Novel Approaches in Molecular Characterization of Classical Hodgkin Lymphoma

SIMPLE SUMMARY: The unique tumor composition of classical Hodgkin lymphoma (cHL), with only a small fraction of malignant Hodgkin and Reed–Sternberg cells within the tumor tissue, has created many challenges to characterize the genetic alterations that drive this lymphoid malignancy. Major advances in sequencing technologies and detailed analysis of circulating tumor DNA in blood samples of patients have provided important contributions to enhance our understanding of the pathogenesis of cHL. In this review, we provide an overview of the recent advances in genotyping the clonal and mutational landscape of cHL. In addition, we discuss different next-generation sequencing applications to characterize tumor tissue and cell-free DNA, which are now available to improve the diagnosis of cHL, and to monitor therapeutic response or disease progression during treatment and follow up of cHL patients. ABSTRACT: Classical Hodgkin lymphoma (cHL) represents a B-cell lymphoproliferative disease characterized by clonal immunoglobulin gene rearrangements and recurrent genomic aberrations in the Hodgkin Reed–Sternberg cells in a reactive inflammatory background. Several methods are available for the molecular analysis of cHL on both tissue and cell-free DNA isolated from blood, which can provide detailed information regarding the clonal composition and genetic alterations that drive lymphoma pathogenesis. Clonality testing involving the detection of immunoglobulin and T cell receptor gene rearrangements, together with mutation analysis, represent valuable tools for cHL diagnostics, especially for patients with an atypical histological or clinical presentation reminiscent of a reactive lesion or another lymphoma subtype. In addition, clonality assessment may establish the clonal relationship of composite or subsequent lymphoma presentations within one patient. During the last few decades, more insight has been obtained on the molecular mechanisms that drive cHL development, including recurrently affected signaling pathways (e.g., NF-κB and JAK/STAT) and immune evasion. We provide an overview of the different approaches to characterize the molecular composition of cHL, and the implementation of these next-generation sequencing-based techniques in research and diagnostic settings.