James M Flanagan

Imperial College London | Imperial · Division of Cancer

Background DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging...

Background: Health research utilising commercial data is increasing. The evidence on public acceptability and socio-demographic characteristics of individuals who are willing to share commercial data for health research is scarce. Objective: This survey study investigates the willingness to share commercial data for health research in the UK with t...

BACKGROUND Health research utilising commercial data is increasing. The evidence on public acceptability and socio-demographic characteristics of individuals who are willing to share commercial data for health research is scarce. OBJECTIVE This survey study investigates the willingness to share commercial data for health research in the UK with th...

BACKGROUND Participation in case-control studies is crucial in epidemiological research. The self-sampling bias, low response rate, and poor recruitment of population representative controls are often reported as limitations of case-control studies with limited strategies improve participation. With greater use of web-based methods in health resear...

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regressio...

Background Most uterine cervical high-risk human papillomavirus (HPV) infections are transient, with only a small fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest a significant inherited genetic component. Candidate gene studies and previous genome-wide association studies (GWASs) report associ...

Background: Alcohol consumption, body mass index (BMI) and cigarette smoking are among the most well-studied lifestyle cancer risk exposures which can also change the host’s epigenetic methylation patterns. Some of the changes associated with lifestyle exposure are specific and stable over time, thus, can be used to predict and quantify the exposur...

BACKGROUND: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian...

Introduction: Ovarian cancer is the eighth most common cancer in women worldwide, and about 1 in 5 women with ovarian cancer do not receive treatment, because they are too unwell by the time they are diagnosed. Symptoms of ovarian cancer are non-specific or can be associated with other common conditions, and women experiencing these symptoms have...

Introduction: Ovarian cancer is the eighth most common cancer in women worldwide, and about 1 in 5 women with ovarian cancer do not receive treatment, because they are too unwell by the time they are diagnosed. Symptoms of ovarian cancer are non-specific or can be associated with other common conditions, and women experiencing these symptoms have b...

BACKGROUND Longer patient intervals can lead to more late-stage cancer diagnoses and higher mortality rates. Individuals may delay presenting to primary care with red flag symptoms and instead turn to the internet to seek information, purchase over-the-counter medication, and change their diet or exercise habits. With advancements in machine learni...

Background: The field of epigenetic epidemiology has rapidly advanced and recent work has discovered epigenetic markers of breast cancer risk in white blood cell (WBC) DNA. Using Epigenome-Wide Association Studies (EWAS) on the Illumina 450k methylation array, we and others have shown epigenome-wide hypomethylation (-0.2%, p<2.2x10⁻¹⁶) in incident...

Purpose: DNA damage repair can lead to epigenetic changes. DNA mismatch repair proteins bind to platinum DNA adducts and at sites of DNA damage can recruit the DNA methylating enzyme DNMT1, resulting in aberrant methylation. We hypothesised that DNA damage repair during platinum-based chemotherapy may cause aberrant DNA methylation in normal tissue...

Hepatocellular carcinoma (HCC), the most prevalent type of primary liver cancer, is the second leading cause of cancer death worldwide. It is estimated that early HCC detection would increase the cure rate from 5% to 80%. Approximately 85% of individuals with HCC have underlying liver cirrhosis which is the main risk factor for developing HCC. Ever...

DNA hypomethylation was previously implicated in cancer progression and metastasis. The purpose of this study was to examine whether stilbenoids, resveratrol and pterostilbene thought to exert anticancer effects, target genes with oncogenic function for de novo methylation and silencing, leading to inactivation of related signaling pathways. Follow...

Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase geno...

Alterations in DNA methylation occur at different stages of cancer, including initiation, and may underlie up-regulation of genes with oncogenic functions. The NOTCH pathway is often overactive in breast cancer and plays roles in cancer development and progression. It is therefore a possible target for anti-cancer strategies. However, the mechanism...

Germline pathogenic mutations in BRCA1 increase risk of developing breast cancer. Screening for mutations in BRCA1 frequently identifies sequence variants of unknown pathogenicity and recent work has aimed to develop methods for determining pathogenicity. We previously observed that tumor DNA methylation can differentiate BRCA1-mutated from BRCA1-w...

Just as genome-wide association studies (GWAS) grew from the field of genetic epidemiology, so too do epigenome-wide association studies (EWAS) derive from the burgeoning field of epigenetic epidemiology, with both aiming to understand the molecular basis for disease risk. While genetic risk of disease is currently unmodifiable, there is hope that...

Interest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing. We aimed to assess whether epigenome-wide DNA methylation measured in peripheral blood samples obtained before onset of the disease is associated with increased risk of breast cancer. We report on three independent prospective nested case-c...

Hepatocellular carcinoma (HCC), one of the most prevalent types of primary liver cancer, is the sixth most common cancer worldwide and the third leading cause of cancer death with rising mortality and morbidity rates. As late onset of HCC accounts for late diagnosis and poor prognosis and early detection increases cure rate from 5% to 80%, identify...

DNA methylation variability regions (MVRs) across the oestrogen receptor alpha (ESR1) gene have been identified in peripheral blood cells from breast cancer patients and healthy individuals. In contrast to promoter methylation, gene body methylation may be important in maintaining active transcription. This study aimed to assess MVRs in ESR1 in bre...

Background: Epigenome-wide association studies (EWAS) using measurements of blood DNA methylation are performed to identify associations of methylation changes with environmental and lifestyle exposures and disease risk. However, little is known about the variation of methylation markers in the population and their stability over time, both import...

Background ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. Methods The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was...

Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer....

The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R,...

The transcription factor Nrf2 is a key regulator of the cellular antioxidant response, and its activation by chemoprotective agents has been proposed as a potential strategy to prevent cancer. However, activating mutations in the Nrf2 pathway have been found to promote tumorigenesis in certain models. Therefore, the role of Nrf2 in cancer remains c...

Reproductive factors have been linked to both breast cancer and DNA methylation, suggesting methylation as an important mechanism by which reproductive factors impact on disease risk. However, few studies have investigated the link between reproductive factors and DNA methylation in humans. Genome-wide methylation in peripheral blood lymphocytes of...

A missense single nucleotide polymorphism in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561), but the functional implications of this polymorphism are undefined. IL-1α is regulated by and activated by NF-κB, a transcription factor family that induces transcription of IL1A along with other pro-inflammatory gene...

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls...

We have addressed whether inter-individual methylation variation in somatic (white blood cells, WBCs) DNA of ovarian cancer patients provides potential for prognostic and/or pharmacoepigenetic stratification. WBC DNA methylation was analysed by bisulphite pyrosequencing at ataxia telangiectasia mutated (ATM), estrogen receptor 1 (ESR1), progesteron...

Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. More than 100 internationally recognised specialist breast cancer scientists, clini...

The promise of epigenome-wide association studies and cancer-specific somatic DNA methylation changes in improving our understanding of cancer, coupled with the decreasing cost and increasing coverage of DNA methylation microarrays, has brought about a surge in the use of these technologies. Here, we aim to provide both a review of issues encounter...

Background: Cancer cells display epigenetic as well as genetic abnormalities, however, little is known about the possible contribution of epigenetic variability to cancer risk prior to disease. We have previously reported a breast cancer risk marker at the ATM gene, ATMmvp2a, at which hypermethylation, detectable in blood prior to disease onset, is...

Most biomarkers of exposure tend to have short half-lives. This includes cotinine, a metabolite of nicotine widely used to assess smoke exposure. Cotinine is thus unsuitable as a determinant of past exposure to cigarette smoke. We used bisulphite pyrosequencing of a set of four genomic loci (AHRR, 6p21, and two at 2q37) that had differential DNA me...

HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect t...

Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. H...

HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect t...

Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotypin...

TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also...

Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. METHODS: Twenty-seve...

Introduction: Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. / Methods: More than 100 internationally recognised specialist breast...

Borderline ovarian tumors represent an understudied subset of ovarian tumors. Most studies investigating aberrations in borderline tumors have focused on KRAS/BRAF mutations. In this study, we conducted an extensive analysis of mutations and single-nucleotide polymorphisms (SNPs) in borderline ovarian tumors. Using the Sequenom MassArray platform,...

A single cytosine–guanine dinucleotide (CpG) site within coagulation factor II (thrombin) receptor-like 3 (F2RL3) was recently found to be hypomethylated in peripheral blood genomic DNA from smokers compared with former and non-smokers. We performed two epigenome-wide association studies (EWAS) nested in a prospective healthy cohort using the Illum...

Cancer cells display widespread genetic and epigenetic abnormalities, but the contribution to disease risk, particularly in normal tissue prior to disease, is not yet established. Genome-wide hypomethylation occurs frequently in tumours and may facilitate chromosome instability, aberrant transcription and transposable elements reactivation. Several...

An increase in reactive oxygen species (ROS) is a common biochemical change in cancer cells. To investigate the mechanisms of ROS accumulation during the process of tumorigenesis we employed a well-characterized model of stepwise human mesenchymal stem cell (MSC) transformation. Transformed MSC (tMSC) became dependent upon oxidative stress, as trea...

Few studies have evaluated the association between DNA methylation in white blood cells (WBC) and the risk of breast cancer. The evaluation of WBC DNA methylation as a biomarker of cancer risk is of particular importance as peripheral blood is often available in prospective cohorts and easier to obtain than tumor or normal tissues. Here, we used pr...

Genetic epidemiology aims to use the natural variation in the genome, namely single nucleotide polymorphisms and copy number variants to look for associations between particular genotypes and disease risk or prognosis. Recent work is now aiming to look further into the genome at the natural variation present in the epigenome, in DNA methylation as...

Epigenetics is the study of all mechanisms that regulate gene transcription and genome stability that are maintained throughout the cell division, but do not include the DNA sequence itself. The best-studied epigenetic mechanism to date is DNA methylation, where methyl groups are added to the cytosine base within cytosine-guanine dinucleotides (CpG...

Sensitivity analysis for DCN rs516115 and serous epithelial ovarian cancer stratified by case recruitment period. Forest plots represent associations represent ORs (95% CI) for individual study (squares) and study-adjusted pooled (diamonds) estimates. Models are ordinal genetic risk models. HAN-HJO and HAN-HMO were combined for presentation. Phet r...

Sensitivity analysis for LUM rs17018765 and serous epithelial ovarian cancer stratified by case recruitment period. Forest plots represent associations represent ORs (95% CI) for individual study (squares) and study-adjusted pooled (diamonds) estimates. Models are ordinal genetic risk models. HAN-HJO and HAN-HMO were combined for presentation. Phet...

Genotype counts, MAF and HWE statistics and associations between genotypes and risk of ovarian carcinoma for DCN and LUM SNPs among Caucasian subjects in OCAC replication set 2. (DOC)

Haplotype analysis of decorin and lumican genes and invasive serous epithelial ovarian cancer risk among 1,317 Caucasian subjects in the discovery set. (DOC)

Overview of 18 OCAC studies with serous epithelial ovarian cancer cases and controls. (DOC)

Ethics statement. (DOC)

Linkage disequilibrium blocks for tagSNPs in DCN and LUM. Analysis is based on total number of controls from the discovery set and replication set 1. The two genes comprise a contiguous segment on chromosome 12 of approximately 80 kb. Numbers in the squares on the LD block indicate the correlation (r2) between SNPs. * indicates SNPs that were signi...

SNP and location, HWE test P-value and MAF for variants in DCN and LUM in 920 controls in the discovery set and 1,098 controls in replication set 1. (DOC)

Sensitivity analysis for DCN rs13312816 and serous epithelial ovarian cancer stratified by case recruitment period. Forest plots represent associations represent ORs (95% CI) for individual study (squares) and study-adjusted pooled (diamonds) estimates. Models are ordinal genetic risk models. HAN-HJO and HAN-HMO were combined for presentation. Phet...

Odds ratios (OR) and 95% confidence intervals (CI) for the association between genetic polymorphisms in DCN and LUM and serous epithelial ovarian cancer risk among 1,317 Caucasian subjects in the discovery set. (DOC)

Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) am...

Wnt pathways control key biological processes that potentially impact on tumor progression and patient survival. We aimed to evaluate DNA methylation at promoter CpG islands (CGI) of Wnt pathway genes in ovarian tumors at presentation and identify biomarkers of patient progression-free survival (PFS). Epithelial ovarian tumors (screening study n =...

An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3'-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. Ho...

Extensive expression profiling studies have shown that sporadic breast cancer is composed of five clinically relevant molecular subtypes. However, although BRCA1-related tumours are known to be predominantly basal-like, there are few published data on other classes of familial breast tumours. We analysed a cohort of 75 BRCA1, BRCA2 and non-BRCA1/2...

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis...

Epigenetics describes the study of stable, reversible alterations to the genome that affect gene expression and genome function, the most studied mechanisms are DNA methylation and histone modifications. Over recent years there has been rapid progress to elucidate the nature and role of the mechanisms involved in promoter hypermethylation during ca...