Differential Genetic and Functional Markers of Second Neoplasias in Hodgkin's Disease Patients

Abstract

Purpose: The mechanisms involved in the appearance of a second neoplasia in patients with Hodgkin's disease (HD) are probably related to the genomic damage induced by the treatments administered and its repair. Here, we searched for some constitutive molecular mechanisms that in a basal manner may influence the behavior of HD patients. Experimental Design: We aimed to evaluate with the Comet Assay whether baseline, induced, and unrepaired DNA damage differ between HD patients who did not develop a second neoplasia (HD-NST), HD patients who developed a second tumor (HD-ST), and healthy individuals; and to identify, through cDNA microarray hybridization, an expression signature of genes that could discriminate between the three groups. Results: Baseline, induced, and unrepaired DNA damage was higher in HD-ST than in HD-NST and higher in the second group than in healthy donors. The genomic approach revealed two sets of genes that discriminated between healthy subjects and patients and between the three sets of individuals. Hsp40, RAD50, TPMT, Rap2a, E2F2, EPHX2, TBX21, and BATF were validated by reverse transcription-PCR. Conclusions: Functional and genomic techniques revealed that alterations in cell cycle, repair, detoxification, and stress response pathways could be involved in the development of HD and in the occurrence of a primary second neoplasia in these patients. Both approaches may be useful as biological markers in the clinical setting.

Overexpression of Batf induces an apoptotic defect and an associated lymphoproliferative disorder in mice

“…The findings from the present study and other descriptions of elevated Batf expression in human and mouse peripheral lymphoid tumors 12, 13 suggest that the influence of Batf on AP-1 activity and on the transcription of specific genes has a role. ACAD, the apoptotic process that is impaired in CD2-HA-BATF T cells, is associated with both transcriptional and post-translational events that increase the ratio of pro-apoptotic (e.g., Bim) to anti-apoptotic (e.g., Bcl-2) proteins and, by doing so, promote Cytochrome c release by mitochondria and the activation of cytosolic pro-caspases.…”

“…Our studies demonstrate that this lymphoproliferative disorder (LPD) is not associated with an increase in the proliferative capacity of the T cells, but rather with an impaired response to an apoptotic stimulus. Given the observation that increased BATF expression is a feature of secondary neoplasias in human Hodgkin's lymphoma 12 and of MuMLV-induced T-cell lymphoma in mice, 13 the BATF Tg mice described herein represent a useful model for investigating the role of AP-1 mis-regulation in LPD.…”

Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility

“…RUNX3 has important roles in B-cell maturation 48 and downregulation of RUNX1 by RUNX3 is required for EBV-driven LCL growth 49 . BATF also appears to co-ordinate B-cell maturation 50 , and is highly expressed in HRS cells 51 .…”

Hypopharyngeal Epithelioid Malignant Schwannoma Following Treatment of Hodgkin’s Lymphoma

“…It is also important to note that, genetic susceptibility may also play a role (Boice, 1996). Genomic analysis revealed alterations in cell cycle, repair, while detoxification and stress response pathways are suggested to be involved in the development of HL and in the occurrence of second neoplasias in these patients (Lorenzo et al, 2009). M' Kacher et al (2007) investigated the relationship between telomere shortening in peripheral blood lymphocytes, increased chromosome abnormalities, radiation sensitivity and secondary cancers.…”