Deciphering the Genetic Complexity of Classical Hodgkin Lymphoma: Insights and Effective Strategies

: Understanding the genetics of susceptibility to classical Hodgkin lymphoma (cHL) is considerably limited compared to other cancers due to the rare Hodgkin and Reed-Sternberg (HRS) tumor cells, which coexist with the predominant non-malignant microenvironment. This article offers insights into genetic abnormalities in cHL, as well as nucleotide variants and their associated target genes, elucidated through recent technological advancements. Oncogenomes in HRS cells highlight the survival and proliferation of these cells through hyperactive signaling in specific pathways (e.g., NF-kB) and their interplay with microenvironmental cells (e.g., CD4+ T cells). In contrast, the susceptibility genes identified from genome-wide association studies and expression quantitative trait locus analyses only vaguely implicate their potential roles in susceptibility to more general cancers. To pave the way for the era of precision oncology, more intensive efforts are imperative, employing the following strategies: exploring genetic heterogeneity by gender and cHL subtype, investigating colocalization with various types of expression quantitative trait loci, and leveraging single-cell analysis. These approaches provide valuable perspectives for unraveling the genetic complexities of cHL.