Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphoma

Abstract

Hodgkin and Reed/Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) show constitutive activation of nuclear factor (NF)-κB. Several genetic lesions contribute to this deregulated NF-κB activity. Here, we analysed two further NF-κB regulators for genetic lesions, the inhibitory factor TRAF3 and the key signalling component of the alternative NF-κB pathway, MAP3K14 (NIK). Single nucleotide polymorphism (SNP) array analysis of cHL cell lines revealed a uniparental disomy of the long arm of chromosome 14 associated with a biallelic deletion of TRAF3 located on this chromosome in cell line U-HO1. Cloning of the deletion breakpoint showed a 123371 bp deletion. No inactivating mutations of TRAF3 were found in six other cHL cell lines or in microdissected HRS cells from seven cHL. However, in primary cHL samples interphase cytogenetic analyses revealed signal patterns indicating monoallelic deletion of TRAF3 in 3/20 other cases. SNP array analysis revealed a gain of copy number for MAP3K14 in three cHL cell lines. Gains of MAP3K14 were detected in 5/16 cases of primary cHL. In conclusion, in rare instances, HRS cells harbour inactivating mutations of the TRAF3 gene and recurrently show gains of MAP3K14, indicating that more components of NF-κB signalling show genetic lesions in HRS cells than previously known.