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Dawson M.A.,Cancer Research Division | Dawson M.A.,University of Melbourne | Dawson M.A.,Peter MacCallum Cancer Center
Science | Year: 2017

Cancer biology is profoundly influenced by changes in the epigenome. Because the dynamic plasticity of the epigenome lends itself well to therapeutic manipulation, the past few years have witnessed an unprecedented investment in the development, characterization, and translation of targeted epigenetic therapies. In this review, I provide a broad context for recent developments that offer a greater understanding of how epigenetic regulators facilitate the initiation, maintenance, and evolution of cancer. I discuss newly developed epigenetic therapies and the cellular and molecular mechanisms that may govern sensitivity and resistance to these agents. I also review the rationale for future combination therapies involving existing and emerging epigenetic drugs. © 2017, American Association for the Advancement of Science. All rights reserved.

George A.J.,University of Queensland | George A.J.,Cancer Research Division | George A.J.,University of Melbourne | Hannan R.D.,University of Queensland | And 4 more authors.
FEBS Journal | Year: 2013

To influence physiology and pathophysiology, G protein-coupled receptors (GPCRs) have evolved to appropriate additional signalling modalities, such as activation of adjacent membrane receptors. Epidermal growth factor receptors (EGFRs) mediate growth and remodelling actions of GPCRs, although the precise network of gene products and molecular cascades linking GPCRs to EGFRs (termed EGFR transactivation) remains incomplete. In this review, we describe the current view of GPCR-EGFR transactivation, identifying the established models of receptor cross-talk. We consider the limitations in our current knowledge, and propose that recent advances in molecular and cell biology technology, including functional genomics approaches, will allow a renewed focus of efforts to understand the mechanism underlying EGFR transactivation. Using an unbiased approach for identification of the molecules required for GPCR-mediated EGFR transactivation will provide a contemporary and more complete representation from which to extrapolate therapeutic control in diseases from cardiovascular remodelling to cancer. Cross-talk between G protein-coupled receptors (GPCRs) and the epidermal growth factor receptor (EGFR) facilitate many important cellular activities. However, the molecular mechanism still remains poorly understood. In this review, we discuss the current view of GPCR-EGFR transactivation, and propose that functional genomics approaches will allow a renewed concentration of our efforts to further investigate the mechanism underlying this process. © 2013 FEBS.

Faure A.J.,European Bioinformatics Institute | Schmidt D.,Cancer Research UK Research Institute | Schmidt D.,Hutchison Research Center | Watt S.,Cancer Research UK Research Institute | And 14 more authors.
Genome Research | Year: 2012

The cohesin protein complex contributes to transcriptional regulation in a CTCF-independent manner by colocalizing with master regulators at tissue-specific loci. The regulation of transcription involves the concerted action of multiple transcription factors (TFs) and cohesin's role in this context of combinatorial TF binding remains unexplored. To investigate cohesin-non-CTCF (CNC) binding events in vivo we mapped cohesin and CTCF, as well as a collection of tissuespecific and ubiquitous transcriptional regulators using ChIP-seq in primary mouse liver. We observe a positive correlation between the number of distinct TFs bound and the presence of CNC sites. In contrast to regions of the genome where cohesin and CTCF colocalize, CNC sites coincide with the binding of master regulators and enhancer-markers and are significantly associated with liver-specific expressed genes. We also show that cohesin presence partially explains the commonly observed discrepancy between TF motif score and ChIP signal. Evidence from these statistical analyses in wildtype cells, and comparisons to maps of TF binding in Rad21-cohesin haploinsufficient mouse liver, suggests that cohesin helps to stabilize large protein-DNA complexes. Finally, we observe that the presence of mirrored CTCF binding events at promoters and their nearby cohesin-bound enhancers is associated with elevated expression levels. © 2012, Published by Cold Spring Harbor Laboratory Press.

Yu X.Q.,Cancer Research Division | Yu X.Q.,University of Sydney | Baade P.D.,Viertel Center for Research in Cancer Control | Baade P.D.,Queensland University of Technology | And 3 more authors.
BMC Cancer | Year: 2012

Background: Estimated conditional survival for cancer patients diagnosed at different ages and disease stage provides important information for cancer patients and clinicians in planning follow-up, surveillance and ongoing management.Methods: Using population-based cancer registry data for New South Wales Australia, we estimated conditional 5-year relative survival for 11 major cancers diagnosed 1972-2006 by time since diagnosis and age and stage at diagnosis.Results: 193,182 cases were included, with the most common cancers being prostate (39,851), female breast (36,585) and colorectal (35,455). Five-year relative survival tended to increase with increasing years already survived and improvement was greatest for cancers with poor prognosis at diagnosis (lung or pancreas) and for those with advanced stage or older age at diagnosis. After surviving 10 years, conditional 5-year survival was over 95% for 6 localised, 6 regional, 3 distant and 3 unknown stage cancers. For the remaining patient groups, conditional 5-year survival ranged from 74% (for distant stage bladder cancer) to 94% (for 4 cancers at different stages), indicating that they continue to have excess mortality 10-15 years after diagnosis.Conclusion: These data provide important information for cancer patients, based on age and stage at diagnosis, as they continue on their cancer journey. This information may also be used by clinicians as a tool to make more evidence-based decisions regarding follow-up, surveillance, or ongoing management according to patients' changing survival expectations over time. © 2012 Yu et al.; licensee BioMed Central Ltd.

Kitchener H.C.,University of Manchester | Canfell K.,University of New South Wales | Canfell K.,Cancer Research Division | Gilham C.,London School of Hygiene and Tropical Medicine | And 4 more authors.
Health Technology Assessment | Year: 2014

Background: The ARTISTIC (A Randomised Trial In Screening To Improve Cytology) trial originally reported after two rounds of primary cervical screening with human papillomavirus (HPV). Extended follow-up of the randomised trial cohort through a third round could provide valuable insight into the duration of protection of a negative HPV test, which could allow extended screening intervals. If HPV primary screening is to be considered in the national programme, then determining its cost-effectiveness is key, and a detailed economic analysis using ARTISTIC data is needed. Aims/objectives: (1) To determine the round 3 and cumulative rates of cervical intraepithelial neoplasia (CIN) grade 2 or worse (2+) and CIN grade 3 or worse (CIN3+) between the revealed and concealed arms of ARTISTIC after three screening rounds over 6 years. (2) To compare the cumulative incidence of CIN2+ over three screening rounds following negative screening cytology with that following negative baseline HPV. (3) To determine whether or not HPV screening could safely extend the screening interval from 3 to 6 years. (4) To study the potential clinical utility of an increased cut-off of 2 relative light unit/mean control (RLU/Co) for Hybrid Capture 2 (HC2) and HPV genotyping in primary cervical screening. (5) To determine the potential impact of HPV vaccination with Cervarix™ in terms of preventing abnormal cytology and CIN2+. (6) To determine the cost-effectiveness of HPV primary screening compared with current practice using cervical cytology in England. Design: The ARTISTIC study cohort was recalled for a third round of screening 3 years after round 2 and 6 years following their enrolment to the study. Both arms of the original trial used a single protocol during round 3. Setting: ARTISTIC study cohort undergoing cervical screening in primary care in Greater Manchester, UK. Participants: Between July 2007 and September 2009, 8873 women participated in round 3; 6337 had been screened in round 2 and 2536 had not been screened since round 1. Interventions: All women underwent liquid-based cytology and HPV testing and genotyping. Colposcopy was offered to women with moderate dyskaryosis or worse and with HPV-positive mild dyskaryosis/ borderline changes. Women with negative cytology or HPV-negative mild dyskaryosis/borderline changes were returned to routine recall. Main outcome measures: Principal outcomes were cumulative rates of CIN2+ over three screening rounds by cytology and HPV status at entry; HPV type specific rates of CIN2+; effect of age on outcomes correlated with cytology and HPV status; comparison of HC2 cut-off RLU/Co of both 1 and 2; and cost-effectiveness of HPV primary screening. Results: The median duration of follow-up was 72.7 months in round 3. Over the three screening rounds, there was no significant difference in CIN2+ [odds ratio (OR): 1.06, 95% confidence interval (CI) 0.89 to 1.26, p = 0.5)] or CIN3+ (OR: 0.90, 95% CI 0.72 to 1.14, p = 0.4) rates between the trial arms (revealed vs. concealed). Overall, 16% of women were HC2 positive at entry, decreasing from 40% in women aged 20-24 years to around 7% in women aged over 50 years. Abnormal cytology rates at entry were 13% for borderline+ and 2% for moderate+ cytology. Following positive cytology at entry, the cumulative rate of CIN2+ was 20.5%, and was 20.1% following a HPV-positive result at baseline. The cumulative CIN2+ rate for women who were HPV negative at baseline was only 0.87% (95% CI 0.70% to 1.06%) after three rounds of screening, significantly lower than that for women with negative cytology, which was 1.41% (95% CI 1.19% to 1.65%). Women who were HPV negative at baseline had similar protection from CIN2+ after 6 years as women who were cytology negative at baseline after 3 years. Women who were HPV positive/cytology negative at baseline had a cumulative CIN2+ rate at 6 years of 7.7%, significantly higher than that for women who were cytology positive/HPV negative (3.2%). Women who were HPV type 16 positive at baseline had a cumulative CIN2+ rate over three rounds of 43.6% compared with 20.1% for any HPV-positive test. Using a HC2 cut-off of RLU/Co ≥ 2 would maintain acceptable sensitivity and result in 16% fewer HPV-positive results. Typing data suggested that around 55-60% of high-grade cytology and CIN2+, but less than 25% of low-grade cytology, would be prevented by HPV vaccine given current rates of coverage in the UK national programme. For the cost-effectiveness analysis, most of the primary HPV strategies examined where HPV was used as the sole primary test were cost saving in both unvaccinated and vaccinated cohorts under baseline cost assumptions, with a 7-18% reduction in annual screening-associated costs in unvaccinated cohorts and a 9-22% reduction for vaccinated cohorts. Utilising partial genotyping at the primary screening stage to identify women with HPV 16/18 and referring them to colposcopy was the most effective strategy (barring co-testing, which is significantly more costly than any other strategies considered), resulting in 83 additional life-years per 100,000 women for unvaccinated women when compared with current practice, and similar life-years saved compared with current practice for vaccinated women. In unvaccinated cohorts, however, this genotyping strategy is predicted to result in a 20% increase in the number of colposcopies performed in England, although in vaccinated cohorts the number of colposcopy referrals was predicted to be lower than in current practice. For all strategies in which HPV is used as the sole primary screening test, decreasing the follow-up interval for intermediate-risk women from 24 to 12 months increased the overall effectiveness of primary HPV screening. In exploratory analysis, strategies for which cytology screening was retained until either age 30 or 35 years, and for which HPV testing was used at older ages, were predicted to be of higher costs and intermediate effectiveness than those associated with full implementation of primary HPV screening from age 25 years. However, this finding should be interpreted with caution as it depends on assumptions made about screening behaviour and compliance with recommendations at the 'switch over' point. Conclusions: HPV testing as an initial screen was significantly more protective over three rounds (6 years) than the current practice of cytology and the use of primary HPV screening could allow a safe lengthening of the screening interval. A substantial decrease in high-grade cytology and CIN2+ can be expected as a consequence of the HPV vaccination programme. A HC2 cut-off of 2RLU/Co instead of the manufacturer's recommended cut-off of 1 would be clinically beneficial in terms of an optimal balance between sensitivity and specificity. Modelled analysis predicts that primary HPV screening would be both more effective and cost saving compared with current practice with cervical cytology for a number of potential strategies in both unvaccinated and vaccinated cohorts. Compliance with surveillance and optimal management of HPV-positive/cytology-negative women after primary HPV screening is of key importance. Limitations of the economic investigation included the need to make assumptions around compliance with screening attendance and follow-up for longer screening intervals in the future, assumptions regarding maintenance of current uptake vaccination in the future, and assumptions regarding the stability of cost of HPV and cytology tests in the future. Detailed sensitivity analysis across a range of possible assumptions was conducted to address these issues. This study and the economic evaluation lend support to convert from cytology to HPV-based screening. Future work should include researching (i) the attitudes of women who test HPV positive/cytology negative, (ii) the value of complementary biomarkers and (iii) activities relevant to primary HPV screening in unvaccinated and vaccinated populations from the point of view of QALY assessment. Study registration: Current Controlled Trials ISRCTN25417821. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 23. See the NIHR Journals Library programme website for further project information. © Queen's Printer and Controller of HMSO 2014.

Sitas F.,Cancer Research Division | Sitas F.,University of Sydney | Sitas F.,University of New South Wales | Egger S.,Cancer Research Division | And 5 more authors.
The Lancet | Year: 2013

Background The full eventual effects of current smoking patterns cannot yet be seen in Africa. In South Africa, however, men and women in the coloured (mixed black and white ancestry) population have smoked for many decades. We assess mortality from smoking in the coloured, white, and black (African) population groups. Methods In this case-control study, 481640 South African notifications of death at ages 35-74 years between 1999 and 2007 yielded information about age, sex, population group, education, smoking 5 years ago (yes or no), and underlying disease. Cases were deaths from diseases expected to be affected by smoking; controls were deaths from selected other diseases, excluding only HIV, cirrhosis, unknown causes, external causes, and mental disorders. Disease-specific case-control comparisons yielded smoking-associated relative risks (RRs; diluted by combining some ex-smokers with the never-smokers). These RRs, when combined with national mortality rates, yielded smoking-attributed mortality rates. Summation yielded RRs and smoking-attributed numbers for overall mortality. Findings In the coloured population, smoking prevalence was high in both sexes and smokers had about 50% higher overall mortality than did otherwise similar non-smokers or ex-smokers (men, RR 1·55, 95% CI 1·43-1·67; women, 1·49, 1·38-1·60). RRs were similar in the white population (men, 1·37, 1·29-1·46; women, 1·51, 1·40- 1·62), but lower among Africans (men, 1·17, 1·15- 1·19; women, 1·16, 1·13-1·20). If these associations are largely causal, smoking-attributed proportions for overall male deaths at ages 35-74 years were 27% (5608/20767) in the coloured, 14% (3913/28951) in the white, and 8% (20398/264011) in the African population. For female deaths, these proportions were 17% (2728/15593) in the coloured, 12% (2084/17899) in the white, and 2% (4038/205623) in the African population. Because national mortality rates were also substantially higher in the coloured than in the white population, the hazards from smoking in the coloured population were more than double those in the white population. Interpretation The highest smoking-attributed mortality rates were in the coloured population and the lowest were in Africans. The substantial hazards already seen among coloured South Africans suggest growing hazards in all populations in Africa where young adults now smoke. Funding South African Medical Research Council, UK Medical Research Council, Cancer Research UK, British Heart Foundation, New South Wales Cancer Council. © 2013 Elsevier Ltd.

Geetha B.S.,Tropical Botanic Garden and Research Institute | Nair M.S.,Indian National Institute for Interdisciplinary Science and Technology | Latha P.G.,Tropical Botanic Garden and Research Institute | Remani P.,Cancer Research Division
Journal of Biomedicine and Biotechnology | Year: 2012

This study was designed to isolate the compounds responsible for the cytotoxic properties of South Indian Elephantopus scaber L. and further investigate their effects on quiescent and proliferating cells. Bioassay-guided isolation of the whole plant of chloroform extract of South Indian Elephantopus scaber afforded the known sesquiterpene lactone, deoxyelephantopin, and isodeoxyelephantopin whose structures were determined by spectroscopic methods. These compounds caused a dose dependent reduction in the viability of L-929 tumour cells in 72h culture (IC 50 value of 2.7μg/mL and 3.3μg/mL) by the cell viability assay. Both the compounds act selectively on quiescent and PHA-stimulated proliferating human lymphocytes and inhibited tritiated thymidine incorporation into cellular DNA of DLA tumour cells. The compound deoxyelephantopin at a concentration of 3μg/mL caused maximum apoptotic cells. It also exhibited significant in vivo antitumour efficacy against DLA tumour cells. The results, therefore, indicate that the antiproliferative property of deoxyelephantopin and isodeoxyelephantopin could be used in regimens for treating tumors with extensive proliferative potencies. Copyright 2012 B. S. Geetha et al.

Raymond J.,University of Sydney | Harmer A.R.,University of Sydney | Temesi J.,University of Sydney | Van Kemenade C.,Cancer Research Division
Spinal Cord | Year: 2010

Study design: Cross-sectional, observational study. Objectives: To evaluate the associations of physical activity and neurological lesion level with glucose tolerance in people with spinal cord injury (SCI). Setting: New South Wales, Australia. Methods: Twenty-five people (5 women, 20 men) with SCI (>6 months post-injury) aged between 18 and 65 years were recruited. Exclusion criteria included known coronary heart disease, stroke or diabetes. Participants underwent an oral glucose tolerance test. Fasting and 2-h plasma glucose concentrations were classified according to the World Health Organization categories of glycemia. Participants also completed the Physical Activity Scale for Individuals with Physical Disabilities and mean MET-hours day 1 was calculated. Associations with the 2-h plasma glucose concentration were calculated through multiple and stepwise regressions. Results: Participants presented with complete or incomplete tetraplegia (n11 TETRA) or complete or incomplete paraplegia (n14 PARA) with neurological lesion levels ranging from C3/4 to T12. Mean 2-h plasma glucose was 7.132.32 mmol l 1. Nine participants had disordered glycemia (n6 TETRA; n3 PARA) and the remaining participants had normal glucose tolerance. Those participants with normal glucose tolerance participated in more moderate-vigorous and strength exercise and undertook more non-exercise-related mobility than those with disordered glycemia. Physical activity and age, but not lesion level were independent determinants of 2-h plasma glucose concentration (r0.683, P0.001), explaining 47% of the variance. Conclusion: Physical activity level is independently associated with glucose tolerance in people with SCI. Non-exercise activity may also be important for maintaining normal glycemia. © 2010 International Spinal Cord Society All rights reserved.

Yu X.Q.,Cancer Research Division | Luo Q.,Cancer Research Division | Smith D.P.,Cancer Research Division | O'Connell D.L.,Cancer Research Division | Baade P.D.,Viertel Center for Research in Cancer Control
Medical Journal of Australia | Year: 2014

Objectives: To determine whether the previously reported urban-rural diff erential in prostate cancer survival remains after adjusting for demographic and clinical factors, and to investigate temporal trends in this diff erential. Design, setting and participants: Retrospective population-based survival analysis of 68 686 men diagnosed with prostate cancer from January 1982 to December 2007 in New South Wales. Main outcome measures: Survival rate and relative excess risk (RER) of death over 10 years of follow-up in relation to geographic remoteness after adjusting for other prognostic factors. Results: Overall, 10-year survival increased during the study period, increasing from 57.5% in 1992-1996 and 75.7% in 1997-2001 to 83.7% in 2002-2007. The increasing trends were also observed across categories of geographic remoteness and socioeconomic status. Urban-rural diff erentials were signifi cant (P < 0.001) after adjusting for fi ve important prognostic factors, with men living outside major cities having higher risk of death from prostate cancer (RER, 1.18 and 1.32 for inner regional and rural areas, respectively). Socioeconomic status was also a signifi cant factor (P < 0.001) for prostate cancer mortality, with the risk of dying being 34% to 40% higher for men living in socioeconomically disadvantaged areas than those living in least disadvantaged areas. There was no evidence that this inequality is reducing over time, particularly for men living in inner regional areas. Conclusions: Despite the increasing awareness of urban-rural diff erentials in cancer outcomes, little progress has been made. Appropriately detailed data, including details of tumour characteristics, treatment and comorbid conditions, to help understand why these inequalities exist are required urgently so interventions and policy changes can be guided by appropriate evidence.

Weber M.F.,Cancer Research Division | Banks E.,Australian National University | Sitas F.,Cancer Research Division
Drug and Alcohol Review | Year: 2011

Introduction and Aims. Approximately 25% of the Australian population was born abroad, yet there has been very little tobacco control aimed at culturally and linguistically diverse communities and limited data exist on smoking among Australian migrants. The aim of this study was to compare smoking characteristics of Australian migrants (in terms of place of birth and age migrated) to those of Australian-born residents. Design and Methods. A cross-sectional analysis of self-reported questionnaire data from 53207 women and 48777 men aged 45years or over in The 45 and Up Study in Australia (2006-2008) was performed. Results. 52.6% (95% confidence intervals 52.1-53.0) of men and 35.5% (35.1-35.9) of women reported ever being a regular smoker and 7.6% (7.4-7.8) and 7.3% (7.1-7.5) reported current smoking, respectively. Compared with Australian-born men, a higher proportion of men born in Europe, North Africa and the Middle East were current smokers, with odds ratios adjusted for age, income, education and place of residence (OR; 95% confidence intervals) ranging from 1.30 (1.16-1.45) to 1.96 (1.49-2.58). Compared with Australian-born women, a lower proportion of women from East (0.21; 0.12-0.36) and Southeast Asia (0.38; 0.26-0.54) were current smokers and a higher proportion of women from New Zealand (1.45; 1.17-1.79) and the UK/Ireland (1.25; 1.12-1.40) were current smokers. Among women born in Asia, the risk of smoking increased significantly the younger they migrated to Australia. Duration smoked and amount smoked per day were primarily lower among migrants than Australian-born. Conclusions. Smoking prevalence varies substantially across cultural subgroups. Understanding smoking dynamics across diverse cultural groups will assist in better targeting of tobacco control programs. © 2010 Australasian Professional Society on Alcohol and other Drugs.

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