Mutational profiling of HIV+ diffuse large B-cell lymphoma reveals distinct mutational features with evidence of genomic instability.

People with HIV (PWH) remain underrepresented in molecular studies and clinical trials of diffuse large B-cell lymphoma (DLBCL), despite DLBCL being a leading cause of cancer-related death in this population. We performed whole-exome sequencing on 30 DLBCL tumors (24 with paired germline) from a Malawian cohort including both HIV-positive (HIV+) and HIV-negative (HIV-) individuals. KMT2D , BIRC6 , TP53 , and ARID1A were among the most frequently mutated genes. Compared to HIV- DLBCL, the HIV+ DLBCL tumors in this cohort were enriched for mutations in KMT2D , among others, and prior antiretroviral therapy associated with increased tumor mutational burden (TMB) and neoantigen load. Five HIV+ DLBCL tumors exhibited microsatellite instability (MSI), each with strong contributions from mutational signatures related to DNA repair. Furthermore, ARID1A mutations were observed in several MSI samples and in tumors with MSH2 loss. Integration with a published HIV+ DLBCL dataset revealed recurrent driver mutations including LILRB1 p.R30S, MYD88 p.S206C and p.S238N, and NRAS p.Q61K, as well as PTEN mutation as negatively prognostic. Together, these results highlight distinct tumorigenic mechanisms in HIV+ DLBCL and underscore the need for mutational profiling of HIV+ DLBCL cohorts worldwide to identify biomarkers and therapeutic targets.