publications
publications by categories in reversed chronological order. generated by jekyll-scholar.
2024
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Cigarette smoking and e-cigarette use induce shared DNA methylation changes linked to carcinogenesisChiara Herzog, Allison Jones, Iona Evans, and 7 more authorsCancer Research, 2024Tobacco use is a major modifiable risk factor for adverse health outcomes, including cancer, and elicits profound epigenetic changes thought to be associated with long-term cancer risk. While electronic cigarettes (e-cigarettes) have been advocated as harm reduction alternatives to tobacco products, recent studies have revealed potential detrimental effects, highlighting the urgent need for further research into the molecular and health impacts of e-cigarettes. Here, we applied computational deconvolution methods to dissect the cell- and tissue-specific epigenetic effects of tobacco or e-cigarette use on DNA methylation (DNAme) in over 3,500 buccal/saliva, cervical, or blood samples, spanning epithelial and immune cells at directly and indirectly exposed sites. The 535 identified smoking-related DNAme loci (CpGs) clustered into four functional groups, including detoxification or growth signaling, based on cell type and anatomical site. Loci hypermethylated in buccal epithelial cells of smokers associated with NOTCH1/RUNX3/growth factor receptor signaling also exhibited elevated methylation in cancer tissue and progressing lung carcinoma in situ lesions, and hypermethylation of these sites predicted lung cancer development in buccal samples collected from smokers up to 22 years prior to diagnosis, suggesting a potential role in driving carcinogenesis. Alarmingly, these CpGs were also hypermethylated in e-cigarette users with a limited smoking history. This study sheds light on the cell type-specific changes to the epigenetic landscape induced by smoking-related products.
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Validation of biomarkers of agingMahdi Moqri*, Chiara Herzog*, Jesse R. Poganik*, and 26 more authorsNature Medicine, 2024The search for biomarkers that quantify biological aging (particularly ‘omic’-based biomarkers) has intensified in recent years. Such biomarkers could predict aging-related outcomes and could serve as surrogate endpoints for the evaluation of interventions promoting healthy aging and longevity. However, no consensus exists on how biomarkers of aging should be validated before their translation to the clinic. Here, we review current efforts to evaluate the predictive validity of omic biomarkers of aging in population studies, discuss challenges in comparability and generalizability and provide recommendations to facilitate future validation of biomarkers of aging. Finally, we discuss how systematic validation can accelerate clinical translation of biomarkers of aging and their use in gerotherapeutic clinical trials. Robust validation of biomarkers of aging will be critical to their clinical translation; here, authors review the key challenges and propose recommendations to overcome them.
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Natural Killer Cell Dysfunction in Premenopausal BRCA1 Mutation Carriers: A Potential Mechanism for Ovarian CarcinogenesisShaun Haran, Kantaraja Chindera, May Sabry, and 17 more authorsCancers, 2024Since the discovery of a BRCA1 mutation nearly 30 years ago, definitive methods for ovarian cancer-risk reduction has remained unchanged, requiring carriers of a pathogenic mutation to consider undergoing surgical removal of both fallopian tubes and ovaries from the ages of 35 to 40 years. The sequelae of these invasive measures include a profound impact on general health, psychological well-being, sexual and reproductive function. Identifying targetable aberrances in BRCA1 mutation carriers, such as sex hormones, or adopting mechanisms aimed at enhancing tumor immunosurveillance may facilitate the reduction of early cancer-promoting events. This is particularly relevant for the fimbrial fallopian tube, where the majority of epithelial ovarian cancers originate. Utilizing a proof-of-concept for potentially targetable aberrances may further the development of non-surgical adjuncts or surveillance methods aimed at cancer-risk reduction for women deferring or declining surgery. Background: Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in BRCA1 mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germline BRCA1 mutation in the context of cancer immunosurveillance of CD3− CD56+ natural killer (NK) cells. Methods: Premenopausal BRCA1 mutation carriers versus age-matched non-carriers were compared. Daily urinary 5β-pregnanediol levels were used to determine progesterone metabolomics across an ovarian cycle. Using peripherally acquired NK cells the cell-mediated cytotoxicity of tumor targets (OVCAR-3, K-562) was determined using live cellular impedance (xCELLigence®) and multicolor flow cytometry. Hypoxia-inducible factor 1-alpha (HIF-1α) immunohistochemistry of cancer-free fallopian tube specimens allowed a comparison of proximal versus distal portions. Utilizing these findings the role of environmental factors relevant to the fimbrial fallopian tube (progesterone, hypoxia) on NK cell functional activity were studied in an ovarian phase-specific manner. Results: BRCA1 mutation carriers demonstrate a differential progesterone metabolome with a phase-specific reduction of peripheral NK cell functional activity. Progesterone exposure further impairs NK cell-mediated cytotoxicity in a dose-dependent manner, which is reversed with the addition of mifepristone (1.25 µM). The fimbrial fallopian tube demonstrated significantly higher HIF-1α staining, particularly in BRCA1 mutation carriers, reflecting a site-specific ‘hypoxic niche’. Exposure to hypoxic conditions (1% O2) can further impair tumor cytotoxicity in high-risk carriers. Conclusions: Phase-specific differential NK cell activity in BRCA1 mutation carriers, either systemically or locally, may favor site-specific pre-invasive carcinogenesis. These cumulative effects across a reproductive lifecycle in high-risk carriers can have a detrimental effect further supporting epidemiological evidence for ovulation inhibition.
2023
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Performance of the WID-qEC test versus sonography to detect uterine cancers in women with abnormal uterine bleeding (EPI-SURE): a prospective, consecutive observational cohort study in the UKIona Evans*, Daniel Reisel*, Allison Jones*, and 11 more authorsThe Lancet Oncology, 2023 -
Plasma cell‐free DNA methylation analysis for ovarian cancer detection: Analysis of samples from a case‐control study and an ovarian cancer screening trialChiara Herzog, Allison Jones, Iona Evans, and 18 more authorsInternational Journal of Cancer, 2023Analysis of cell‐free DNA methylation (cfDNAme), alone or combined with CA125, could help to detect ovarian cancers earlier and may reduce mortality. We assessed cfDNAme in regions of ZNF154, C2CD4D and WNT6 via targeted bisulfite sequencing in diagnostic and early detection (preceding diagnosis) settings. Diagnostic samples were obtained via prospective blood collection in cell‐free DNA tubes in a convenience series of patients with a pelvic mass. Early detection samples were matched case‐control samples derived from the UK Familial Ovarian Cancer Screening Study (UKFOCSS). In the diagnostic set (ncases = 27, ncontrols = 41), the specificity of cfDNAme was 97.6% (95% CI: 87.1%‐99.9%). High‐risk cancers were detected with a sensitivity of 80% (56.3%‐94.3%). Combination of cfDNAme and CA125 resulted in a sensitivity of 94.4% (72.7%‐99.9%) for high‐risk cancers. Despite technical issues in the early detection set (ncases = 29, ncontrols = 29), the specificity of cfDNAme was 100% (88.1%‐100.0%). We detected 27.3% (6.0%‐61.0%) of high‐risk cases with relatively lower genomic DNA (gDNA) contamination. The sensitivity rose to 33.3% (7.5%‐70.1%) in samples taken <1 year before diagnosis. We detected ovarian cancer in several patients up to 1 year before diagnosis despite technical limitations associated with archival samples (UKFOCSS). Combined cfDNAme and CA125 assessment may improve ovarian cancer screening in high‐risk populations, but future large‐scale prospective studies will be required to validate current findings. Our findings indicate that combining cell‐free DNA methylation analysis in three genetic regions with CA125 may improve the sensitivity of ovarian cancer detection in high‐risk women. Women with a positive score in either diagnostic modality, particularly double‐positive individuals, could be referred for a PET‐CT scan to rule out a positive result due to a different cancer, and could undergo surgery even in the absence of a visible ovarian tumour on imaging given the high specificity of cfDNAme.
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DNA methylation at quantitative trait loci (mQTLs) varies with cell type and nonheritable factors and may improve breast cancer risk assessmentChiara Herzog, Allison Jones, Iona Evans, and 8 more authorsnpj Precision Oncology, 2023To individualise breast cancer (BC) prevention, markers to follow a person’s changing environment and health extending beyond static genetic risk scores are required. Here, we analysed cervical and breast DNA methylation (n=1848) and single nucleotide polymorphisms (n=1442) and demonstrate that a linear combination of methylation levels at 104 BC-associated methylation quantitative trait loci (mQTL) CpGs, termed the WID™-qtBC index, can identify women with breast cancer in hormone-sensitive tissues (AUC=0.71 [95% CI: 0.65–0.77] in cervical samples). Women in the highest combined risk group (high polygenic risk score and WID™-qtBC) had a 9.6-fold increased risk for BC [95% CI: 4.7–21] compared to the low-risk group and tended to present at more advanced stages. Importantly, the WID™-qtBC is influenced by non-genetic BC risk factors, including age and body mass index, and can be modified by a preventive pharmacological intervention, indicating an interaction between genome and environment recorded at the level of the epigenome. Our findings indicate that methylation levels at mQTLs in relevant surrogate tissues could enable integration of heritable and non-heritable factors for improved disease risk stratification.
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Biomarkers of aging for the identification and evaluation of longevity interventionsMahdi Moqri*, Chiara Herzog*, Jesse R. Poganik*, and 25 more authorsCell, 2023With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice.
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HPV‐induced host epigenetic reprogramming is lost upon progression to high‐grade cervical intraepithelial neoplasiaChiara Herzog*, Charlotte D. Vavourakis*, James E. Barrett, and 6 more authorsInternational Journal of Cancer, 2023The impact of a pathogen on host disease can only be studied in samples covering the entire spectrum of pathogenesis. Persistent oncogenic Human Papilloma Virus (HPV) infection is the most common cause for cervical cancer. Here, we investigate HPV‐induced host epigenome‐wide changes prior to development of cytological abnormalities. Using cervical sample methylation array data from disease‐free women with or without an oncogenic HPV infection, we develop the WID (Women’s cancer risk identification)‐HPV, a signature reflective of changes in the healthy host epigenome related to high‐risk HPV strains (AUC=0.78, 95% CI: 0.72‐0.85, in non‐diseased women). Looking at HPV‐associated changes across disease development, HPV‐infected women with minor cytological alterations (cervical intraepithelial neoplasia grade 1/2, CIN1/2), but surprisingly not those with precancerous changes or invasive cervical cancer (CIN3+), show an increased WID‐HPV index, indicating the WID‐HPV may reflect a successful viral clearance response absent in progression to cancer. Further investigation revealed the WID‐HPV is positively associated with apoptosis (ρ=0.48; p<0.001) and negatively associated with epigenetic replicative age (ρ=‐0.43; p<0.001). Taken together, our data suggest the WID‐HPV captures a clearance response associated with apoptosis of HPV‐infected cells. This response may be dampened or lost with increased underlying replicative age of infected cells, resulting in progression to cancer. This article is protected by copyright. All rights reserved.
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The WID‐EC test for the detection and risk prediction of endometrial cancerJames E. Barrett*, Allison Jones*, Iona Evans*, and 21 more authorsInternational Journal of Cancer, 2023The incidence of endometrial cancer is rising. Measures to identify women at risk and to detect endometrial cancer earlier are required to reduce the morbidity triggered by the aggressive treatment required for advanced endometrial cancer. We developed the WID‐EC (Women’s cancer risk IDentification‐Endometrial Cancer) test, which is based on DNA methylation at 500 CpG sites, in a discovery set of cervical liquid‐based cytology samples from 1086 women with and without an endometrial cancer (217 cancer cases and 869 healthy controls) with a worse prognosis (grade 3 or ≥stage IB). We validated the WID‐EC test in an independent external validation set of 64 endometrial cancer cases and 225 controls. We further validated the test in 150 healthy women (prospective set) who provided a cervical sample as part of the routine Swedish cervical screening programme, 54 of whom developed endometrial cancer within 3 years of sample collection. The WID‐EC test identified women with endometrial cancer with a receiver operator characteristic area under the curve (AUC) of 0.92 (95% CI: 0.88‐0.97) in the external set and of 0.82 (95% CI: 0.74‐0.89) in the prospective validation set. Using an optimal cutoff, cancer cases were detected with a sensitivity of 86% and a specificity of 90% in the external validation set, and a sensitivity and specificity of 52% and 98% respectively in the prospective validation set. The WID‐EC test can identify women with or at risk of endometrial cancer. The endometrial cancer incidence is rising, and imaging‐based screening is often not suitably accurate for endometrial cancers. Here, the authors show that a new DNA methylation signature (Women’s cancer risk IDentification‐Endometrial Cancer, or WID‐EC) can both detect the presence and predict the risk of endometrial cancer. Together with three other recently‐reported methylation indices that detect breast, ovarian, and cervical cancers (WID‐BC, WID‐OC, and WID‐CIN), WID‐EC completes a list of signatures that can detect/predict all four women‐specific cancers using a single cervical sample and the same technology platform for methylation array‐based tests.
2022
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Dietary restriction in senolysis and prevention and treatment of diseaseSepideh Aminzadeh-Gohari, Barbara Kofler, and Chiara HerzogCritical Reviews in Food Science and Nutrition, 2022Aging represents a key risk factor for a plethora of diseases. Targeting detrimental processes which occur during aging, especially before onset of age-related disease, could provide drastic improvements in healthspan. There is increasing evidence that dietary restriction (DR), including caloric restriction, fasting, or fasting-mimicking diets, extend both lifespan and healthspan. This has sparked interest in the use of dietary regimens as a non-pharmacological means to slow aging and prevent disease. Here, we review the current evidence on the molecular mechanisms underlying DR-induced health improvements, including removal of senescent cells, metabolic reprogramming, and epigenetic rejuvenation.
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A Simple Cervicovaginal Epigenetic Test for Screening and Rapid Triage of Women With Suspected Endometrial Cancer: Validation in Several Cohort and Case/Control SetsChiara Herzog*, Fátima Marín*, Allison Jones, and 28 more authorsJournal of Clinical Oncology, 2022PURPOSE: Endometrial cancer (EC) incidence has been rising over the past 10 years. Delays in diagnosis reduce survival and necessitate more aggressive treatment. We aimed to develop and validate a simple, noninvasive, and reliable triage test for EC to reduce the number of invasive diagnostic procedures and improve patient survival.
METHODS: We developed a test to screen and triage women with suspected EC using 726 cervical smear samples from women with and without EC, and validated the test in 562 cervicovaginal samples using three different collection methods (cervical smear: n = 248; vaginal swab: n = 63; and self-collection: n = 251) and four different settings (case/control: n = 388; cohort of women presenting with postmenopausal bleeding: n = 63; a cohort of high-risk women with Lynch syndrome: n = 25; and a nested case/control setting from a screening cohort and samples taken up to 3 years before EC diagnosis: n = 86).
RESULTS: We describe the Women’s cancer risk IDentification – quantitative polymerase chain reaction test for Endometrial Cancer (WID-qEC), a three-marker test that evaluates DNA methylation in gene regions of GYPC and ZSCAN12. In cervical, self-collected, and vaginal swab samples derived from symptomatic patients, it detected EC with sensitivities of 97.2% (95% CI, 90.2 to 99.7), 90.1% (83.6 to 94.6), and 100% (63.1 to 100), respectively, and specificities of 75.8% (63.6 to 85.5), 86.7% (79.3 to 92.2), and 89.1% (77.8 to 95.9), respectively. The WID-qEC identified 90.9% (95% CI, 70.8 to 98.9) of EC cases in samples predating diagnosis up to 1 year. Test performance was similar across menopausal status, age, stage, grade, ethnicity, and histology.
CONCLUSION: The WID-qEC is a noninvasive reliable test for triage of women with symptoms suggestive of ECs. Because of the potential for self-collection, it could improve early diagnosis and reduce the reliance for in-person visits. -
DNA methylation-based detection and prediction of cervical intraepithelial neoplasia grade 3 and invasive cervical cancer with the WID™-qCIN testChiara Herzog*, Karin Sundström*, Allison Jones, and 14 more authorsClinical Epigenetics, 2022Cervical screening using primary human papilloma virus (HPV) testing and cytology is being implemented in several countries. Cytology as triage for colposcopy referral suffers from several shortcomings. HPV testing overcomes some of these but lacks specificity in women under 30. Here, we aimed to develop and validate an automatable triage test that is highly sensitive and specific independently of age and sample heterogeneity, and predicts progression to CIN3+ in HPV+ patients. The WID™-qCIN, assessing three regions in human genes DPP6, RALYL, and GSX1, was validated in both a diagnostic (case–control) and predictive setting (nested case–control), in a total of 761 samples. Using a predefined threshold, the sensitivity of the WID™-qCIN test was 100% and 78% to detect invasive cancer and CIN3, respectively. Sensitivity to detect CIN3+ was 65% and 83% for women < and ≥ 30 years of age. The specificity was 90%. Importantly, the WID™-qCIN test identified 52% of ≥ 30-year-old women with a cytology negative (cyt−) index sample who were diagnosed with CIN3 1–4 years after sample donation. We identified suitable DNAme regions in an epigenome-wide discovery using HPV+ controls and CIN3+ cases and established the WID™-qCIN, a PCR-based DNAme test. The WID™-qCIN test has a high sensitivity and specificity that may outperform conventional cervical triage tests and can in an objective, cheap, and scalable fashion identify most women with and at risk of (pre-)invasive cervical cancer. However, evaluation was limited to case–control settings and future studies will assess performance and generalisability in a randomised controlled trial.
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The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancerJames E. Barrett, Karin Sundström, Allison Jones, and 5 more authorsGenome Medicine, 2022Cervical screening is transitioning from primary cytology to primary human papillomavirus (HPV) testing. HPV testing is highly sensitive but there is currently no high-specificity triage method for colposcopy referral to detect cervical intraepithelial neoplasia grade 3 or above (CIN3+) in women positive for high-risk (hr) HPV subtypes. An objective, automatable test that could accurately perform triage, independently of sample heterogeneity and age, is urgently required. We analyzed DNA methylation at 850,000 CpG sites across the genome in a total of 1254 cervical liquid-based cytology (LBC) samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). Samples were provided by a state-of-the-art population-based cohort biobank and consisted of (i) a discovery set of 170 CIN3+ cases and 202 hrHPV-positive/cytology-negative controls; (ii) a diagnostic validation set of 87 CIN3+, 90 CIN2, 166 CIN1, and 111 hrHPV-positive/cytology-negative controls; and (iii) a predictive validation set of 428 cytology-negative samples (418 hrHPV-positive) of which 210 were diagnosed with CIN3+ in the upcoming 1–4 years and 218 remained disease-free. We developed the WID-CIN (Women’s cancer risk IDentification-Cervical Intraepithelial Neoplasia) test, a DNA methylation signature consisting of 5000 CpG sites. The receiver operating characteristic area under the curve (AUC) in the independent diagnostic validation set was 0.92 (95% CI 0.88–0.96). At 75% specificity (≤CIN1), the overall sensitivity to detect CIN3+ is 89.7% (83.3–96.1) in all and 92.7% (85.9–99.6) and 65.6% (49.2–82.1) in women aged ≥30 and <30. In hrHPV-positive/cytology-negative samples in the predictive validation set, the WID-CIN detected 54.8% (48.0–61.5) cases developing 1–4 years after sample donation in all ages or 56.9% (47.6–66.2) and 53.5% (43.7–63.2) in ≥30 and <30-year-old women, at a specificity of 75%. The WID-CIN test identifies the vast majority of hrHPV-positive women with current CIN3+ lesions. In the absence of cytologic abnormalities, a positive WID-CIN test result is likely to indicate a significantly increased risk of developing CIN3+ in the near future.
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The WID‐qEC test: Performance in a hospital‐based cohort and feasibility to detect endometrial and cervical cancersLena Schreiberhuber, Chiara Herzog, Charlotte D. Vavourakis, and 13 more authorsInternational Journal of Cancer, 2022The majority of endometrial and cervical cancers present with abnormal vaginal bleeding but only a small proportion of women suffering from vaginal bleeding actually have such a cancer. A simple, operator‐independent and accurate test to correctly identify women presenting with abnormal bleeding as a consequence of endometrial or cervical cancer is urgently required. We have recently developed and validated the WID‐qEC test, which assesses DNA methylation of ZSCAN12 and GYPC via real‐time PCR, to triage women with symptoms suggestive of endometrial cancer using ThinPrep‐based liquid cytology samples. Here, we investigated whether the WID‐qEC test can additionally identify women with cervical cancer. Moreover, we evaluate the test’s applicability in a SurePath‐based hospital‐cohort by comparing its ability to detect endometrial and cervical cancer to cytology. In a set of 23 cervical cancer cases and 28 matched controls the receiver operating characteristic (ROC) area under the curve (AUC) is 0.99 (95% confidence interval [CI]: 0.97‐1.00) with a sensitivity and specificity of 100% and 92.9%, respectively. Amongst the hospital‐cohort (n = 330), the ROC AUC is 0.99 (95% CI: 0.98‐1) with a sensitivity and specificity of 100% and 82.5% for the WID‐qEC test, respectively, and 33.3% and 96.9% for cytology (considering PAP IV/V as positive). Our data suggest that the WID‐qEC test detects both endometrial and cervical cancer with high accuracy. While abnormal vaginal bleeding is a presenting symptom of endometrial and cervical cancers, only a small proportion of women who present with vaginal bleeding have endometrial or cervical cancer. Currently, the tests used to triage women with abnormal bleeding, such as ultrasound or cytology, are subjective and have modest accuracy. Here, the authors demonstrate that a real‐time PCR‐based test, which assesses DNA methylation at three gene regions using a cervical or vaginal sample, is able to identify 100% of women who have cervical or endometrial cancer with a high specificity (>80%), irrespective of the sample collection system.
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Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy womenThomas E. Bartlett, Iona Evans, Allison Jones, and 20 more authorsGenome Medicine, 2022Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation. In healthy premenopausal women with and without a BRCA mutation we studied (i) estrogen and progesterone levels in saliva over an entire menstrual cycle (n = 20); (ii) cancer-free normal breast-tissue from a control population who had no family or personal history of breast cancer and equivalently from BRCA1/2 mutation carriers (n = 28); triple negative breast cancer (TNBC) biopsies and healthy breast tissue taken from sites surrounding the TNBC in the same individuals (n = 14); and biopsies of ER+ve/PR+ve stage T1–T2 cancers and healthy breast tissue taken from sites surrounding the cancer in the same individuals (n = 31); and (iii) DNA methylation and DNA mutations in normal breast tissue (before and after treatment) from clinical trials that assessed the potential preventative effects of vitamins and antiprogestins (mifepristone and ulipristal acetate; n = 44). Daily levels of progesterone were higher throughout the menstrual cycle of BRCA1/2 mutation carriers, raising the prospect of targeting progesterone signalling as a means of cancer risk reduction in this population. Furthermore, breast field cancerization DNA methylation signatures reflective of (i) the mitotic age of normal breast epithelium and (ii) the proportion of luminal progenitor cells were increased in breast cancers, indicating that luminal progenitor cells with elevated replicative age are more prone to malignant transformation. The progesterone receptor antagonist mifepristone reduced both the mitotic age and the proportion of luminal progenitor cells in normal breast tissue of all control women and in 64% of BRCA1/2 mutation carriers. These findings were validated by an alternate progesterone receptor antagonist, ulipristal acetate, which yielded similar results. Importantly, mifepristone reduced both the TP53 mutation frequency as well as the number of TP53 mutations in mitotic-age-responders. These data support the potential usage of antiprogestins for primary prevention of poor-prognostic breast cancers. Clinical trial 1 Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control – a randomized controlled trial, clinicaltrialsregister.eu, 2009-009014-40; registered on 20 July 2009. Clinical trial 2 The effect of a progesterone receptor modulator on breast tissue in women with BRCA1 and 2 mutations, clinicaltrials.gov, NCT01898312; registered on 07 May 2013. Clinical trial 3 A pilot prevention study of the effects of the anti- progestin Ulipristal Acetate (UA) on surrogate markers of breast cancer risk, clinicaltrialsregister.eu, 2015-001587-19; registered on 15 July 2015.
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The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samplesJames E. Barrett*, Chiara Herzog*, Allison Jones, and 22 more authorsNature Communications, 2022Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women’s risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80–0.88) and 0.81 (95% CI: 0.76–0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk. Breast cancer is most commonly diagnosed via a needle biopsy. In this study, the authors show that cervical samples from women with breast cancer have a methylation signature different to that of healthy controls.
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The DNA methylome of cervical cells can predict the presence of ovarian cancerJames E. Barrett, Allison Jones, Iona Evans, and 10 more authorsNature Communications, 2022The vast majority of epithelial ovarian cancer arises from tissues that are embryologically derived from the Müllerian Duct. Here, we demonstrate that a DNA methylation signature in easy-to-access Müllerian Duct-derived cervical cells from women with and without ovarian cancer (i.e. referred to as the Women’s risk IDentification for Ovarian Cancer index or WID-OC-index) is capable of identifying women with an ovarian cancer in the absence of tumour DNA with an AUC of 0.76 and women with an endometrial cancer with an AUC of 0.81. This and the observation that the cervical cell WID-OC-index mimics the epigenetic program of those cells at risk of becoming cancerous in BRCA1/2 germline mutation carriers (i.e. mammary epithelium, fallopian tube fimbriae, prostate) further suggest that the epigenetic misprogramming of cervical cells is an indicator for cancer predisposition. This concept has the potential to advance the field of risk-stratified cancer screening and prevention. Most ovarian cancers originate from cells originally derived from Müllerian Duct cells. Here, the authors show that the methylation profile of Müllerian Duct cells isolated from cervical samples can predict whether a woman has cervical cancer.
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Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clockJames E. Barrett*, Chiara Herzog*, Yoo-Na Kim*, and 12 more authorsGenome Biology, 2022A variety of epigenetic clocks utilizing DNA methylation changes have been developed; these clocks are either tissue-independent or designed to predict chronological age based on blood or saliva samples. Whether discordant tick rates between tissue-specific and general epigenetic clocks play a role in health and disease has not yet been explored. Here we analyze 1941 cervical cytology samples, which contain a mixture of hormone-sensitive cervical epithelial cells and immune cells, and develop the WID general clock (Women’s IDentification of risk), an epigenetic clock that is shared by epithelial and immune cells and optimized for cervical samples. We then develop the WID epithelial clock and WID immune clock, which define epithelial- and immune-specific clocks, respectively. We find that the WID-relative-epithelial-age (WID-REA), defined as the difference between the epithelial and general clocks, is significantly reduced in cervical samples from pre-menopausal women with breast cancer (OR 2.7, 95% CI 1.28-5.72). We find the same effect in normal breast tissue samples from pre-menopausal women at high risk of breast cancer and show that potential risk reducing anti-progesterone drugs can reverse this. In post-menopausal women, this directionality is reversed. Hormone replacement therapy consistently leads to a significantly lower WID-REA in cancer-free women, but not in post-menopausal women with breast or ovarian cancer. Our findings imply that there are multiple epigenetic clocks, many of which are tissue-specific, and that the differential tick rate between these clocks may be an informative surrogate measure of disease risk.
