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No study has systematically compared the suitability of DNA methylation (DNAme) profiles in non-invasive samples for the detection of breast cancer (BC). We assess non-tumour DNAme in 1,100 cervical, buccal, and blood samples from BC cases and controls and find that cervical samples exhibit the largest nuber of differentially methylated sites, followed by buccal samples. No sites were significant in blood after FDR adjustment. Deriving DNAme-based classifiers for BC detection in each sample type (WID-buccal-, cervical-, or blood-BC), we achieve validation AUCs of 0.75, 0.66, and 0.51, respectively. Buccal and cervical BC-associated DNAme alterations distinguish between BC cases and controls in both surrogate and breast tissue (AUC > 0.88), yet individual sites and the directionality of methylation changes are not identical between these two sample types, and buccal sample DNAme aligns with breast methylation changes more closely. Pending additional validation, these insights may have the potential to improve non-invasive personalized BC prevention. The suitability of non-invasive surrogate samples for detecting breast cancer remains to be systematically explored. Here, the authors compare non-invasive, non-tumour DNA methylation profiles from cervical, buccal, and blood samples and develop classifiers for breast cancer detection for each sample type.

Biomarkers of aging have the potential to transform geroscience clinical trials because of their broad applications in stratifying participants, prioritizing interventions, and monitoring responses to geroprotectors. As longevity biotechnology companies (LBCs) continue to plan and launch innovative clinical trials, standard practices in collecting data and applying biomarkers of aging will allow the field to support parallel and ongoing validation and benchmarking efforts for aging biomarkers. Moreover, defining best practices will ensure future reuse of valuable clinical data through pre-competitive alignment on shared tools. Here, we propose recommendations for such collections. We believe that wide adoption of these recommendations will allow LBCs to produce and leverage the highest quality data from their clinical trials, while also benefiting the geroscience field more broadly with minimal additional effort.

Biomarkers of aging (BOA) are quantitative parameters that predict biological age and ideally its changes in response to interventions. In recent years, many promising molecular and omic BOA have emerged with an enormous potential for translational geroscience and improving healthspan. However, clinical translation remains limited, in part due to the gap between preclinical research and the application of BOA in clinical research and other translational settings. We surveyed experts in these areas to better understand current challenges for the translation of aging biomarkers. We identified six key barriers to clinical translation and developed guidance for the field to overcome them. Core recommendations include linking BOA to clinically actionable insights, improving affordability and availability to broad populations and validation of biomarkers that are robust and responsive at the level of individuals. Our work provides key insights and practical recommendations to overcome barriers impeding clinical translation of BOA. Biomarkers of aging have potential to accelerate the clinical translation of interventions that promote healthy aging but are currently limited to research. The authors identify six barriers to be overcome to enable biomarker translation, providing a roadmap to clinical implementation.

The 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.

Background Aging is a key risk factor for many diseases, including cancer, and a better understanding of its underlying molecular mechanisms may help to prevent, delay, or treat age-related pathologies. Epigenetic alterations such as DNA methylation (DNAme) changes are a hallmark of aging and form the basis of so-called epigenetic clocks, yet their functional relevance and directionality in different organs during disease development is often unclear. Methods Here, we link cell-specific age-related DNAme changes with three key hallmarks of aging and cancer (senescence, promoter methylation in genes associated with stem cell fate, and dysregulated proliferation) to comprehensively dissect their association with current and future cancer development, carcinogen exposure or preventive measures, and mortality using data in different organs from over 12,510 human and 105 mouse samples, benchmarking against existing epigenetic clocks. Results Our findings offer insights into the association of functionally enriched groups of age-related DNAme changes with cancer, identify sites perturbed earliest during carcinogenesis, as well as those distinct between cancer and reprogramming that could inform strategies to prevent teratoma formation upon in vivo reprogramming. Surprisingly, both mouse and human data reveal accelerated aging in breast cancer tissue but decelerated epigenetic aging in some non-cancer surrogate samples from breast cancer patients, in particular cervical samples. Conclusions This work provides evidence for discordant systemic tissue aging in breast cancer. Plain language summary DNA contains genetic information about an individual. DNA is often chemically modified, a process called epigenetics, and it has been found that this occurs with distinct patterns during aging and in cancer cells. We looked at age-related DNA modification changes associated with the function of mouse and human cells. Our findings show that although cancer cells generally look epigenetically older than normal tissue, some non-cancerous cells from cancer patients show a younger epigenetic age. These findings highlight that aging may occur at different rates across the body and that cancer may be associated with deceleration of aging in some body parts. Our findings indicate that more research is needed to understand the role of these epigenetic modifications in aging as well as how aging rates across tissues mediate health and disease. Herzog et al. dissect functionally enriched groups of CpG associated with cellular senescence, proliferation and aging. Some non-cancer tissues from breast cancer patients show younger epigenetic ages than in controls, while breast cancer tissue looks generally older, providing evidence for discordant systemic aging in breast cancer.

Genetic 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.

To detect uterine cancer, simpler and more specific index tests are needed to triage women with abnormal uterine bleeding to a reference histology test. We aimed to compare the performance of conventional index imaging tests with the novel WID-qEC DNA methylation test in terms of detecting the presence or absence of uterine cancers in women with abnormal uterine bleeding. EPI-SURE was a prospective, observational study that invited all women aged 45 years and older with abnormal uterine bleeding attending a tertiary gynaecological diagnostic referral centre at University College London Hospital (London, UK) to participate. Women meeting these inclusion criteria who consented to participate were included. Pregnant women and those with previous hysterectomy were excluded. A cervicovaginal sample for the WID-qEC test was obtained before standard assessment using index imaging tests (ie, ultrasound) and, where applicable, reference histology (ie, biopsy, hysteroscopy, or both) was performed. Technicians performing the WID-qEC test were masked to the final clinical outcome. The result of the WID-qEC test is defined as the sum of the percentage of fully methylated reference (ΣPMR) of the ZSCAN12 and GYPC regions. Patients were followed until diagnostic resolution or until June 12, 2023. The primary outcome was to assess the real-world performance of the WID-qEC test in comparison with ultrasound with regard to the area under the receiver-operating-characteristic curve (AUC), sensitivity, specificity, and positive and negative predictive values. EPI-SURE is registered with ISRCTN (16815568). From June 1, 2022, to Nov 24, 2022, 474 women were deemed eligible to participate. 74 did not accept the invitation to participate, and one woman withdrew after providing consent. 399 women were included in the primary analysis cohort. Based on 603 index imaging tests, 186 (47%) women were recommended for a reference histology test (ie, biopsy, hysteroscopy, or both). 12 women were diagnosed with cancer, 375 were not diagnosed with cancer, and 12 had inconclusive clinical outcomes and were considered study dropouts. 198 reference histology test procedures detected nine cases of cancer and missed two; one further cancer was directly diagnosed at hysterectomy without a previous reference test. The AUC for detection of uterine cancer based on endometrial thickness in mm was 87·2% (95% CI 71·1–100·0) versus 94·3% (84·7–100·0) based on WID-qEC (p=0·48). Endometrial thickness assessment on ultrasound scan was possible in 379 (95%) of the 399 women and a prespecified cut-off of 4·5 mm or more showed a sensitivity of 90·9% (95% CI 62·3–98·4), a specificity of 79·1% (74·5–82·9), a positive predictive value of 11·8% (6·5–20·3), and a negative predictive value of 99·6% (98·0–99·9). The WID-qEC test was possible in 390 (98%) of the 399 patients with a sensitivity of 90·9% (95% CI 62·3–98·4), a specificity of 92·1% (88·9–94·4), a positive predictive value of 25·6% (14·6–41·1), and a negative predictive value of 99·7% (98·3–99·9), when the prespecified threshold of 0·03 ΣPMR or more was applied. When a higher threshold (≥0·3 ΣPMR) was applied the specificity increased to 97·3% (95% CI 95·1–98·5) without a change in sensitivity. The WID-qEC test delivers fast results and shows improved performance compared with a combination of imaging index tests. Triage of women with abnormal uterine bleeding using the WID-qEC test could reduce the number of women requiring histological assessments for identification of potential malignancy and specifically reduce the false positive rate. The Eve Appeal, Land Tirol, and the European Research Council under the European Union's Horizon 2020 Research and Innovation Programme

Recent epigenome-wide studies have identified a large number of genomic regions that consistently exhibit changes in their methylation status with aging across diverse populations, but the functional consequences of these changes are largely unknown. On the other hand, transcriptomic changes are more easily interpreted than epigenetic alterations, but previously identified age-related gene expression changes have shown limited replicability across populations. Here, we develop an approach that leverages high-resolution multi-omic data for an integrative analysis of epigenetic and transcriptomic age-related changes and identify genomic regions associated with both epigenetic and transcriptomic age-dependent changes in blood. Our results show that these multi-omic aging genes in blood are enriched for adaptive immune functions, replicate more robustly across diverse populations and are more strongly associated with aging-related outcomes compared to the genes identified using epigenetic or transcriptomic data alone. These multi-omic aging genes may serve as targets for epigenetic editing to facilitate cellular rejuvenation. DNA methylation and gene expression data integration identify aging-related genes in blood that predict health outcomes, offering new insights into aging biology and potential therapeutic targets.

Background Cervical 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. Methods 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. Results 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%. Conclusions 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.

Background A 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. Results 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. Conclusions 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.