Targeted Next-Generation Sequencing of Cell-Free DNA to Detect MYC-Immunoglobulin Translocation and Epstein-Barr Virus DNA in Plasma of Burkitt Lymphoma Patients in East Africa.
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PURPOSE: Epstein-Barr virus (EBV)-positive Burkitt lymphoma (BL) affects children in sub-Saharan Africa, but diagnosis via tissue biopsy is challenging. We explored a liquid biopsy approach using targeted next-generation sequencing to detect the MYC-immunoglobulin (MYC-Ig) translocation and EBV DNA, assessing its potential for minimally invasive BL diagnosis. MATERIALS AND METHODS: The panel included targets for the characteristic MYC-Ig translocation, mutations in intron 1 of MYC, mutations in exon 2 of MYC, and three EBV genes: EBV-encoded RNA (EBER)1, EBER2, and EBV nuclear antigen 2. It was first tested in a small derivation cohort of four precharacterized BL-derived cell lines with known translocation status and eight precharacterized plasma samples with known EBV DNA status by quantitative polymerase chain reaction (qPCR). These different data modalities were combined to assess the accuracy of this approach in the diagnosis of BL in 20 patient plasma samples in Tanzania and Uganda. RESULTS: The next-generation sequencing panel detected three of four MYC-Ig translocations in the BL-derived cell lines. EBV viral load by targeted sequencing correlated strongly with qPCR results (Spearman's rho = 0.94) in precharacterized plasma samples. Using the patient plasma samples, mutations in MYC intron 1 were associated with the presence of a MYC translocation with 25 or more mutations being predictive of a translocation with AUC, sensitivity, and specificity of 1. Overall, liquid biopsy parameters associated with a diagnosis of BL (P < .05) included cell-free DNA concentration, circulating tumor DNA concentration, MYC intron 1 mutations, MYC-Ig translocation, and autosome entropy. Integrating these parameters into a diagnostic model demonstrated excellent performance with an AUC of 0.95, sensitivity of 0.9, and specificity of 1. CONCLUSION: This analysis demonstrates the potential of liquid biopsy to improve BL diagnosis in settings with limited pathology resources. Validation of our approach in a larger data set is needed.