Treatment outcomes for patients with peripheral T-cell lymphomas (PTCLs) and advanced-stage cutaneous T-cell lymphomas (CTCLs) remain poor. The past few years have witnessed an explosion in our understanding of the genetics of these diverse malignancies. Many subtypes harbor highly recurrent mutations, including single-nucleotide variants, insertions/deletions, and chromosomal rearrangements, that affect T-cell receptor signaling, costimulatory molecules, JAK/STAT and phosphatidylinositol 3-kinase pathways, transcription factors, and epigenetic modifiers. An important subset of these mutations is included within commercially available, multigene panels and, in rare circumstances, indicate therapeutic targets. However, current preclinical and clinical evidence suggests that only a minority of mutations identified in TCLs indicate biologic dependence. With a few exceptions that we highlight, mutations identified in TCLs should not be routinely used to select targeted therapies outside of a clinical trial. Participation in trials and publication of both positive and negative results remain the most important mechanisms for improving patient outcomes.

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