TP53 gene mutations in Hodgkin lymphoma are infrequent and not associated with absence of Epstein-Barr virus

Abstract

Epstein-Barr virus (EBV) infection probably has a role in this transforming event, which renders RS precursors resistance to apoptosis, as clonal EBV genomes can be detected in RS cells of classical HL in 30 -50% of cases. 3,4 EBV-encoded LMP-1 protein, known to be expressed in RS cells, is known for its immortalizing activity. 1,4 -6 EBV encoded EBNA-1 protein is also thought to have transforming capacity. 7,8 Moreover EBV is involved in immune suppression. 9,10 The major subset of HL of the nodular sclerosis subtype among the Western population is, however, frequently EBV negative. The distinct epidemiology of these cases has led to various speculations about their pathogenesis, but no other viruses have been identified to date. However, other transforming events such I B␣ gene mutations resulting in over-expression of NF-B as possible explanation of the rescue of these cells from apoptosis have been demonstrated. 11,12 The frequent finding of immunohistochemically detectable p53 protein expression in the nuclei of RS cells 4,13,14 suggests a possible role for p53 protein in the rescue of RS precursors from apoptosis. Wild-type p53 protein has the ability to intervene in cell proliferation and is necessary to maintain the integrity of the DNA.An aberrant p53 protein with lack of transcriptional activity can result in the survival of genetically unstable cells susceptible to malignant transformation. 15 A mutation in the TP53 gene is often associated with detectable p53 protein expression, because it stabilizes the protein as a consequence of conformational change. Several studies have demonstrated that a TP53 gene mutation causes impairment of p53 protein-mediated trans-activation. For HL a few studies have reported the presence of TP53 gene mutations in RS cells in only a minority of cases. 14,16,17 The low percentages of TP53 gene mutations (Ͻ10%) detected could be the result of the paucity of RS cells in the specimens, which may lead to false-negative findings. In general, higher TP53 gene mutation percentages were reported in studies with enrichment for RS cells. 13,18 -20 One exception was reported in a recent study in which even with enrichment no mutations were found. 21 Because TP53 gene mutations and EBV both can play a role in the resistance of RS precursors to apoptosis, the question arises whether these 2 potentially transforming events exclude each other. Chen et al. 13 found TP53 gene mutations in 6 of 16 EBVnegative cases and no mutations in 7 EBV-positive cases. This finding suggests that in some of the EBV-negative cases a TP53 gene mutation may be fundamental for the inhibition of apoptosis.To gain more insight in the frequency of TP53 gene mutations in HL and to test the hypothesis of an inverse correlation between the presence of TP53 gene mutations and EBV, we analyzed 67 cases of HL-involved tissues. All HL-involved tissues were analyzed for the presence of immunohistochemically detectable p53 protein and the presence of EBV. We enriched 15 EBV-positive and 11 EBV-negative HL-involved ti...

Pharmacologic activation of p53-dependent and p53-independent apoptotic pathways in Hodgkin/Reed-Sternberg cells

“…Immunohistochemical analyses have demonstrated that primary HRS cells contain high levels of p53 protein, 21 an observation that is often indicative of p53 mutation. 24 However, on the basis of analysis of micromanipulated primary HRS cells, TP53 defects appear to be rare, [10][11][12] suggesting that other mechanisms are responsible for the accumulation of p53 protein in cHL. Moreover, it was unclear whether the p53-dependent apoptotic pathways remain functionally intact in HRS cells.…”

“…21 However, on the basis of genetic analyses of Hodgkin cell lines and single primary tumor cells, it is generally assumed that this constitutes wild-type p53 protein. [10][11][12] It was thus unexpected that three Hodgkin cell lines were completely unaffected by nutlin-3a, and such unresponsiveness has so far only been observed in cells with mutant or deleted TP53. [4][5][6][7] We therefore sequenced the complete coding region of TP53, PCRamplified from cDNA, for all HRS cell lines studied.…”

“…However, it should also be noted that all three mutations observed in this study involve larger scale loss of TP53 coding sequence, as opposed to the more commonly reported point mutations. Furthermore, the location in exon 4 (L428) as well as the association with splice junctions (HDLM-2, L1236) suggest that mutation analysis of TP53 via the common practice of exons 5-8 specific PCR [10][11][12]22 may be insufficient for a proper assessment. For example, whereas this analysis was sufficient to detect the TP53 abnormality in HDLM-2, the defect in L428 was missed.…”

“…Although mutation of TP53 is one of the most frequent events during cancerogenesis, its prevalence differs considerably between cancers. 9 In cHL, TP53 mutations are rarely found, [10][11][12] suggesting that activation of the p53 pathway could be an effective therapeutic approach for this malignancy.…”

Regulation of Chk2 gene expression in lymphoid malignancies: involvement of epigenetic mechanisms in Hodgkin's lymphoma cell lines

“…[33][34][35][36] While p53 mutations are rather rare in H/RS cells, 37 the expression of genes or proteins involved in the DNA damage response in these cells has not been thoroughly examined.…”