Chromosomal Instability in Hodgkin Lymphoma: An In-Depth Review and Perspectives

Abstract

The study of Hodgkin lymphoma (HL), with its unique microenvironment and long-term follow-up, has provided exceptional insights into several areas of tumor biology. Findings in HL have not only improved our understanding of human carcinogenesis, but have also pioneered its translation into the clinics. HL is a successful paradigm of modern treatment strategies. Nonetheless, approximately 15-20% of patients with advanced stage HL still die following relapse or progressive disease and a similar proportion of patients are over-treated, leading to treatment-related late sequelae, including solid tumors and organ dysfunction. The malignant cells in HL are characterized by a highly altered genomic landscape with a wide spectrum of genomic alterations, including somatic mutations, copy number alterations, complex chromosomal rearrangements, and aneuploidy. Here, we review the chromosomal instability mechanisms in HL, starting with the cellular origin of neoplastic cells and the mechanisms supporting HL pathogenesis, focusing particularly on the role of the microenvironment, including the influence of viruses and macrophages on the induction of chromosomal instability in HL. We discuss the emerging possibilities to exploit these aberrations as prognostic biomarkers and guides for personalized patient management.

Keywords: Hodgkin lymphoma; genomic instability; micronucleus; microsatellite; telomeres; viral infections.

Figure 1

Immunohistochemistry detection of p53 proteins in HL lymph nodes (10× magnification). (A) p53 (mutated and wildtype) protein expression in human colon mucosa (positive control); (B) High p53 protein expression in HRS cells in HL lymph nodes; (C) Phos-p53 expression in human colon mucosa show the functionality of p53; (D) Lack of expression of phos-p53 in HRS cells and all HL lymph nodes, demonstrating the inhibition of p53 in HL lymph nodes.

Figure 2

Errors of chromosome segregation and micronucleus and nucleoplasmic bridge formation in HL cells detected after four days of culture in the presence of cytocalasine B, an agent that has been most widely used to block cytokinesis and the separation of daughter cells after mitosis (40× magnification). (A) FISH painting of chromosome 9 (red) and 16 (green), showing the presence of defects in chromosome segregation after mitosis and the presence of nucleoplasmic bridges; (B) Telomere (red) and centromere (green) staining, showing the presence of multiple micronuclei with only telomere sequences (terminal deletion) and micronuclei with telomere and centromere sequences (chromosome lagging). In addition, the presence of telomere and centromere sequences in the nucleoplasmic bridge demonstrates the presence of dicentric chromosomes related to telomere fusion and the involvement of breakage-fusion-bridge cycles.

Figure 3

Immunohistochemical detection of JCV and EBV in HL lymph nodes (10× magnification). (A) Expression of LMP1 is almost always detectable in the HRS cells of EBV-associated HL (B) The expression of T-antigen in HL tumor cells demonstrates intense reactivity in nuclei and cytoplasm of HRS and Hodgkin tumor cells (C) Immunohistochemical double-labeling in HL cells demonstrates co-expression of T-antigen (Pal) and LMP1 (fast reed) in HRS cells; (D) Absence of immunoreactivity for anti-T-antigen and anti-LMP1 in a control sample.