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

Van Allen EM1, Wagle N1, Stojanov P1, Perrin DL2, Cibulskis K2, Marlow S1, Jane-Valbuena J1, Friedrich DC2, Kryukov G2, Carter SL2, McKenna A3,Sivachenko A2, Rosenberg M2, Kiezun A2, Voet D2, Lawrence M2, Lichtenstein LT2, Gentry JG2, Huang FW1, Fostel J2, Farlow D2, Barbie D4, Gandhi L4,Lander ES2, Gray SW4, Joffe S5, Janne P4, Garber J4, MacConaill L6, Lindeman N6, Rollins B4, Kantoff P4, Fisher SA2, Gabriel S7, Getz G8, Garraway LA9.

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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.