Presence of simian virus 40 in diffuse large B-cell lymphomas in Tunisia correlates with germinal center B-cell immunophenotype, t(14;18) translocation, and P53 accumulation

Abstract

Previously we have reported the presence of simian virus 40 DNA in 56% of diffuse large B-cell lymphomas in Tunisia. Here, we investigated the relationship between the status of simian virus 40 and t(14;18) translocation, germinal center status, and P53 and BCL2 expression to assess the clinical and biological relevance of simian virus 40 presence in diffuse large B-cell lymphomas. Therefore, we evaluated by immunohistochemistry the expression patterns of CD10, BCL6, MUM1, BCL2, and P53 in 86 diffuse large B-cell lymphomas (48 simian virus 40-positive and 38 simian virus 40-negative cases). The t(14;18) translocation was investigated by polymerase chain reaction. Immunostaining patterns for CD10, BCL6, and MUM1 were used to subclassify diffuse large B-cell lymphoma cases as germinal center or non-germinal center phenotypes. Germinal center phenotype, t(14;18), P53, and BCL2 expression were found in 71, 30, 55, and 65% of cases, respectively. Interestingly, germinal center phenotype, t(14;18), and P53 accumulation were found to be more frequent in simian virus 40-positive cases than in simian virus 40-negative ones (81, 44, 69 vs 58, 13, 37%; P ¼ 0.018, 0.002, and 0.003, respectively). However, there were no correlations between the presence of simian virus 40 and the expression of CD10, BCL6, MUM1 and BCL2, patient's age and gender, clinical stage, or the International Prognosis Index. Multivariate logistic regression analyses revealed that the germinal center phenotype, P53 accumulation, and t(14;18) were independent factors for simian virus 40 association (P ¼ 0.029, 0.006, and 0.014, respectively). There were no significant differences in overall survival regarding P53, BCL2, or t(14;18) status. However, patients with germinal center phenotype or low International Prognosis Index scores displayed a significantly better survival than those with non-germinal center phenotype or high International Prognosis Index scores (P ¼ 0.003 and 0.0001, respectively). These two prognosis factors remain independent in multivariate analyses (P ¼ 0.001 and o0.0001, respectively). Interestingly, among patients with germinal center phenotype, simian virus 40-positive subgroup displayed a significantly shorter survival than simian virus 40-negative subgroup (P ¼ 0.034). In summary, these findings support a role of simian virus 40 in the pathogenesis of diffuse large B-cell lymphomas. On other hand, they suggest that a significant proportion of diffuse large B-cell lymphoma cases with germinal center phenotype may result from early transformation by simian virus 40, mainly those harboring the t(14;18).

Evidence for a role of the Simian Virus 40 in human breast carcinomas

“…This observation supports a role of SV40 in the inactivation of P53 in human BC. Similar results have been also demonstrated in human mesotheliomas, brain tumors, and lymphomas [60][61][62].…”

A New Immunostain Algorithm Classifies Diffuse Large B-Cell Lymphoma into Molecular Subtypes with High Accuracy

“…For the remaining 42 cases (9 GCB and 33 ABC), we again used the data-sort function and found that sequential use of either monoclonal or polyclonal BCL6 (≥30%) followed by FOXP1 (≥80%) classified 37 (88%) of the cases correctly. Monoclonal BCL6 was chosen because it does not require additional procedures to decrease background staining, and it was the BCL6 antibody most commonly used in recent studies (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)23). Whereas changing the cutoffs of monoclonal BCL6 or FOXP1 in this algorithm led to worse overall accuracy, we found that changing the cutoffs for GCET1 and MUM1 to ≥80%, and CD10 to ≥30%, did not affect the concordance with the GEP classification.…”

“…To facilitate translational application of the GEP classification for prognostication using formalin-fixed, paraffinembedded tissues, we have previously proposed an immunohistochemical (IHC) stain algorithm (Hans' algorithm) using three antibodies [CD10, multiple myeloma oncogene 1 (MUM1), and polyclonal B-cell lymphoma 6 (BCL6)] to classify DLBCL into GCB and non-GCB (ABC and unclassified) subtypes (9). It resulted in a concordance of ∼80% when compared with the GEP classification (9), and subsequent studies have yielded conflicting results regarding its prognostic prediction (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Most of these studies included patients from the pre-rituximab era (10)(11)(12)(13)(14)(15)(17)(18)(19)(20)(21)(22)(23), but the controversy has extended to R-CHOP-treated patients as well (15,19,22,23).…”

SV40 and p53 as team players in childhood lymphoproliferative disorders

“…A recent report reflects on the common mechanism of transformation by small DNA viruses, such as SV40, and the inactivation of p53 (69). Except for one report, correlating SV40 and p53 in diffuse large B-cell lymphoma in Tunesia (70), such a correlation has not been studied as far as we know for childhood lymphoproliferative disorders. That study looked for the accumulation of p53 in the nucleus, not for p53 mutations, specifically.…”