Menopause accelerates biological aging.
PNAS 113(33):9327 (2016)
Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the "epigenetic clock"), which is based on DNA methylation levels. H...
Epigenetic drift, epigenetic clocks and cancer risk.
Epigenomics 8(5):705 (2016)
It is well-established that the DNA methylation landscape of normal cells undergoes a gradual modification with age, termed as 'epigenetic drift'. Here, we review the current state of knowledge of epigenetic drift and its potential role in cancer etiology. We propose a new terminology to help di...
Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial.
The Lancet 387(10022):945 (2016)
Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality.
In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in...
PPM1D Mosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations.
JNCI Journal of the National Cancer Institute 108(3) (2016)
Mosaic truncating mutations in the protein phosphatase, Mg(2+)/Mn(2+)-dependent, 1D (PPM1D) gene have recently been reported with a statistically significantly greater frequency in lymphocyte DNA from ovarian cancer case patients compared with unaffected control patients. Using massively paralle...
DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer.
Nature Communications 7:10478 (2016)
Identifying molecular alterations in normal tissue adjacent to cancer is important for understanding cancer aetiology and designing preventive measures. Here we analyse the DNA methylome of 569 breast tissue samples, including 50 from cancer-free women and 84 from matched normal cancer pairs. We...
Erratum to: The integrative epigenomic-transcriptomic landscape of ER positive breast cancer.
Clinical Epigenetics 8:63 (2016)
Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution.
Nature Communications 7:11620 (2016)
The exact timing and contribution of epigenetic reprogramming to carcinogenesis are unclear. Women harbouring BRCA1/2 mutations demonstrate a 30-40-fold increased risk of high-grade serous extra-uterine Müllerian cancers (HGSEMC), otherwise referred to as 'ovarian carcinomas', which frequently d...
Enumeration and Molecular Characterisation of Circulating Tumour Cells in Endometrial Cancer.
Oncology (Basel) 91(1):48 (2016)
This is a feasibility study to determine whether circulating tumour cells (CTCs) are detectable and suitable for molecular profiling in advanced endometrial cancer (aEC).
Between October 2012 and February 2014, 30 patients with aEC had baseline and up to 3 follow-up samples. CTCs and stathmin ex...
Stochastic epigenetic outliers can define field defects in cancer.
BMC Bioinformatics 17:178 (2016)
There is growing evidence that DNA methylation alterations may contribute to carcinogenesis. Recent data also suggest that DNA methylation field defects in normal pre-neoplastic tissue represent infrequent stochastic "outlier" events. This presents a statistical challenge for standard feature se...
Osteoprotegerin (OPG), The Endogenous Inhibitor of Receptor Activator of NF-κB Ligand (RANKL), is Dysregulated in BRCA Mutation Carriers.
EBioMedicine 2(10):1331 (2015)
Breast cancer development in BRCA1/2 mutation carriers is a net consequence of cell-autonomous and cell nonautonomous factors which may serve as excellent targets for cancer prevention. In light of our previous data we sought to investigate the consequences of the BRCA-mutation carrier state on ...
A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State.
EBioMedicine 2(10):1318 (2015)
Predisposition to breast and extrauterine Müllerian carcinomas in BRCA1 mutation carriers is due to a combination of cell-autonomous consequences of BRCA1 inactivation on cell cycle homeostasis superimposed on cell-nonautonomous hormonal factors magnified by the effects of BRCA1 mutations on hor...
Correlation of Smoking-Associated DNA Methylation Changes in Buccal Cells With DNA Methylation Changes in Epithelial Cancer.
JAMA Oncology 1(4):476 (2015)
The utility of buccal cells as an epithelial source tissue for epigenome-wide association studies (EWASs) remains to be demonstrated. Given the direct exposure of buccal cells to potent carcinogens such as smoke, epigenetic changes in these cells may provide insights into the development of smok...
Risk Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening.
Journal of Clinical Oncology 33(18):2062 (2015)
Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates.
In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,2...
HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer.
Genome Medicine 7(1):108 (2015)
Understanding carboplatin resistance in ovarian cancer is critical for the improvement of patients' lives. Multipotent mesenchymal stem cells or an aggravated epithelial to mesenchymal transition phenotype of a cancer are integrally involved in pathways conferring chemo-resistance. Long non-codi...
An integrative pan-cancer-wide analysis of epigenetic enzymes reveals universal patterns of epigenomic deregulation in cancer.
Genome Biology 16(1):140 (2015)
One of the most important recent findings in cancer genomics is the identification of novel driver mutations which often target genes that regulate genome-wide chromatin and DNA methylation marks. Little is known, however, as to whether these genes exhibit patterns of epigenomic deregulation tha...
Brca1 Mutations Enhance Mouse Reproductive Functions by Increasing Responsiveness to Male-Derived Scent.
PLoS ONE 10(10):e0139013 (2015)
We compared the gene expression profiles of ovarian granulosa cells harboring either mutant or wild type Brca1 to follow up on our earlier observation that absence of a functional Brca1 in these important regulators of menstrual/estrous cycle progression leads to prolongation of the pre-ovulator...
The integrative epigenomic-transcriptomic landscape of ER positive breast cancer.
Clinical Epigenetics 7:126 (2015)
While recent integrative analyses of copy number and gene expression data in breast cancer have revealed a complex molecular landscape with multiple subtypes and many oncogenic/tumour suppressor driver events, much less is known about the role of DNA methylation in shaping breast cancer taxonomy...
Intra-Gene DNA Methylation Variability Is a Clinically Independent Prognostic Marker in Women's Cancers.
PLoS ONE 10(12):e0143178 (2015)
We introduce a novel per-gene measure of intra-gene DNA methylation variability (IGV) based on the Illumina Infinium HumanMethylation450 platform, which is prognostic independently of well-known predictors of clinical outcome. Using IGV, we derive a robust gene-panel prognostic signature for ova...
A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell transplantation.
Genome Medicine 7(1):128 (2015)
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, ...
A systems-level integrative framework for genome-wide DNA methylation and gene expression data identifies differential gene expression modules under epigenetic control.
There is a growing number of studies generating matched Illumina Infinium HumanMethylation450 and gene expression data, yet there is a corresponding shortage of statistical tools aimed at their integrative analysis. Such integrative tools are important for the discovery of epigenetically regulat...