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1.  Serum CA19-9 is significantly up-regulated up to 2 years prior to diagnosis with pancreatic cancer: implications for early disease detection 
Purpose
Biomarkers for the early detection of pancreatic cancer are urgently needed. The primary objective of this study was to evaluate whether increased levels of serum CA19-9, CA125, CEACAM1 and REG3A are present prior to clinical presentation of pancreatic cancer and to assess the performance of combined markers for early detection and prognosis.
Experimental Design
This nested case control study within UKCTOCS included 118 single- and 143 serial-serum samples from 154 post-menopausal women who were subsequently diagnosed with pancreatic cancer and 304 matched non-cancer controls. Samples were split randomly into independent training and test sets. CA19-9, CA125, CEACAM1 and REG3A were measured using ELISA and/or CLIA. Performance of markers to detect cancers at different times prior to diagnosis and for prognosis was evaluated.
Results
At 95% specificity, CA19-9 (>37 U/mL) had a sensitivity of 68% up to 1 year, and 53% up to 2 yrs before diagnosis. Combining CA19-9 and CA125 improved sensitivity as CA125 was elevated (>30 U/mL) in ~20% of CA19-9-negative cases. CEACAM1 and REG3A were late markers adding little in combined models. Average lead times of 20-23 months were estimated for test-positive cases. Pre-diagnostic levels of CA19-9 and CA125 were associated with poor overall survival (HR 2.69 and 3.15, respectively).
Conclusions
CA19-9 and CA125 have encouraging sensitivity for detecting pre-clinical pancreatic cancer and both markers can be used as prognostic tools. This work challenges the prevailing view that CA19-9 is up-regulated late in the course of pancreatic cancer development.
doi:10.1158/1078-0432.CCR-14-0365
PMCID: PMC4181906  PMID: 24938522
pancreatic cancer; preclinical serum biomarkers; UKCTOCS; CA19-9; CA125; CEACAM1; REG3A
2.  Serum CA19-9 is significantly up-regulated up to 2 years prior to diagnosis with pancreatic cancer: implications for early disease detection 
Purpose
Biomarkers for the early detection of pancreatic cancer are urgently needed. The primary objective of this study was to evaluate whether increased levels of serum CA19-9, CA125, CEACAM1 and REG3A are present prior to clinical presentation of pancreatic cancer and to assess the performance of combined markers for early detection and prognosis.
Experimental Design
This nested case control study within UKCTOCS included 118 single- and 143 serial-serum samples from 154 post-menopausal women who were subsequently diagnosed with pancreatic cancer and 304 matched non-cancer controls. Samples were split randomly into independent training and test sets. CA19-9, CA125, CEACAM1 and REG3A were measured using ELISA and/or CLIA. Performance of markers to detect cancers at different times prior to diagnosis and for prognosis was evaluated.
Results
At 95% specificity, CA19-9 (>37 U/mL) had a sensitivity of 68% up to 1 year, and 53% up to 2 yrs before diagnosis. Combining CA19-9 and CA125 improved sensitivity as CA125 was elevated (>30 U/mL) in ~20% of CA19-9-negative cases. CEACAM1 and REG3A were late markers adding little in combined models. Average lead times of 20–23 months were estimated for test-positive cases. Pre-diagnostic levels of CA19-9 and CA125 were associated with poor overall survival (HR 2.69 and 3.15, respectively).
Conclusions
CA19-9 and CA125 have encouraging sensitivity for detecting pre-clinical pancreatic cancer and both markers can be used as prognostic tools. This work challenges the prevailing view that CA19-9 is up-regulated late in the course of pancreatic cancer development.
doi:10.1158/1078-0432.CCR-14-0365
PMCID: PMC4181906  PMID: 24938522
pancreatic cancer; preclinical serum biomarkers; UKCTOCS; CA19-9; CA125; CEACAM1; REG3A
3.  Socioeconomic indicators of health inequalities and female mortality: a nested cohort study within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) 
BMC Public Health  2015;15:253.
Background
Evidence is mounting that area-level socioeconomic indicators are important tools for predicting health outcomes. However, few studies have examined these alongside individual-level education. This nested cohort study within the control arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) assesses the association of mutually adjusted individual (education) and area-level (Index of Multiple Deprivation-IMD 2007) socioeconomic status indicators and all-cause female mortality.
Methods
Participants resident in England who had completed both baseline (Wave 1) and follow up (Wave 2) questionnaires were included. Follow-up was through the Health and Social Care Information Centre with deaths censored on 31st December 2012. IMD, education and a range of covariates were explored. Cox regression models adjusted for all covariates were used. Sensitivity analysis using imputation was performed (1) including those with missing data and (2) on the entire cohort who had completed the baseline questionnaire.
Results
Of the 54,539 women resident in England who completed both Wave 1 and Wave 2 questionnaires, 4,510 had missing data. The remaining 50,029 women were included in the primary analysis. Area-level IMD was positively associated with all-cause mortality for the most deprived group compared to the least deprived (HR=1.42, CI=1.14-1.78) after adjusting for all potential confounders. Sensitivity analyses showed similar results with stronger associations in the entire cohort (HR=1.90, CI=1.68-2.16). The less educated an individual, the higher the mortality risk (test for trend p=<0.001). However, the crude effect on mortality of having no formal education compared to college/university education disappeared when adjusted for IMD rank (HR=1.08, CI=0.93-1.26).
Conclusion
Women living in more deprived areas continue to have higher mortality even in this less deprived cohort and after adjustment for a range of potential confounders.
Trial Registration
This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-015-1609-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12889-015-1609-5
PMCID: PMC4367890  PMID: 25848938
UKCTOCS; Mortality; Socioeconomic; Education; IMD
4.  The role and interaction of imprinted genes in human fetal growth 
Identifying the genetic input for fetal growth will help to understand common, serious complications of pregnancy such as fetal growth restriction. Genomic imprinting is an epigenetic process that silences one parental allele, resulting in monoallelic expression. Imprinted genes are important in mammalian fetal growth and development. Evidence has emerged showing that genes that are paternally expressed promote fetal growth, whereas maternally expressed genes suppress growth. We have assessed whether the expression levels of key imprinted genes correlate with fetal growth parameters during pregnancy, either early in gestation, using chorionic villus samples (CVS), or in term placenta. We have found that the expression of paternally expressing insulin-like growth factor 2 (IGF2), its receptor IGF2R, and the IGF2/IGF1R ratio in CVS tissues significantly correlate with crown–rump length and birthweight, whereas term placenta expression shows no correlation. For the maternally expressing pleckstrin homology-like domain family A, member 2 (PHLDA2), there is no correlation early in pregnancy in CVS but a highly significant negative relationship in term placenta. Analysis of the control of imprinted expression of PHLDA2 gave rise to a maternally and compounded grand-maternally controlled genetic effect with a birthweight increase of 93/155 g, respectively, when one copy of the PHLDA2 promoter variant is inherited. Expression of the growth factor receptor-bound protein 10 (GRB10) in term placenta is significantly negatively correlated with head circumference. Analysis of the paternally expressing delta-like 1 homologue (DLK1) shows that the paternal transmission of type 1 diabetes protective G allele of rs941576 single nucleotide polymorphism (SNP) results in significantly reduced birth weight (−132 g). In conclusion, we have found that the expression of key imprinted genes show a strong correlation with fetal growth and that for both genetic and genomics data analyses, it is important not to overlook parent-of-origin effects.
doi:10.1098/rstb.2014.0074
PMCID: PMC4305174  PMID: 25602077
genomic imprinting; fetal growth restriction; placenta; chorionic villus sampling; birth weight; type 1 diabetes
5.  Validity of self-reported hysterectomy: a prospective cohort study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) 
BMJ Open  2014;4(3):e004421.
Objective
To evaluate the validity of self-reported hysterectomy against the gold standard of uterine visualisation using pelvic ultrasound.
Design
Prospective cohort study.
Setting
UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) based in 13 National Health Service (NHS) Trusts in England, Wales and Northern Ireland.
Participants
Between April 2001 and October 2005, 48 215 postmenopausal women aged 50–74 randomised to the ultrasound screening arm of UKCTOCS underwent the first (initial) scan on the trial.
Interventions
At recruitment, the women completed a recruitment questionnaire (RQ) which included previous hysterectomy. The sonographer asked each woman regarding previous hysterectomy (interview format, IF) prior to the scan. At the scan, in addition to ovarian morphology, endometrial thickness (ET)/endometrial abnormality were captured if the uterus was visualised at the scan.
Outcome measures
Self-reported hysterectomy at RQ or IF was compared to ultrasound data on ET/endometrial abnormality (as surrogate uterine visualisation markers) on the first (initial) scan.
Results
Of 48 215 women, 3 had congenital uterine agenesis and 218 inconclusive results. The uterus was visualised in 39 121 women. 8871 self-reported hysterectomy at RQ, 8641 at IF and 8487 at both. The uterus was visualised in 39 123, 39 353 and 38 969 women not self-reporting hysterectomy at RQ, IF or both. Validity, sensitivity, specificity, positive predictive value and negative predictive value of using RQ alone, IF or both RQ/IF were 99.6%, 98.9%, 99.7%, 98.9% and 99.7%; 98.9%, 98.4%, 99.1%, 95.9% and 99.7%; 99.8%, 99.6%, 99.9%, 99.4% and 99.9%, respectively.
Conclusions
Self-reported hysterectomy is a highly accurate and valid source for studying long-term associations of hysterectomy with disease onset.
Trial registration
International Standard Randomised Controlled Trial Number (ISRCTN)—22488978
doi:10.1136/bmjopen-2013-004421
PMCID: PMC3939665  PMID: 24589827
Gynaecology; Epidemiology; Oncology
6.  Impact on mortality and cancer incidence rates of using random invitation from population registers for recruitment to trials 
Trials  2011;12:61.
Background
Participants in trials evaluating preventive interventions such as screening are on average healthier than the general population. To decrease this 'healthy volunteer effect' (HVE) women were randomly invited from population registers to participate in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and not allowed to self refer. This report assesses the extent of the HVE still prevalent in UKCTOCS and considers how certain shortfalls in mortality and incidence can be related to differences in socioeconomic status.
Methods
Between 2001 and 2005, 202 638 postmenopausal women joined the trial out of 1 243 312 women randomly invited from local health authority registers. The cohort was flagged for deaths and cancer registrations and mean follow up at censoring was 5.55 years for mortality, and 2.58 years for cancer incidence. Overall and cause-specific Standardised Mortality Ratios (SMRs) and Standardised Incidence Ratios (SIRs) were calculated based on national mortality (2005) and cancer incidence (2006) statistics. The Index of Multiple Deprivation (IMD 2007) was used to assess the link between socioeconomic status and mortality/cancer incidence, and differences between the invited and recruited populations.
Results
The SMR for all trial participants was 37%. By subgroup, the SMRs were higher for: younger age groups, extremes of BMI distribution and with each increasing year in trial. There was a clear trend between lower socioeconomic status and increased mortality but less pronounced with incidence. While the invited population had higher mean IMD scores (more deprived) than the national average, those who joined the trial were less deprived.
Conclusions
Recruitment to screening trials through invitation from population registers does not prevent a pronounced HVE on mortality. The impact on cancer incidence is much smaller. Similar shortfalls can be expected in other screening RCTs and it maybe prudent to use the various mortality and incidence rates presented as guides for calculating event rates and power in RCTs involving women.
Trial Registration
This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978.
Medical Research Council (grant no. G990102), Cancer Research UK (grant no. C1479/A2884) and Department of Health
doi:10.1186/1745-6215-12-61
PMCID: PMC3058013  PMID: 21362184
7.  An Epigenetic Signature in Peripheral Blood Predicts Active Ovarian Cancer 
PLoS ONE  2009;4(12):e8274.
Background
Recent studies have shown that DNA methylation (DNAm) markers in peripheral blood may hold promise as diagnostic or early detection/risk markers for epithelial cancers. However, to date no study has evaluated the diagnostic and predictive potential of such markers in a large case control cohort and on a genome-wide basis.
Principal Findings
By performing genome-wide DNAm profiling of a large ovarian cancer case control cohort, we here demonstrate that active ovarian cancer has a significant impact on the DNAm pattern in peripheral blood. Specifically, by measuring the methylation levels of over 27,000 CpGs in blood cells from 148 healthy individuals and 113 age-matched pre-treatment ovarian cancer cases, we derive a DNAm signature that can predict the presence of active ovarian cancer in blind test sets with an AUC of 0.8 (95% CI (0.74–0.87)). We further validate our findings in another independent set of 122 post-treatment cases (AUC = 0.76 (0.72–0.81)). In addition, we provide evidence for a significant number of candidate risk or early detection markers for ovarian cancer. Furthermore, by comparing the pattern of methylation with gene expression data from major blood cell types, we here demonstrate that age and cancer elicit common changes in the composition of peripheral blood, with a myeloid skewing that increases with age and which is further aggravated in the presence of ovarian cancer. Finally, we show that most cancer and age associated methylation variability is found at CpGs located outside of CpG islands.
Significance
Our results underscore the potential of DNAm profiling in peripheral blood as a tool for detection or risk-prediction of epithelial cancers, and warrants further in-depth and higher CpG coverage studies to further elucidate this role.
doi:10.1371/journal.pone.0008274
PMCID: PMC2793425  PMID: 20019873
8.  Epigenotyping in Peripheral Blood Cell DNA and Breast Cancer Risk: A Proof of Principle Study 
PLoS ONE  2008;3(7):e2656.
Background
Epigenetic changes are emerging as one of the most important events in carcinogenesis. Two alterations in the pattern of DNA methylation in breast cancer (BC) have been previously reported; active estrogen receptor-α (ER-α) is associated with decreased methylation of ER-α target (ERT) genes, and polycomb group target (PCGT) genes are more likely than other genes to have promoter DNA hypermethylation in cancer. However, whether DNA methylation in normal unrelated cells is associated with BC risk and whether these imprints can be related to factors which can be modified by the environment, is unclear.
Methodology/Principal Findings
Using quantitative methylation analysis in a case-control study (n = 1,083) we found that DNA methylation of peripheral blood cell DNA provides good prediction of BC risk. We also report that invasive ductal and invasive lobular BC is characterized by two different sets of genes, the latter particular by genes involved in the differentiation of the mesenchyme (PITX2, TITF1, GDNF and MYOD1). Finally we demonstrate that only ERT genes predict ER positive BC; lack of peripheral blood cell DNA methylation of ZNF217 predicted BC independent of age and family history (odds ratio 1.49; 95% confidence interval 1.12–1.97; P = 0.006) and was associated with ER-α bioactivity in the corresponding serum.
Conclusion/Significance
This first large-scale epigenotyping study demonstrates that DNA methylation may serve as a link between the environment and the genome. Factors that can be modulated by the environment (like estrogens) leave an imprint in the DNA of cells that are unrelated to the target organ and indicate the predisposition to develop a cancer. Further research will need to demonstrate whether DNA methylation profiles will be able to serve as a new tool to predict the risk of developing chronic diseases with sufficient accuracy to guide preventive measures.
doi:10.1371/journal.pone.0002656
PMCID: PMC2442168  PMID: 18628976

Results 1-8 (8)