Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome

Abstract

In classical Hodgkin lymphoma (cHL) the mechanisms underlying primary refractory disease and relapse remain unknown. To gain further insight into cHL pathogenesis and genomic changes linked to treatment response, we studied 53 cHL patients by array comparative genomic hybridization, including 23 patients whose primary treatment failed, using DNA from microdissected HRS cells. Copy number alterations found in more than 20% of cases included gains of 2p, 9p, 16p, 17q, 19q, 20q, and losses of 6q, 11q, and 13q. We identified at high resolution recurrent changes defining minimally gained and lost regions harboring genes involved in nuclear factor B signaling, such as REL, IKBKB, CD40, and MAP3K14. Gains of chromosome 16p11.2-13.3 were significantly more frequent in pretreatment and relapse biopsies of unresponsive patients and were associated with shortened disease-specific survival (P ‫؍‬ .028). In the therapyresistant HL cell line KMH2, we found genomic gains and overexpression of the multidrug resistance gene ABCC1 mapping to cytoband 16p13.11. We show that doxorubicin exposure to KMH2 induces ABCC1 expression and that siRNA silencing of ABCC1 sensitizes KMH2 cells to doxorubicin toxicity in vitro, suggesting that overexpression of ABCC1 contributes to the drug resistance phenotype found in KMH2. (Blood. 2010;116(3): 418-427)

EBV-Positive and EBV-Negative Posttransplant Diffuse Large B Cell Lymphomas Have Distinct Genomic and Transcriptomic Features

“…Expression data, however, point to PDLCD1LG2 as the target of this aberration. Patients with the 9p24.1 gain/amplification did not reveal particular clinical features, but their mean survival was slightly shorter than in the remaining EBV Copy number gain of 9p24.1 is a known aberration in lymphoma, particularly in primary mediastinal B cell lymphoma (PMBCL) and classic Hodgkin lymphoma (cHL) (14)(15)(16)(17). It was postulated that in PMBCL this aberration leads to increased dosage of both PDL1 and PDL2, and their induction by the neighboring JAK2 (14).…”

“…The most frequent CNA was gain of 9p sequences detected in five cases (no. 10,13,15,17,20). The commonly gained region was localized at 9p24.1p24.3 Additionally examined with probes for JAK2 CDKNA2,and PDL1/PDL2, and optionally CEP 9.…”

Gene expression profiling of microdissected Hodgkin Reed-Sternberg cells correlates with treatment outcome in classical Hodgkin lymphoma

“…Copy number changes and clinical outcomes of these 29 patients have been reported as part of a larger cohort that was previously published. 18 Furthermore, gene expression of target genes was studied by ISH and immunohistochemistry (IHC) in an independent validation cohort of 166 pretreatment formalin-fixed, paraffin-embedded tissue biopsies of CHL. Clinical characteristics and outcomes of this patient cohort enriched for events and disease-specific deaths have been previously reported.…”

Classical Hodgkin lymphoma

“…Mutations have been found in the tumour suppressor genes FAS (CD95) and TP53. Further genomic imbalances, identified by comparative genomic hybridization studies include gains of IKBKB, CD40 and MAP3K14 that are regulators of NF-kappaB signaling (Küppers and Re, 2007;Hartmann et al, 2008;Steidl et al, 2010;Küppers 2011;Küppers et al, 2012;Pasqualucci and Dalla Favera, 2014). Interestingly, HRS cells show aberrant somatic hypermutation of several proto-oncogenes (PIM1, RHOH (TTF), MYC, PAX5) in a considerable fraction of cases (Küppers et al, 2012;Pasqualucci and Dalla Favera, 2014).…”

“…Diploid as well as aneuploid metaphases are commonly found in chromosome studies, both direct and after culturing. Using FISH 1-12% of "normal" nuclei in cHL exhibit abnormalities, especially trisomies for various chromosomes (Atkin, 1998;Jensen et al, 1998;Hartmann et al, 2008;Schmitz et al, 2009;Steidl et al, 2010;Küppers 2011).…”