Classical Hodgkin lymphoma (cHL) is one of the most frequent lymphomas in the Western world. Its malignant Hodgkin and Reed/Sternberg (HRS) cells are derived from pre-apoptotic germinal center B cells and only account for ca. 1% of the tumor cell mass. The surrounding inflammatory infiltrate is unable to establish an effective immune response against the HRS cells. To better understand HRS cell formation and their molecular pathogenesis, we aim to determine the mutational landscape of HRS cells. HRS cells of a total of 30 cases were isolated by microdissection or flow cytometry and subjected to exome or whole-genome sequencing. We confirmed recurrently mutated genes (e.g. SOCS1, TNFAIP3) but also found novel promising genes such as NLRC5, which is involved in MHCI expression and negative NFkB regulation. Intriguingly, mutational signatures associated with APOBEC and somatic hypermutation were identified. Moreover we are currently analyzing the WGS samples for mutations in gene regulatory regions, miRNA binding sites and gains and losses. Both WGS and WES show a wide variation in their mutational loads.
Lilian Beeck, Markus Schneider, Navid Farsijani, Bettina Budeus, Julia Bein, Hendrik Schaefer, Sylvia Hartmann, Martin-Leo Hansmann, Ralf Küppers