Characterization of the genomic landscape of HIV-associated lymphoma reveals heterogeneity across histological subtypes

OBJECTIVE: Individuals with HIV experience an increased risk of lymphoma, making this an important cause of death among people with HIV. Nevertheless, little is known regarding the underlying genetic aberrations, which we therefore set out to characterize. DESIGN: We conducted next-generation panel sequencing to explore the mutational status of diagnostic lymphoma biopsies from 18 patients diagnosed with lymphoma secondary to HIV infection. METHODS: Ion Torrent next-generation sequencing was performed with an AmpliSeq panel on diagnostic lymphoma biopsies from HIV-associated B-cell lymphomas ( n = 18), comprising diffuse large B-cell lymphoma ( n = 9), classic Hodgkin lymphoma ( n = 6), Burkitt lymphoma ( n = 2), follicular lymphoma ( n = 1), and marginal zone lymphoma ( n = 1). The panel comprised 69 lymphoid and/or myeloid-relevant genes, in which either the entire coding sequence or a hotspot region was sequenced. RESULTS: Among the 18 lymphomas, we detected 213 variants. The number of detected mutations ranged from 4 to 41 per tumor distributed among 42 genes, including both exonic and intronic regions. The most frequently mutated genes included KMT2D (67%), TNFAIP3 (50%), and TP53 (61%). Notably, no gene was found to harbor variants across all the HIV-associated lymphomas, nor did we find subtype-specific variants. While some variants were shared among patients, most were unique to the individual patient and were often not reported as malignant genetic variants in databases. CONCLUSION: Our findings demonstrate genetic heterogeneity across histological subtypes of HIV-associated lymphomas and thus help elucidate the genetics and pathophysiological mechanisms underlying the disease.