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1.  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.
To evaluate the validity of self-reported hysterectomy against the gold standard of uterine visualisation using pelvic ultrasound.
Prospective cohort study.
UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) based in 13 National Health Service (NHS) Trusts in England, Wales and Northern Ireland.
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.
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.
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.
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
PMCID: PMC3939665  PMID: 24589827
Gynaecology; Epidemiology; Oncology
2.  An Epigenetic Signature in Peripheral Blood Predicts Active Ovarian Cancer 
PLoS ONE  2009;4(12):e8274.
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.
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.
PMCID: PMC2793425  PMID: 20019873
3.  Epigenotyping in Peripheral Blood Cell DNA and Breast Cancer Risk: A Proof of Principle Study 
PLoS ONE  2008;3(7):e2656.
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.
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.
PMCID: PMC2442168  PMID: 18628976

Results 1-3 (3)