Mutational landscape of Hodgkin lymphoma: Functional consequences and pathogenetic relevance

The tumor cells in Hodgkin lymphoma (HL) are characterized by constitutive activation of several signaling pathways. This characteristic phenotype is partly caused by mutations in genes of these pathways. Most of these mutations were identified as part of a targeted sequencing approach on cell lines or microdissected HL tumor cells, i.e. the so-called Hodgkin and Reed-Sternberg (HRS) cells.
In this thesis, we determined the mutational landscape of HL cell lines by whole exome sequencing (WES). We identified 463 recurrently mutated genes in HL. Among them are several genes related to functionality of the immune system (B2M, CIITA, CD58, CSF2RB). Inactivating mutations in B2M were common and explain the loss of HLA class I expression commonly observed in HL. Inactivation of CIITA might explain downregulation of the HLA class II expression in cHL cases. Loss of CD58 expression is common in HL cell lines and possibly a late event in HL pathogenesis. In tissue samples loss of CD58 is associated with relapse of disease. CSF2RB mutations are common in HL, with mutations in more than half of the HL cell lines. These mutations may all contribute to tumor cell escape from immune responses. Mutations in the oncogenic transcription factor MYB were also found in part of the HL cell lines. Strong oncogenic effects of wild type and truncated MYB were observed in HL cell lines. This knowledge might contribute to a better understanding of HL pathogenesis.