Whole-Exome Sequencing of Archival Tissue Can Guide Personalized Medicine

Whole-exome sequencing (WES) efforts have helped to map the genetic landscape of various tumor types and provide insight into the underlying biology. Despite increased availability and reduced costs, several obstacles to clinical implementation of WES remain, including optimization of sequence generation from archival formalin-fixed, paraffin-embedded (FFPE) tumors, interpretation of WES data, and validation of variants of uncertain significance. To determine whether FFPE tissue can provide sufficient input DNA, Van Allen and colleagues compared WES data generated from FFPE samples with WES data from non-FFPE samples and observed no significant difference in sequence coverage. Comparison of WES data from matched FFPE and frozen samples showed cross-validation of approximately 90% of mutations and strong correlation of copy number data. To aid in clinical interpretation, a “Precision Heuristics for Interpreting the Alteration Landscape” (PHIAL) algorithm was designed that relies on an open-source database of tumor alterations relevant for genomics-driven therapy (TARGET) to prioritize somatic variants based on their biologic and clinical relevance. TARGET gene alterations were identified in 80% of patient tumor tissues analyzed retrospectively, a large proportion of which occurred in a small subset of patients, and in 15 of 16 patients with advanced cancers analyzed prospectively in a pilot study, with data delivery by 16 days after sample receipt. In one patient with metastatic lung adenocarcinoma, a genetic alteration identified by exome sequencing prompted the patient's enrollment in a clinical trial that resulted in disease stabilization. In contrast, a potentially actionable JAK3 mutation identified in a patient with metastatic castration-resistant prostate cancer was not activating in vitro, suggesting that the patient would not likely benefit from JAK3 inhibitor treatment and demonstrating the need for rapid experimental validation of unknown variants. This archival tissue-based approach thus has the potential to facilitate clinical implementation of WES and provide a framework for interpretation of genomic alterations.

Van Allen EM, Wagle N, Stojanov P, Perrin DL, Cibulskis K, Marlow S, et al. Whole-exome sequencing and clinical interpretation of formalin-fixed, paraffin-embedded tumor samples to guide precision medicine. Nat Med 2014;20:682–8.

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