year of Publication2014
AuthorsVan Allen, EM, Wagle, N, Stojanov, P, Perrin, DL, Cibulskis, K, Marlow, S, Jané-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
JournalNat Med
Date Published2014 Jun
KeywordsAlgorithms, Computational Biology, Databases, Genetic, Exome, HEK293 Cells, Humans, Massachusetts, Mutagenesis, Site-Directed, Neoplasms, Precision Medicine, Sequence Analysis, DNA, Statistics, Nonparametric

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.


Alternate JournalNat. Med.
PubMed ID24836576
PubMed Central IDPMC4048335
Grant ListP30 CA014051 / CA / NCI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
1U24CA126546 / CA / NCI NIH HHS / United States
R33 CA155554 / CA / NCI NIH HHS / United States
1U01HG006492 / HG / NHGRI NIH HHS / United States
U24CA143845 / CA / NCI NIH HHS / United States
U01 HG006492 / HG / NHGRI NIH HHS / United States