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

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 - Nat. Med. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Show MeSH

Related in: MedlinePlus

Clinically relevant findings from individual patientsPHIAL results for 14 patients with a spectrum of malignancies, highlighting nominated clinically actionable alterations in 13 of 14 patients (A). Using the level of evidence schematic (Table 1), all nominated alterations for patients in this study were manually curated and assigned a level of evidence (B, Supplementary Table 7). *Denotes patient sequencing data that predated the rapid WES protocol.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4048335&req=5

Figure 4: Clinically relevant findings from individual patientsPHIAL results for 14 patients with a spectrum of malignancies, highlighting nominated clinically actionable alterations in 13 of 14 patients (A). Using the level of evidence schematic (Table 1), all nominated alterations for patients in this study were manually curated and assigned a level of evidence (B, Supplementary Table 7). *Denotes patient sequencing data that predated the rapid WES protocol.

Mentions: To pilot prospective sequencing and clinical interpretation, we performed WES and PHIAL on 16 appropriately consented patients with a range of advanced cancers (Fig. 4A). WES data for 3 of these 16 patients predated the WES protocol described herein, but were included to assess PHIAL output. WES from all patients in the rapid sequencing protocol met our quality control parameters irrespective of tissue processing type (Supplementary Table 7). By completion of the pilot period, sample receipt through data delivery was 16 days.


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

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 - Nat. Med. (2014)

Clinically relevant findings from individual patientsPHIAL results for 14 patients with a spectrum of malignancies, highlighting nominated clinically actionable alterations in 13 of 14 patients (A). Using the level of evidence schematic (Table 1), all nominated alterations for patients in this study were manually curated and assigned a level of evidence (B, Supplementary Table 7). *Denotes patient sequencing data that predated the rapid WES protocol.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4048335&req=5

Figure 4: Clinically relevant findings from individual patientsPHIAL results for 14 patients with a spectrum of malignancies, highlighting nominated clinically actionable alterations in 13 of 14 patients (A). Using the level of evidence schematic (Table 1), all nominated alterations for patients in this study were manually curated and assigned a level of evidence (B, Supplementary Table 7). *Denotes patient sequencing data that predated the rapid WES protocol.
Mentions: To pilot prospective sequencing and clinical interpretation, we performed WES and PHIAL on 16 appropriately consented patients with a range of advanced cancers (Fig. 4A). WES data for 3 of these 16 patients predated the WES protocol described herein, but were included to assess PHIAL output. WES from all patients in the rapid sequencing protocol met our quality control parameters irrespective of tissue processing type (Supplementary Table 7). By completion of the pilot period, sample receipt through data delivery was 16 days.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Show MeSH
Related in: MedlinePlus