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

Abstract

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.

Keywords: Hodgkin lymphoma; NF-kB; expression quantitative trait locus; genetic etiology; genetic heterogeneity; genetic lesion; genome-wide association study; hodgkin and reed-sternberg cell.

Fig. (1)

Genetic architecture of classical Hodgkin lymphoma (cHL). Pre-apoptotic cell presents regulatory single uncleotide polymorphisms (SNPs, upper part), and their target genes (eGenes, lower part), and Hodgkin and Reed-Sternberg (HRS) cell presents gene aberration after cHL onset. All the displayed SNPs were colocalized by cHL genomewide association study signal and expression quantitative trait locus (eQTL), and SNPs with regulatory function are in bold. The susceptibility genes were eGenes corresponding to eQTL or identified in at least two families. They are categorized by biological function. Human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), pollution, and smoking are presented as enviromental factors. Genetic lesions are classified by pathways and mechanisms underlying pathophysiology of cHL. The cells outside the HRS cell show cHL microenvironment, including diverse innate and adaptive immune cells. Under EBV exposure (EBV⁺), up- and down-regulated gene profiles [9] are presented as a representative example of interaction between genetic and environmental factors.

Fig. (2)

Genetic studies for discovery of classical Hodgkin lymphoma (cHL) susceptibility genes. The speech bubbles refer to strategies that are not currently being implemented but are necessary to increase resolution of genetic architecture of cHL susceptibility. IBD: identical-by-descent.