The identification of high-risk human papillomavirus (HPV) types as a necessary cause of cervical cancer offers the prospect of effective primary prevention and the possibility of improving the efficiency of cervical screening programmes. However, for these opportunities to be realized, a more complete understanding of the natural history of HPV infection, and its relationship to the development of epithelial abnormalities of the cervix, is required. We discuss areas of uncertainty, and their possible effect on disease prevention strategies.

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The Epstein-Barr virus (EBV) is associated with the development of several human tumors, including Hodgkin's lymphoma (HL) and EBV-positive undifferentiated nasopharyngeal carcinoma (NPC).1 In HL, the malignant Hodgkin's and Reed-Sternberg (HRS) cells constitute only a minority of the total tumor mass, and are surrounded by variable proportions of nonmalignant reactive cells. In approximately onehalf of HL, EBV can be detected in HRS cells, where the virus expresses a limited subset of genes; these include the Epstein-Barr nuclear antigen-1 (EBNA1) and the latent membrane proteins, LMP1 and LMP2.2 Although EBV-specific cytotoxic T cells (CTLs) can be detected in HL and NPC and have been shown to kill LMP1-and LMP2-expressing cells in vitro, they are unable to eliminate EBV-infected tumor cells in vivo. [3][4][5] This failure may be because of increased recruitment of regulatory T cells

Although the latent membrane protein-1 (LMP1) of the Epstein-Barr virus (EBV) is believed to be important for the transformation of germinal centre (GC) B cells, the precise contribution of this viral oncogene to lymphoma development is poorly understood. In this study, we used a non-viral vector-based method to express LMP1 in primary human GC B cells. Gene expression profiling revealed that LMP1 induced in GC B cells transcriptional changes characteristic of Hodgkin's lymphoma cell lines. Strikingly, LMP1 down-regulated the expression of B-cell-specific genes including B-cell receptor components such as CD79A, CD79B, CD19, CD20, CD22, and BLNK. LMP1 also induced the expression of ID2, a negative regulator of B-cell differentiation. Our data suggest that in EBV-positive cases, LMP1 is likely to be a major contributor to the altered transcriptional pattern characteristic of Hodgkin/Reed-Sternberg cells, including the loss of B-cell identity.

Objective To determine the cost to the NHS and the impact on anxiety of a one stop clinic for assessing women with suspected breast cancer. Study design Randomised controlled trial. Participants Women aged 35 or over referred with a breast lump. Study setting Teaching hospital, north west England. Interventions Women were randomly allocated to attend a one stop clinic or a dedicated breast clinic. Outcome measures Reduction in mean anxiety from baseline at 24 hours after the first visit and at 3 weeks and 3 months after diagnosis; mean cost per patient. Results 670 women were randomised. Compared with women who attended the dedicated clinic, patients attending the one stop clinic were less anxious 24 hours after the visit (adjusted mean change in state anxiety − 5.7 (95% confidence interval − 8.4 to − 3.0)) but not at 3 weeks or 3 months after diagnosis. The additional cost to the NHS of a one stop attendance was £32 per woman; this was largely explained by greater cytopathological and radiological staff costs. Conclusion One stop clinics may not be justified in terms of a reduction in short term anxiety.

There is now evidence for both increased and decreased activity of the enzymes controlling the methylation of lysine 27 on histone 3 (H3K27) in cancer. One of these enzymes, KDM6B formally known as JMJD3, a histone demethylase, which removes the trimethyl mark from H3K27, is required for the lineage commitment and terminal differentiation of neural stem cells and of keratinocytes. Our results suggest that KDM6B may also have a role in antigen-driven B-cell differentiation. KDM6B expression increases in B-cell subsets with increasing stage of differentiation, and gene expression profiling shows that KDM6B transcriptional targets in germinal centre B (GC B) cells are significantly enriched for those differentially expressed during memory and plasma cell differentiation. Our results also suggest that aberrant expression of KDM6B may contribute to the pathogenesis of Hodgkin's Lymphoma (HL), an Epstein-Barr virus (EBV) associated malignancy. KDM6B is over-expressed in primary HL and induced by the EBV oncogene, latent membrane protein (LMP1) in GC B cells, the presumptive progenitors of HL. Consistent with these observations, we found that KDM6B transcriptional targets in GC B cells are enriched for genes differentially expressed in HL, and that KDM6B depletion can restore the tri-methylation of H3K27 on these genes.

An important pathogenic event in EpsteinBarr virus (EBV)- IntroductionThe Epstein-Barr virus (EBV) is a ␥-herpesvirus that infects the majority of the world's adult population. In most persons, the virus is carried life-long as an asymptomatic infection where it establishes persistence by latently infecting memory B lymphocytes. However, in a minority of persons, EBV can contribute to the development of one of several B-cell malignancies, including Burkitt lymphoma (BL). 1 In vitro infection of normal B cells with EBV gives rise to lymphoblastoid cell lines (LCLs) in which there is expression of a limited subset of latent virus genes that include the Epstein-Barr nuclear antigens (2, 3A, 3B, 3C, and LP) and the latent membrane proteins (LMP-1, and LMP-2). 2 In contrast, most EBV-associated lymphomas show a more restricted pattern of latency; for example, in the majority of EBV ϩ BL, Epstein-Barr nuclear antigen-1 is the only viral protein expressed. 3,4 As well as maintaining latency in B lymphocytes, the virus can also induce its replicative cycle in these cells. Thus, at any one time, a small proportion of cells in an LCL may spontaneously enter the lytic cycle or be induced to do so by treatment with chemical agents, such as phorbol esters, or by ligation of surface immunoglobulin (Ig). 5 The replicative cycle of EBV is induced by expression of the immediate-early gene, BZLF1, which alone is sufficient to activate downstream lytic genes and complete viral replication in a permissive cell type. 6,7 A number of studies suggest that EBV replicates in terminally differentiated plasma cells. [8][9][10][11][12] These findings are supported by in vitro studies, which show that the BZLF1 promoter is active in memory cells only after they have been differentiated into plasma cells. 12 The intimate association between terminal differentiation and EBV replication in B cells suggests that the switch from latency to the lytic cycle is controlled by factors that normally regulate plasma cell differentiation. We speculated that the absence of such factors could be important in the pathogenesis of EBV-associated lymphomas because virus replication would otherwise result in tumor cell death.We have focused on BLIMP1, a transcription factor encoded by the PRDM1 gene, which orchestrates plasma cell differentiation by repressing genetic programs associated with the germinal center (GC) stages, while at the same time activating those programs associated with plasma cell functions. 13,14 For example, the BLIMP1-mediated silencing of MYC, BCL6, and PAX5 expression has been shown to be required for plasma cell differentiation. [15][16][17][18][19] BLIMP1 also Submitted September 16, 2010; accepted February 21, 2011. Prepublished online as Blood First Edition paper, March 16, 2011; DOI 10.1182 DOI 10. /blood-2010 An Inside Blood analysis of this article appears at the front of this issue.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Th...

The contribution of early virus-induced epigenetic changes to human papillomavirus (HPV)-associated carcinogenesis is poorly understood. Using genome-wide methylation array profiling and a cell-based model, which supports replication of HPV episomes, we found that transfection of primary human foreskin keratinocytes with episomal forms of high-risk HPV types was followed by upregulation of the DNA methyltransferases, DNMT1 and DNMT3B, and changes in the methylation status of cellular genes many of which are reported to be differentially methylated in cervical neoplasia. HPV16- and HPV18-associated changes were not randomly distributed across the genome, but clustered at specific chromosomal locations which mapped on to known HPV integration sites and to chromosomal regions lost and gained in high-grade cervical neoplasia. Methylation changes were directed in part by the same cis-acting factors that appear to direct methylation changes in cancer, the presence of a bivalent chromatin mark in human embryonic stem cells and promoter CpG content; these associations explain much of the ontological profile of genes found to have increased methylation following HPV16 transfection. We were also able to show, using sequential samples from a cohort of young women with incident HPV16 infections, that the detection in cervical samples of methylated forms of the tumour suppressor gene, RARB, often parallels the natural history of cervical HPV infection. Our findings suggest that further investigation of the distribution and determinants of early virus-induced epigenetic reprogramming will provide important insights into the pathogenesis of virus-associated malignancy.