Diffuse large B-cell lymphomas (DLBCL) are the most common type of aggressive lymphomas, with considerable heterogeneity in clinical presentation, molecular characteristics, and outcome. Previous studies have showed significant correlations between DNA methyltransferase (DNMT) overexpression and unfavorable prognosis in human cancers. Therefore, we investigated in this study the biological and prognostic significance of DNMT1, DNMT3a, and DNMT3b protein expression in DLBCL. DNA methyltransferase (DNMT) expression was analyzed by immunohistochemistry in 81 DLBCL cases and correlated with clinicopathological parameters. Kaplan-Meier curves were used to estimate survival rates, and the Cox proportional hazard regression model was used to evaluate the prognostic impact of DNMT expression. Our results showed that overexpression of DNMT1, DNMT3a, and DNMT3b were detected in 48%, 13%, and 45% of investigated cases, respectively. DNA methyltransferase 1 (DNMT1) and DNMT3b overexpression was significantly correlated with advanced clinical stages (P = 0.028 and P = 0.016, respectively). Moreover, concomitant expression of DNMT1 and DNMT3b was significantly correlated with resistance to treatment (P = 0.015). With regard to survival rates, although data was available only for 40 patients, DNMT3b overexpression was significantly correlated with shorter overall survival (P = 0.006) and progression-free survival (P = 0.016). Interestingly, multivariate analysis demonstrated that DNMT3b overexpression was an independent prognostic factor for predicting shortened overall survival (P = 0.004) and progression-free survival (P = 0.024). In conclusion, DNMT3b overexpression was identified as an independent prognostic factor for predicting shortened survival of patients with DLBCL and could be, therefore, useful in identifying patients who would benefit from aggressive therapy. (Cancer Sci 2010; 101: 1722-1730 D iffuse large B-cell lymphomas (DLBCL) are the most common form of aggressive lymphoma.(1,2) Although curable in the majority of cases with anthracycline-based combination chemotherapy and the monoclonal antibody rituximab, approximately 40% of patients with DLBCL will relapse after standard first-line therapy.(1,2) Several biological markers have been studied in attempting to identify high-risk patients, but none has proved to be completely effective, (2,3) and the international prognostic index (IPI) has remained the gold standard for predicting prognosis.(4) Recently, microarray gene expression studies have identified multiple genes of potential prognostic significance in DLBCL, and have led to the subdivision of DLBCL into two major biological categories based on presumed cell of origin: germinal centre B-cell like (GCB), and non-GCB ⁄ activated B-cell like.(5) However, the prognostic value of genetic markers in DLBCL remains controversial. The identification of new molecular prognostic markers would therefore improve the prognostic predictability and understanding of the clinical behavior of those lymphomas. (2,3) DNA me...

This study demonstrates that DLBCLs with hypermethylated P16, VHL, DAPK, and SHP1 commonly show a biologically aggressive phenotype and worse prognosis. Interestingly, hypermethylation of DAPK was found to be an independent prognostic factor that may be used in conjunction with the conventional prognostic factors such as the IPI and the germinal center status.

The simian virus SV40 (SV40), a potent DNA oncogenic polyomavirus, has been detected in several human tumors including lymphomas, mainly in diffuse large B-cell type (DLBCL). However, a causative role for this virus has not been convincingly established. Hypermethylation in promoter regions is a frequent process of silencing tumor suppressor genes (TSGs) in cancers, which may be induced by oncogenic viruses. In this study, we investigated the relationship between the presence of SV40 DNA sequences and the methylation status of 13 TSGs in 108 DLBCLs and 60 nontumoral samples from Tunisia. SV40 DNA presence was investigated by PCR assays targeting the large T-antigen, the regulatory and the VP1 regions. Hypermethylation was carried out by methylationspecific PCR. SV40 DNA was detected in 63/108 (56%) of DLBCL and in 4/60 (6%) of nontumoral samples. Hypermethylation frequencies for the tested TSGs were 74% for DAPK, 70% for CDH1, SHP1, and GSTP1, 58% for p16, 54% for APC, 50% for p14, 39% for p15, 19% for RB1, 15% for BLU, 3% for p53, and 0% for p300 and MGMT. No hypermethylation was observed in nontumoral samples. Hypermethylation of SHP1, DAPK, CDH1, GSTP1 and p16 genes were significantly higher in SV40-positive than in SV40-negative DLBCL samples (p values ranging from 0.0006 to <0.0001). Our findings showed a high prevalence of SV40 DNA in DLBCLs in Tunisia. The significant association of promoter hypermethylation of multiple TSGs with the presence of SV40 DNA in DLBCLs supports a functional effect of the virus in those lymphomas. ' 2007 Wiley-Liss, Inc.Key words: diffuse large B-cell lymphomas; simian virus 40; hypermethylation; tumor suppressor genes; Tunisia Simian virus 40 (SV40) is a potent DNA oncogenic polyomavirus of rhesus monkey origin which seems to have spread to human beings via contamination of poliovirus stocks between 1955 and 1963 as well as by other means, 1 and mounting evidence suggests that it is an emergent human pathogen. 2-4 SV40 DNA sequences have been detected in pediatric and adult brain tumors, 5,6 mesotheliomas, 7 osteosarcomas, 8 bronchopulmonary carcinomas, 9 bone tumors 10 and papillary thyroid carcinomas. 11 There also increasing evidence that SV40 is associated with non-Hodgkin's lymphomas, particularly with diffuse large B-cell lymphomas (DLBCL), 12-21 in spite of several negative studies. [22][23][24] However, although these observations indicate an association between this virus and specific human tumors, they do not demonstrate a causal role, and the molecular mechanism by which SV40 thought to be involved is still unclear.SV40 oncogenic potential is assumed to be associated with the primary viral gene product, large T-antigen (Tag), protein responsible for SV40 replication and SV40-mediated cell transformation. 1 In vitro, the infection of human cells by SV40 has showed that SV40 Tag can promote malignancy transformation by blocking the products of several tumor suppressor genes (TSGs), 1,25 inducing telomerase activity, 26 and stimulating other oncogenes and growth facto...

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The aim of this study was to evaluate the prevalence of broad range of anogenital HPVs in a series of 123 Tunisian breast carcinoma cases. PCR assays were performed to amplify regions within the L1, E1, E6 and E7 open reading frames of a broad range of anogenital HPVs and specific types HPV16, 18, 31 and 33. In addition, we performed an in situ hybridization analysis using HPV biotinylated DNA probes for the detection of broad spectrum of anogenital HPV types, high-risk HPV types (16 and 18), intermediate-risk HPV types (31 and 33) and low-risk HPV types (6 and 11). None of the 123 breast carcinoma samples showed PCR amplification of HPV DNA using the broad spectrum consensus primer-pairs E1-350L/E1-547R and GP5+/GP6+ primers. Furthermore, neither high risk nor low-risk HPV types were detected in any of these cases. Moreover, using in situ hybridization for the detection of HPVs, we failed to detect a positive signal in neoplastic cells in any case. Our results suggest that anogenital papillomaviruses are unlikely to play a role in the development of breast carcinomas in Tunisian patients.

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CD10 is a cell surface zinc metalloprotease expressed through a variety of normal cell types, including lymphoid precursor cells, germinal center B lymphocytes, and some epithelial cells. Many studies showed that CD10 expression is associated with the tumor progression of a large variety of cancers, such as breast and colorectal carcinomas. The aim of this study was to investigate the expression of CD10 in nasopharyngeal carcinoma (NPC). The expression of CD10 was immunohistochemically examined in 47 paraffin embedded NPC biopsies from Tunisian patients compared with 16 reactional nasopharyngeal mucosas. A significant expression of CD10 was observed in stromal fusiform cells in 46.8% of NPC cases but was not in malignant and normal epithelial cells. There was no significant expression of CD10 in control group. The stromal expression of CD10 was more frequently detected in advanced clinical stage than early stage (56 vs 23%; p=0.04) and in patients older than 25 years than in patients under 25 years (56.2 vs 26.5%; p=0.05). Our study is the first in investigating CD10 expression in nasopharyngeal carcinoma and showed that CD10 expression by stromal cells in this malignancy play an important role in tumor progression, particularly in older patients.

We conclude that the prevalence of EBV-associated GC in Tunisia is low (4.1%), suggesting that this virus is not an important etiological factor in GC arising in north African populations. The clinicopathological profile of EBV-associated GC in Tunisia did not differ markedly from that found elsewhere.