Recurrent Mutations in Refractory/Relapsed Diffuse Large B-Cell Lymphoma by Targeted Gene Sequencing

<b><i>Introduction:</i></b> Whole-genome sequencing of diffuse large B-cell lymphoma (DLBCL) has identified recurrent mutations involved in pathogenesis and potentially affecting response to therapy. In this pilot study, a targeted gene panel was created to identify mutations associated with relapse/refractoriness. <b><i>Material and Methods:</i></b> A 14-gene targeted panel was designed to sequence thirteen patients who were in remission and 8 cases that had relapsed/refractory to treatment. A paired diagnostic biopsy and a relapse biopsy were sequenced to find genes repeatedly altered in relapse. <b><i>Results:</i></b> A total of 751 nonsynonymous and truncating mutations were identified. Truncated mutations in <i>NOTCH1, TNFAIP3</i>, and <i>CD58</i> were associated with poor treatment outcomes. In cases that did not respond to treatment, a high number of mutations were found in the <i>EZH2</i> gene, followed by the DNA-binding domain of <i>TP53</i> and <i>MYD88</i>. Termination mutations in the intracellular domain of <i>NOTCH</i> were found in 75% of non-responsive cases. Co-occurrence of loss of function mutations of <i>TNFAIP3</i> and missense mutations in <i>MYD88</i> was associated with a non-responsive cohort. <b><i>Discussion:</i></b> The study highlights mutations associated with chemotherapeutic response in DLBCL with implications for initial diagnostic biopsy response prediction.