Exome sequencing of Hodgkin and non-Hodgkin composite lymphomas identifies shared somatic mutations indicative of common founding precursors

The occurrence of both non-Hodgkin lymphoma (NHL) and classic Hodgkin lymphoma (cHL) in an individual patient (hereafter referred to as composite lymphoma) is a relatively rare and poorly characterized phenomenon. We hypothesized that analysis of the shared and divergent mutations harbored by composite lymphomas might shed light on genetic drivers of composite lymphomagenesis. We performed exome sequencing of two cases of composite NHL and cHL, and validated somatic variants using the AmpliSeq platform. Additionally, we utilized B-cell receptor sequencing of the immunoglobulin heavy chain (IGH) gene region as a tool to provide an orthogonal comparison of the composite lymphomas. Interestingly, both cases contained stop gain mutations in TNFRSF14 that were shared between the cHL and NHL samples. Other genes with shared somatic variants of potential biologic significance included TP53, SRSF6, PLCG2, BCL10, and PCLO. Furthermore, sequencing of the B-cell receptor immunoglobulin heavy chain (IGH) gene region revealed clones with common V(D)J gene usage in the NHL and cHL cases. Our data suggest a common precursor in these two cases of composite lymphoma. The shared somatic variants we identified may represent early events in lymphomagenesis and potential therapeutic targets.