Publications
129 results found
Stoffel ST, Law JH, Kerrison R, et al., 2024, Testing Behavioral Messages to Increase Recruitment to Health Research When Embedded Within Social Media Campaigns on Twitter: Web-Based Experimental Study., JMIR Form Res, Vol: 8
BACKGROUND: Social media is rapidly becoming the primary source to disseminate invitations to the public to consider taking part in research studies. There is, however, little information on how the contents of the advertisement can be communicated to facilitate engagement and subsequently promote intentions to participate in research. OBJECTIVE: This paper describes an experimental study that tested different behavioral messages for recruiting study participants for a real-life observational case-control study. METHODS: We included 1060 women in a web-based experiment and randomized them to 1 of 3 experimental conditions: standard advertisement (n=360), patient endorsement advertisement (n=345), and social norms advertisement (n=355). After seeing 1 of the 3 advertisements, participants were asked to state (1) their intention to take part in the advertised case-control study, (2) the ease of understanding the message and study aims, and (3) their willingness to be redirected to the website of the case-control study after completing the survey. Individuals were further asked to suggest ways to improve the messages. Intentions were compared between groups using ordinal logistic regression, reported in percentages, adjusted odds ratio (aOR), and 95% CIs. RESULTS: Those who were in the patient endorsement and social norms-based advertisement groups had significantly lower intentions to take part in the advertised study compared with those in the standard advertisement group (aOR 0.73, 95% CI 0.55-0.97; P=.03 and aOR 0.69, 95% CI 0.52-0.92; P=.009, respectively). The patient endorsement advertisement was perceived to be more difficult to understand (aOR 0.65, 95% CI 0.48-0.87; P=.004) and to communicate the study aims less clearly (aOR 0.72, 95% CI 0.55-0.95; P=.01). While the patient endorsement advertisement had no impact on intention to visit the main study website, the social norms advertisement decreased willingness compared with the standard advertisement group (1
Harris BHL, Mccabe C, Shafique H, et al., 2024, Diversity of thought: public perceptions of genetic testing across ethnic groups in the UK, Journal of Human Genetics, Vol: 69, Pages: 19-25, ISSN: 1434-5161
Genetic testing is becoming rapidly more accessible to the general populous either through or outside healthcare systems. Few large-scale studies have been carried out to gauge public opinion in this growing area. Here, we undertook the largest cross-sectional study on genetic testing in the UK. The primary purpose of this study is to identify the differences in attitudes toward genetic testing across ethnic groups. A cohort of 6500 individuals from a diverse population completed a 72-item survey in a cross-sectional study. Responses between ethnic minority and white individuals in the UK were compared using a wilcoxon rank-sum and chi-square tests. The white cohort was approximately twice as likely to have taken a genetic test and 13% more had heard about genetic testing before the survey. The ethnic minority cohort appeared more apprehensive about the impact of genetic testing on employability. This study highlights that in the UK, significant differences in opinions regarding genetic testing exist between white individuals and ethnic minority individuals. There is an urgent need to develop more inclusive strategies to equally inform individuals from all backgrounds to avoid disparities in the utilisation of genetic testing.
Avramenko A, Flanagan J, 2023, An epigenetic hypothesis for ovarian cancer prevention by oral contraceptive pill use, Clinical Epigenetics, Vol: 15, ISSN: 1868-7075
Background:Ovarian cancer is the second most common gynecological cancer type after uterine cancers. In 2020, according to worldwide statistics, there were more than 313,000 new cases of ovarian cancer. Most concerning with ovarian cancer is the poor overall survival, with only 30% of patients surviving for longer than 5 years after diagnosis. The reason for this poor outcome includes late diagnosis due to non-specific symptoms and a lack of any highly effective biomarkers of the early stages of ovarian carcinogenesis. However, it is important to note that some modifiable lifestyle factors can be preventative [pregnancy, breastfeeding and combined oral contraceptives pill (COCP) use].Results:There is now increasing data reporting the role of epigenetic changes, which are detectable in ovarian cancer tumors, suggesting the possibility that epigenetics may also play a key role in the mechanism of long-term effective prevention of ovarian cancer. To our knowledge, there is a lack of high-quality data on the molecular mechanisms of ovarian cancer prevention, although several hypotheses have been proposed.Conclusions:This review focusses on the evidence for a proposed novel hypothesis—that COCPs act as a chemoprevention through the impact on the epigenome of the cells of origin of ovarian cancer—fallopian tubes epithelium.
Bowden SJ, Doulgeraki T, Bouras E, et al., 2023, Risk factors for human papillomavirus infection, cervical intraepithelial neoplasia and cervical cancer: an umbrella review and follow-up Mendelian randomisation studies, BMC Medicine, Vol: 21, Pages: 1-15, ISSN: 1741-7015
Background: Persistent infection by oncogenic human papillomavirus (HPV) is necessary although not sufficient for development of cervical cancer. Behavioural, environmental, or comorbid exposures may promote or protect against malignant transformation. Randomised evidence is limited and the validity of observational studies describing these associations remains unclear.Methods: In this umbrella review we searched electronic databases to identify meta-analyses of observational studies that evaluated risk or protective factors and the incidence of HPV infection, cervical intra-epithelial neoplasia (CIN), cervical cancer incidence and mortality. Following re-analysis, evidence was classified and graded based on a pre-defined set of statistical criteria. Quality was assessed with AMSTAR-2. For all associations graded as weak evidence or above, with available genetic instruments, we also performed Mendelian randomisation to examine the potential causal effect of modifiable exposures with risk of cervical cancer. The protocol for this study was registered on PROSPERO (CRD42020189995).Results: We included 171 meta-analyses of different exposure contrasts from 50 studies. Systemic immunosuppression including HIV infection (RR=2.20(95%CI=1.89-2.54)) and immunosuppressive medications for inflammatory bowel disease (RR=1.33(95%CI=1.27-1.39)), as well as an altered vaginal microbiome (RR=1.59(95%CI=1.40-1.81)) were supported by strong and highly suggestive evidence for an association with HPV persistence, CIN or cervical cancer. Smoking, number of sexual partners and young age at first pregnancy were supported by highly suggestive evidence and confirmed by Mendelian randomisation.Conclusions: Our main analysis supported the association of systemic (HIV infection, immunosuppressive medications) and local immunosuppression (altered vaginal microbiota) with increased risk for worse HPV and cervical disease outcomes. Mendelian randomisation confirmed the link for genetically predic
Brewer H, Chadeau-Hyam M, Johnson E, et al., 2023, Cancer Loyalty Card Study (CLOCS): feasibility outcomes for an observational case-control study focusing on the patient interval in ovarian cancer, BMJ Open, Vol: 13, Pages: 1-10, ISSN: 2044-6055
Objectives: Ovarian cancer symptoms are often non‐specific and can be normalised before patients seek medical help. The Cancer Loyalty Card Study (CLOCS) investigated self‐management behaviours of ovarian cancer patients prior to their diagnosis using loyaltycard data collected by two United Kingdom (UK)‐based high street retailers. Here, we discuss the feasibility outcomes for this novel research. Design: Observational case‐control study. Setting: Control participants were invited to the study using social media and other sources from the general public. Once consented, control participants were required to submit proof of identification (ID) for their loyalty card data to be shared. Cases were identifiedusing unique National Health Service (NHS) numbers (a proxy for ID) and were recruited through 12 NHS tertiary care clinics.Participants: Women in the UK, 18 years or older, with at least one of the participating high street retailers’ loyalty cards. Those with an ovarian cancer diagnosis within two years of recruitment were considered cases, and those without an ovarian cancer diagnosis were considered controls.Primary Outcome Measures: Recruitment rates, demographics of participants and identification of any barriers to recruitment.Results: In total, 182 cases and 427 controls were recruited with significant differences by age, number of people in participants’ households and the geographical region in the UK. However, only 37% (n=160/427) of control participants provided sufficient ID details and81% (130/160) matched retailers’ records. The majority of the participants provided complete responses to the 24‐Item Ovarian Risk Questionnaire.Conclusions: Our findings show that recruitment to a study aiming to understand self‐care behaviours using loyalty card data is challenging but feasible. The general public were willing to share their data for health research. Barriers in data sharing mechanisms need to be addressed to maximise participant rete
Bowden SJ, Ellis L, Kalliala I, et al., 2023, Protocol for a systematic review and meta-analysis of the diagnostic test accuracy of host and HPV DNA methylation in cervical cancer screening and management, BMJ Open, Vol: 13, Pages: 1-8, ISSN: 2044-6055
Introduction Human papillomavirus (HPV) is necessary but not sufficient for cervical cancer development. During cervical carcinogenesis, methylation levels increase across host and HPV DNA. DNA methylation has been proposed as a test to diagnose cervical intraepithelial neoplasia (CIN); we present a protocol to evaluate the accuracy of methylation markers to detect high-grade CIN and cervical cancer.Methods and analysis We will search electronic databases (Medline, Embase and Cochrane Library), from inception, to identify studies examining DNA methylation as a diagnostic marker for CIN or cervical cancer, in a cervical screening population. The primary outcome will be to assess the diagnostic test accuracy of host and HPV DNA methylation for high-grade CIN; the secondary outcomes will be to examine the accuracy of different methylation cut-off thresholds, and accuracy in high-risk HPV positive women. Our reference standard will be histology. We will perform meta-analyses using Cochrane guidelines for diagnostic test accuracy. We will use the number of true positives, false negatives, true negatives and false positives from individual studies. We will use the bivariate mixed effect model to estimate sensitivity and specificity with 95% CIs; we will employ different bivariate models to estimate sensitivity and specificity at different thresholds if sufficient data per threshold. For insufficient data, the hierarchical summary receiver operating curve model will be used to calculate a summary curve across thresholds. If there is interstudy and intrastudy variation in thresholds, we will use a linear mixed effects model to calculate the optimum threshold. If few studies are available, we will simplify models by assuming no correlation between sensitivity and specificity and perform univariate, random-effects meta-analysis. We will assess the quality of studies using QUADAS-2 and QUADAS-C.Ethics and dissemination Ethical approval is not required. Results will be dissemin
Carbajo-García MC, Juarez-Barber E, Segura-Benítez M, et al., 2023, H3K4me3 mediates uterine leiomyoma pathogenesis via neuronal processes, synapsis components, proliferation, and Wnt/β-catenin and TGF-β pathways, Reproductive Biology and Endocrinology, Vol: 21, Pages: 1-11, ISSN: 1477-7827
BACKGROUND: Uterine leiomyomas (UL) are the most common benign tumor in women of reproductive age. Their pathology remains unclear, which hampers the development of safe and effective treatments. Raising evidence suggests epigenetics as a main mechanism involved in tumor development. Histone modification is a key component in the epigenetic regulation of gene expression. Specifically, the histone mark H3K4me3, which promotes gene expression, is altered in many tumors. In this study, we aimed to identify if the histone modification H3K4me3 regulates the expression of genes involved in uterine leiomyoma pathogenesis. METHODS: Prospective study integrating RNA-seq (n = 48) and H3K4me3 CHIP-seq (n = 19) data of uterine leiomyomas versus their adjacent myometrium. Differentially expressed genes (FDR < 0.01, log2FC > 1 or < - 1) were selected following DESeq2, edgeR, and limma analysis. Their differential methylation and functional enrichment (FDR < 0.05) were respectively analyzed with limma and ShinyGO. RESULTS: CHIP-seq data showed a global suppression of H3K4me3 in uterine leiomyomas versus their adjacent myometrial tissue (p-value< 2.2e-16). Integrating CHIP-seq and RNA-seq data highlighted that transcription of 696/922 uterine leiomyoma-related differentially expressed genes (DEG) (FDR < 0.01, log2FC > 1 or < - 1) was epigenetically mediated by H3K4me3. Further, 50 genes were differentially trimethylated (FDR < 0.05), including 33 hypertrimethylated/upregulated, and 17 hypotrimethylated/downregulated genes. Functional enrichment analysis of the latter showed dysregulation of neuron-related processes and synapsis-related cellular components in uterine leiomyomas, and a literature review study of these DEG found additional implications with tumorigenesis (i.e. aberrant proliferation
Brewer HR, Hirst Y, Chadeau-Hyam M, et al., 2023, Association between purchase of over-the-counter medications and ovarian cancer diagnosis in the Cancer Loyalty Card Study (CLOCS): observational case-control study, JMIR Public Health and Surveillance, Vol: 9, ISSN: 2369-2960
BACKGROUND: Over-the-counter (OTC) medications are frequently used to self-care for nonspecific ovarian cancer symptoms prior to diagnosis. Monitoring such purchases may provide an opportunity for earlier diagnosis. OBJECTIVE: The aim of the Cancer Loyalty Card Study (CLOCS) was to investigate purchases of OTC pain and indigestion medications prior to ovarian cancer diagnosis in women with and without ovarian cancer in the United Kingdom using loyalty card data. METHODS: An observational case-control study was performed comparing purchases of OTC pain and indigestion medications prior to diagnosis in women with (n=153) and without (n=120) ovarian cancer using loyalty card data from two UK-based high street retailers. Monthly purchases of pain and indigestion medications for cases and controls were compared using the Fisher exact test, conditional logistic regression, and receiver operating characteristic (ROC) curve analysis. RESULTS: Pain and indigestion medication purchases were increased among cases 8 months before diagnosis, with maximum discrimination between cases and controls 8 months before diagnosis (Fisher exact odds ratio [OR] 2.9, 95% CI 2.1-4.1). An increase in indigestion medication purchases was detected up to 9 months before diagnosis (adjusted conditional logistic regression OR 1.38, 95% CI 1.04-1.83). The ROC analysis for indigestion medication purchases showed a maximum area under the curve (AUC) at 13 months before diagnosis (AUC=0.65, 95% CI 0.57-0.73), which further improved when stratified to late-stage ovarian cancer (AUC=0.68, 95% CI 0.59-0.78). CONCLUSIONS: There is a difference in purchases of pain and indigestion medications among women with and without ovarian cancer up to 8 months before diagnosis. Facilitating earlier presentation among those who self-care for symptoms using this novel data source could improve ovarian cancer patients' options for treatment and improve survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT03994653; https
Hirst Y, Stoffel ST, Brewer HR, et al., 2023, Understanding Public Attitudes and Willingness to Share Commercial Data for Health Research: Survey Study in the United Kingdom, JMIR PUBLIC HEALTH AND SURVEILLANCE, Vol: 9, ISSN: 2369-2960
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Dugue P-A, Bodelon C, Chung FF, et al., 2022, Methylation-based markers of aging and lifestyle-related factors and risk of breast cancer: a pooled analysis of four prospective studies, Breast Cancer Research, Vol: 24, Pages: 1-9, ISSN: 1465-542X
BackgroundDNA 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 and lifestyle-related factors in association with risk of breast cancer.MethodsUsing data from four prospective case–control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage.ResultsNone of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath ‘age acceleration’ (AA): OR per SD = 1.02, 95%CI: 0.95–1.10; AA-Hannum: OR = 1.03, 95%CI:0.95–1.12; PhenoAge: OR = 1.01, 95%CI: 0.94–1.09 and GrimAge: OR = 1.03, 95%CI: 0.94–1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01–1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did no
Stoffel ST, Law JH, Kerrison R, et al., 2022, Testing the Effectiveness of an Animated Decision Aid to Improve Recruitment of Control Participants in a Case-Control Study: Web-Based Experiment, JOURNAL OF MEDICAL INTERNET RESEARCH, Vol: 24, ISSN: 1438-8871
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Carbajo-Garcia MC, De Miguel-Gomez L, Juarez-Barber E, et al., 2022, Targeting histone modifications: H3K27 acetylation regulates the expression of genes involved in key processes of uterine leiomyoma pathogenesis, 38th Hybrid Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 1-2, ISSN: 0268-1161
Yang X, Fox A, DeCarlo C, et al., 2022, Comparative profiles of SARS-CoV-2 spike-specific human milk antibodies elicited by mRNA- and adenovirus-based COVID-19 vaccines, Breastfeeding Medicine, ISSN: 1556-8253
Background: Numerous COVID-19 vaccines are authorized globally. To date, ∼71% of doses comprise the Pfizer/BioNTech vaccine, and ∼17% the Moderna/NIH vaccine, both of which are messenger RNA (mRNA) based. The chimpanzee Ad-based Oxford/AstraZeneca (AZ) vaccine comprises ∼9%, while the Johnson & Johnson/Janssen (J&J) human adenovirus (Ad26) vaccine ranks fourth at ∼2%. No COVID-19 vaccine is yet available for children 0–4. One method to protect this population may be passive immunization through antibodies (Abs) provided in the milk of a lactating vaccinated person. Our early work and other reports have demonstrated that unlike the post-SARS-CoV-2 infection milk Ab profile, which is rich in specific secretory (s)IgA, the vaccine response is highly IgG dominant.Results: In this report, we present a comparative assessment of the milk Ab response elicited by Pfizer, Moderna, J&J, and AZ vaccines. This analysis revealed 86–100% of mRNA vaccine recipient milk exhibited Spike-specific IgG endpoint titers, which were 12- to 28-fold higher than those measured for Ad vaccine recipient milk. Ad-based vaccines elicited Spike-specific milk IgG in only 33–38% of recipients. Specific IgA was measured in 52–71% of mRNA vaccine recipient milk and 17–23% of Ad vaccine recipient milk. J&J recipient milk exhibited significantly lower IgA than Moderna recipients, and AZ recipients exhibited significantly lower IgA titers than Moderna and Pfizer. Less than 50% of milk of any group exhibited specific secretory Ab, with Moderna recipient IgA titers measuring significantly higher than AZ. Moderna appeared to most frequently elicit greater than twofold increases in specific secretory Ab titer relative to prevaccine sample.Conclusion: These data indicate that current Ad-based COVID-19 vaccines poorly elicit Spike-specific Ab in milk compared to mRNA-based vaccines, and that mRNA vaccines are preferred for immunizing the lactating p
Carbajo-Garcia MC, de Miguel-Gomez L, Juarez-Barber E, et al., 2022, Deciphering the role of histone modifications in uterine leiomyoma: acetylation of H3K27 regulates the expression of genes involved in proliferation, cell signaling, cell transport, angiogenesis and extracellular matrix formation, Biomedicines, Vol: 10, Pages: 1-14, ISSN: 2227-9059
Uterine leiomyoma (UL) is a benign tumor arising from myometrium (MM) with a high prevalence and unclear pathology. Histone modifications are altered in tumors, particularly via histone acetylation which is correlated with gene activation. To identify if the acetylation of H3K27 is involved in UL pathogenesis and if its reversion may be a therapeutic option, we performed a prospective study integrating RNA-seq (n = 48) and CHIP-seq for H3K27ac (n = 19) in UL vs MM tissue, together with qRT-PCR of SAHA-treated UL cells (n = 10). CHIP-seq showed lower levels of H3K27ac in UL versus MM (p-value < 2.2 × 10−16). From 922 DEGs found in UL vs. MM (FDR < 0.01), 482 presented H3K27ac. A differential acetylation (FDR < 0.05) was discovered in 82 of these genes (29 hyperacetylated/upregulated, 53 hypoacetylated/downregulated). Hyperacetylation/upregulation of oncogenes (NDP,HOXA13,COL24A1,IGFL3) and hypoacetylation/downregulation of tumor suppressor genes (CD40,GIMAP8,IL15,GPX3,DPT) altered the immune system, the metabolism, TGFβ3 and the Wnt/β-catenin pathway. Functional enrichment analysis revealed deregulation of proliferation, cell signaling, transport, angiogenesis and extracellular matrix. Inhibition of histone deacetylases by SAHA increased expression of hypoacetylated/downregulated genes in UL cells (p < 0.05). Conclusively, H3K27ac regulates genes involved in UL onset and maintenance. Histone deacetylation reversion upregulates the expression of tumor suppressor genes in UL cells, suggesting targeting histone modifications as a therapeutic approach for UL.
Ellis L, Noshin P, Bowden S, et al., 2022, Epigenetic changes associated with Combined Oral Contraceptive Use, Publisher: WILEY, Pages: 44-45, ISSN: 1470-0328
Dareng EO, Tyrer JP, Barnes DR, et al., 2022, Polygenic risk modeling for prediction of epithelial ovarian cancer risk (vol 30, pg 349, 2021), EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 30, Pages: 630-631, ISSN: 1018-4813
Dareng EO, Tyrer JP, Barnes DR, et al., 2022, Polygenic risk modeling for prediction of epithelial ovarian cancer risk, European Journal of Human Genetics, Vol: 30, Pages: 349-362, ISSN: 1018-4813
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 regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Bowden S, Bodinier B, Paraskevaidi M, et al., 2021, 200 Can methylation signals of cervical cancer enhance cervical screening?: an epigenome-wide association study on the Illumina 850k array, ESGO 2021 Congress, Publisher: BMJ Publishing Group, Pages: A12-A17, ISSN: 1048-891X
Gallon J, Curry E, Loomis E, et al., 2021, Chromatin accessibility changes at intergenic regions associate with ovarian cancer drug resistance, Clinical Epigenetics, Vol: 13, Pages: 1-15, ISSN: 1868-7083
BackgroundResistance to DNA damaging chemotherapies leads to cancer treatment failure and poor patient prognosis. We investigated how genomic distribution of accessible chromatin sites is altered during acquisition of cisplatin resistance using matched ovarian cell lines from high grade serous ovarian cancer (HGSOC) patients before and after becoming clinically resistant to platinum-based chemotherapy.ResultsResistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Clusters of cis-regulatory elements at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Further, genome-wide distribution of platinum adducts associates with the chromatin changes observed and distinguish sensitive from resistant lines. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions.ConclusionsChromatin changes at intergenic regulators of gene expression are associated with in vivo derived drug resistance and Pt-adduct distribution in patient-derived HGSOC drug resistance models.
Bowden S, Bodinier B, Kalliala I, et al., 2021, Genetic variation in cervical preinvasive and invasive disease: a genome-wide association study, The Lancet Oncology, Vol: 22, Pages: 548-557, ISSN: 1213-9432
Background: Most uterine cervical high-risk HPV infections (hrHPV) are transient, with only a small 3fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest 4a significant inherited genetic component. Candidate gene studies and previous genome-wide 5association studies (GWAS) report associations between the human leukocyte antigen (HLA) region 6and cervical cancer. 78Methods: Adopting a genome-wide approach, we compared the genetic variation in women with 9invasive cervical cancer (ICC) and cervical intra-epithelial neoplasia (CIN) grade 3, to that in healthy 10controls using the largest reported cohort of unrelated European individuals (N=150,314)to date. We 11sought for replication in a second large independent dataset (N=128,123). We further performed a two-12sample Mendelian Randomisation approach to explore the role of risk factors in the genetic risk of 13cervical cancer.1415Findings: In our analysis (N=4,769 CIN3 and ICC cases; N=145,545 controls), of the (N=9,600,464) 16assayed and imputed SNPs, six independent variants were found associated with CIN3and ICC. These 17included novel loci rs10175462(PAX8; OR=0.87(95%CI=0.84-0.91); P=1.07x10-9) and rs27069 18(CLPTM1L;OR=0.88(95%CI=0.84-0.92); P=2.51x10-9), and previously reported signals at rs9272050 19(HLA-DQA1;OR=1.27(95%CI=1.21-1.32); P=2.51x10-28), rs6938453 (MICA;OR=0.7920(95%CI=0.75-0.83); P=1.97x10-17), rs55986091 (HLA-DQB1;OR=0.66(95%CI=0.60-0.72); 21P=6.42x10-22) and rs9266183 (HLA-B;OR=0.73(95%CI=0.64-0.83); P=1.53x10-6). Mendelian 22randomisation further supported the complementary role of smoking, age at first pregnancy, and number 23of sexual partners in the risk of developing cervical cancer.2425Interpretation: Our results provide substantial new evidence for genetic susceptibility to cervical cancer, 26including PAX8, CLPTM1LandHLA genes, suggesting disruption in apoptotic and immun
Glubb DM, Thompson DJ, Aben KKH, et al., 2021, Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, Vol: 30, Pages: 217-228, ISSN: 1055-9965
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Jahin M, Fenech-Salerno B, Moser N, et al., 2021, Detection of <i>MGMT</i> methylation status using a Lab-on-Chip compatible isothermal amplification method, 43rd Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society (IEEE EMBC), Publisher: IEEE, Pages: 7385-7389, ISSN: 1557-170X
Shenker NS, Perdones-Montero A, Burke A, et al., 2020, Metabolomic and Metataxonomic Fingerprinting of Human Milk Suggests Compositional Stability over a Natural Term of Breastfeeding to 24 Months, NUTRIENTS, Vol: 12
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Brewer H, Hirst Y, Sudha S, et al., 2020, Cancer Loyalty Card Study (CLOCS): protocol for an observational case-control study focusing on the patient interval in ovarian cancer diagnosis, BMJ Open, Vol: 10, Pages: 1-9, ISSN: 2044-6055
IntroductionOvarian Cancer is the eighth most common cancer in women worldwide, and about one infive women with ovarian cancer do not receive treatment, because they are too unwell by thetime they are diagnosed. Symptoms of ovarian cancer are non-specific or can be associatedwith other common conditions, and women experiencing these symptoms have been shownto self-manage them using over-the-counter medication. Results from a recent proof ofconcept study suggest there may be an increase in the purchases of pain killers andindigestion medication 10-12 months before ovarian cancer diagnosis. We propose a casecontrol study, as part of a larger project called the Cancer Loyalty Card Study (CLOCS), toinvestigate whether a significant change in medication purchases could be an indication forearly signs of ovarian cancer, using data already collected through store loyalty cards.Methods and AnalysisUsing a retrospective case-control design, we aim to recruit 500 women diagnosed withovarian cancer (cases) and 500 women without ovarian cancer (controls) in the UnitedKingdom who hold a loyalty card with at least one participating high street retailer. We willuse pre-existing loyalty card data to compare past purchase patterns of cases with those ofcontrols. In order to assess ovarian cancer risk in participants and their purchase patterns, wewill collect information from participants on ovarian cancer risk factors and clinical dataincluding symptoms experienced before diagnosis from recruited women with ovariancancer.Ethics and disseminationCLOCS was reviewed and approved by the North West - Greater Manchester South ResearchEthics Committee (19/NW/0427). Study outcomes will be disseminated through academicpublications, the study website, social media, and a report to the research sites that supportthe study once results are published.Study Registration NumbersCLOCS is registered with ISRCTN (14897082), NIHR portfolio (CPMS 43323), andclinicaltrials.gov (NCT03994653).
Fachal L, Aschard H, Beesley J, et al., 2020, Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes, Nature Genetics, Vol: 52, Pages: 56-73, ISSN: 1061-4036
Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
Bowden SJ, Kalliala I, Veroniki AA, et al., 2019, The use of Human Papillomavirus DNA Methylation in cervical intraepithelial neoplasia: a systematic review and meta-analysis, EBioMedicine, Vol: 50, Pages: 246-259, ISSN: 2352-3964
BackgroundMethylation of viral DNA has been proposed as a novel biomarker for triage of human papillomavirus(HPV) positive women at screening. This systematic review and meta-analysis aims to assess how methylation levels change with disease severity and to determine diagnostic test accuracy (DTA) in detectinghigh-grade cervical intra-epithelial neoplasia (CIN).MethodsWe performed searches in MEDLINE, EMBASE and CENTRAL from inception to October 2019. Studies were eligible if they explored HPV methylation levels in HPV positive women. Data were extracted induplicate and requested from authors where necessary. Random-effects models and a bivariate mixed-effectsbinary regression model were applied to determine pooled effect estimates.Findings44 studies with 8819 high-risk HPV positive women were eligible. The pooled estimates for positive methylation rate in HPV16 L1 gene were higher for high-grade CIN (≥CIN2/high-grade squamousintra-epithelial lesion (HSIL) (95% confidence interval (95%CI:72·7% (47·8–92·2))) vs. low-grade CIN(≤CIN1/low-grade squamous intra-epithelial lesion (LSIL) (44·4% (95%CI:16·0–74·1))). Pooled differencein mean methylation level was significantly higher in ≥CIN2/HSIL vs. ≤CIN1/LSIL for HPV16 L1 (11·3%(95%CI:6·5–16·1)). Pooled odds ratio of HPV16 L1 methylation was 5·5 (95%CI:3·5–8·5) for ≥CIN2/HSIL vs. ≤CIN1/LSIL (p < 0·0001). HPV16 L1/L2 genes performed best in predicting CIN2 or worse(pooled sensitivity 77% (95%CI:63–87), specificity 64% (95%CI:55–71), area under the curve (0·73(95%CI:0·69–0·77)).InterpretationHigher HPV methylation is associated with increased disease severity, whilst HPV16 L1/L2 genes demonstrated high diagnostic accuracy to detect high-grade CIN in HPV16 positive women. Direct clinical use islimited by the need for a multi-genotype and standardised ass
Li A, Geyer FC, Blecua P, et al., 2019, Homologous recombination DNA repair defects in PALB2-associated breast cancers (vol 5, 23, 2019), NPJ BREAST CANCER, Vol: 5
Figlioli G, Bogliolo M, Catucci I, et al., 2019, The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer, npj Breast Cancer, Vol: 5, ISSN: 2374-4677
ArticleOpen AccessPublished: 01 November 2019The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancerGisella Figlioli, Massimo Bogliolo, […]Paolo Peterlongo npj Breast Cancer volume 5, Article number: 38 (2019) Cite this articleArticle metrics937 Accesses22 AltmetricMetricsdetailsAbstractBreast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of trunca
Bowden S, Kalliala I, Veroniki A, et al., 2019, THE USE OF HUMAN PAPILLOMAVIRUS DNA METHYLATION IN CERVICAL INTRAEPITHELIAL NEOPLASIA: A SYSTEMATIC REVIEW AND META-ANALYSIS, Publisher: BMJ PUBLISHING GROUP, Pages: A84-A86, ISSN: 1048-891X
Bowden S, Kalliala I, Wielscher M, et al., 2019, CERVICAL INTRAEPITHELIAL NEOPLASIA AND CERVICAL CANCER: A GENOME WIDE ASSOCIATION STUDY (GWAS) OF THE UK BIOBANK COHORT, Publisher: BMJ PUBLISHING GROUP, Pages: A59-A60, ISSN: 1048-891X
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