Correction: S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells.

The Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma (HL) are characterised by the aberrant activation of multiple signalling pathways. Here we show that a subset of HL displays altered expression of sphingosine-1-phosphate (S1P) receptors (S1PR)s. S1P activates phosphatidylinositide 3-kinase (PI3-K) in these cells that is mediated by the increased expression of S1PR1 and the decreased expression of S1PR2. We also showed that genes regulated by the PI3-K signalling pathway in HL cell lines significantly overlap with the transcriptional programme of primary HRS cells. Genes upregulated by the PI3-K pathway included the basic leucine zipper transcription factor, ATF-like 3 (BATF3), which is normally associated with the development of dendritic cells. Immunohistochemistry confirmed that BATF3 was expressed in HRS cells of most HL cases. In contrast, in normal lymphoid tissues, BATF3 expression was confined to a small fraction of CD30-positive immunoblasts. Knockdown of BATF3 in HL cell lines revealed that BATF3 contributed to the transcriptional programme of primary HRS cells, including the upregulation of S1PR1. Our data suggest that disruption of this potentially oncogenic feedforward S1P signalling loop could provide novel therapeutic opportunities for patients with HL.

Smoking initiation is followed by the early acquisition of epigenetic change in cervical epithelium: a longitudinal study.

BACKGROUND: To prove a causal link between an epigenetic change and an environmental or behavioural risk factor for a given disease, it is first necessary to show that the onset of exposure precedes the first detection of that epigenetic change in subjects who are still free of disease. METHODS: Towards this end, a cohort of women aged 15-19 years, recruited soon after they first had sexual intercourse, were used to provide sequential observations on the relationship between cigarette smoking and the detection in cervical cytological samples of methylated forms of CDKN2A (p16) using nested methylation-specific polymerase chain reaction. RESULTS: Among women who remained cytologically normal and who tested negative for human papillomavirus DNA in cervical smears during follow-up, those who first started to smoke during follow-up had an increased risk of acquiring CDKN2A methylation compared with never-smokers (odds ratio=3.67; 95% confidence interval 1.09-12.33; P=0.04). CONCLUSION: Smoking initiation is associated with the appearance of methylated forms of CDKN2A.

The EBV-encoded latent membrane proteins, LMP2A and LMP2B, limit the actions of interferon by targeting interferon receptors for degradation.

Although frequently expressed in Epstein-Barr virus (EBV)-positive malignancies, the role that latent membrane protein 2A and 2B (LMP2A and LMP2B) have in the oncogenic process remains obscure. Here we show a novel function for these proteins in epithelial cells, namely, their ability to modulate signalling from type I/II interferon receptors (IFNRs). We show that LMP2A- and LMP2B-expressing epithelial cells show decreased responsiveness to interferon (IFN)alpha and IFNgamma, as assessed by STAT1 phosphorylation, ISGF3 and GAF-mediated binding to IFN-stimulated response element and IFNgamma-activated factor sequence elements and luciferase reporter activation. Transcriptional profiling highlighted the extent of this modulation, with both viral proteins impacting 'globally' on IFN-stimulated gene expression. Although not affecting the levels of cell-surface IFNRs, LMP2A and LMP2B accelerated the turnover of IFNRs through processes requiring endosome acidification. This function may form part of EBV's strategy to limit anti-viral responses and define a novel function for LMP2A and LMP2B in modulating signalling from receptors that participate in innate immune responses.

Impact of NHS breast screening on advanced disease and mortality from breast cancer in the North West of England.

A cohort study was undertaken to describe outcomes from breast cancer in women who were aged 54 years or younger when they were first invited for NHS breast screening. The analysis included 5125 women invited for multiple rounds of breast screening by the Wigan screening programme and 10 750 women invited by the Manchester programme. The main outcome measures were rates of advanced disease and mortality from breast cancer. In Wigan 4028 (78.6%) and in Manchester 5485 (51.0%) women accepted all of their invitations for screening. The incidence of invasive cancer was higher in Wigan than in Manchester (24.78 vs 21.11 per 10 000 person-years; chi(2)=2.11, 1 df, P=0.15), but the rate of advanced disease was significantly lower (2.49 vs 4.73 per 10 000 person-years; chi(2)=4.36, 1 df, P=0.04). Mortality was lower in Wigan than in Manchester (2.46 vs 4.31 per 10 000 person-years; chi(2)=3.25, 1 df, P=0.07). In the first report of long-term outcomes in women invited for NHS breast screening, we demonstrated that it is possible to evaluate the impact of screening by comparing programmes with different proportions of regular attenders; a significant difference was shown in the rate of advanced disease between two programmes with different cancer detection and attendance rates.

Loop diathermy excision compared with cervical laser vaporisation for the treatment of intraepithelial neoplasia: a randomised controlled trial.

OBJECTIVE: To determine whether loop diathermy excision of the transformation zone and laser vaporisation are equally effective in the treatment of cervical intraepithelial neoplasia. DESIGN: Randomised controlled trial. POPULATION: Women referred for evaluation of cytological abnormality who were considered suitable for outpatient local destructive treatment. SETTING: Seven colposcopy units in the North West Region. METHODS: Loop diathermy excision of the transformation zone and laser vaporisation. MAIN OUTCOME MEASURE: Smear reported as moderate dyskariosis or worse following treatment. RESULTS: Of 289 women randomised, 285 had one or more smears following treatment. Women were more likely to have a smear reported as moderate dyskariosis or worse following laser vaporisation [hazard ratio 3.01 (95% CI 1.27 to 7.12)]. The cumulative risk of a smear reported as moderate dyskariosis or worse was 6.0% at six months and 12.1% at three years in those allocated laser vaporisation, and 2.0% at six months, and 3.3% at three years in those allocated loop diathermy excision of the transformation zone. CONCLUSIONS: Loop diathermy excision is a more effective treatment of cervical intraepithelial neoplasia than laser vaporisation.

Site distribution of oesophagogastric cancer.

AIMS: It has been suggested that adenocarcinomas of the lower oesophagus and gastric cardia should be reclassified as oesophagogastric junction (OGJ) cancers. This study aimed to define the frequency of OGJ cancers in a geographically defined population of 4.3 million people. METHODS: All cases of oesophageal and gastric cancer occurring in 1993 were identified by the North Western Regional Cancer Registry. A total of 1192 hospital case notes were reviewed and a study group of 1067 patients was defined. Tumour involvement was documented at individual subsites in the oesophagus and stomach, allowing for tumour presence in more than one oesophageal/gastric subsite. RESULTS: There were 627 tumours in men and 440 in women. The tumour was confined to the oesophagus in 281 (26.3%) cases and to the stomach in 454 (42.6%) cases. The tumour encroached upon or crossed the OGJ in 332 (31.1%) cases. Overall, tumours involved the cardia, OGJ, or lower oesophagus in 633 (59.3%) cases; in 179 (18.5%) cases the tumour involved the lower oesophagus but not the OGJ, and in another 122 (11.4%) cases the cardia was involved but not the OGJ. CONCLUSIONS: Oesophagogastric cancers in this population predominantly involve the OGJ, lower oesophagus, and/or cardia.