To 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 WIDTM-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 WIDTM-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 WIDTM-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.
- Publikační typ
- časopisecké články MeSH
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.
- MeSH
- cervix uteri cytologie metabolismus MeSH
- CpG ostrůvky MeSH
- epigenom MeSH
- epigenomika metody MeSH
- epitelové buňky metabolismus MeSH
- lidé MeSH
- metylace DNA * MeSH
- mutace MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nádory prsu genetika metabolismus MeSH
- prognóza MeSH
- prsy cytologie metabolismus MeSH
- ROC křivka MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- práce podpořená grantem MeSH
BACKGROUND: Personal cancer risk assessments enable stratified care, for example, offering preventive surgical measures such as risk-reducing mastectomy (RRM) to women at high risk for breast cancer. In scenario-based experiments, we investigated whether different benefit-harm ratios of RRM influence women's consideration of this, whether this consideration is influenced by women's perception of and desire to know their personal cancer risk, or by their intention to take a novel cancer risk-predictive test, and whether consideration varies across different countries. METHOD: In January 2017, 1,675 women 40 to 75 years of age from five European countries-Czech Republic, Germany, UK, Italy, and Sweden-took part in an online scenario-based experiment. Six different scenarios of hypothetical benefit-harm ratios of RRM were presented in accessible fact box formats: Baseline risk/risk reduction pairings were 20/16, 20/4, 10/8, 10/2, 5/4, and 5/1 out of 1,000 women dying from breast cancer. RESULTS: Varying the baseline risk of dying from breast cancer and the extent of risk reduction influenced the decision to consider RRM for 23% of women. Decisions varied by country, risk perception, and the intention to take a cancer risk-predictive test. Women who expressed a stronger intention to take such a test were more likely to consider having RRM. The desire to know one's risk of developing any female cancer in general moderated women's decisions, whereas the specific desire to know the risk of breast cancer did not. CONCLUSIONS: In this hypothetical scenario-based study, only for a minority of women did the change in benefit-harm ratio inform their consideration of RRM. Because this consideration is influenced by risk perception and the intention to learn one's cancer risks via a cancer risk-predictive test, careful disclosure of different potential preventive measures and their benefit-harm ratios is necessary before testing for individual risk. Furthermore, information on risk testing should acknowledge country-specific sensitivities for benefit-harm ratios.
- MeSH
- chování snižující riziko MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mastektomie psychologie MeSH
- nádory prsu genetika patologie psychologie chirurgie MeSH
- prognóza MeSH
- průzkumy a dotazníky MeSH
- riziko MeSH
- rozhodování * MeSH
- senioři MeSH
- úmysl * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
- Itálie MeSH
- Německo MeSH
- Spojené království MeSH
- Švédsko MeSH
The incidence of cancer is continuing to rise and risk-tailored early diagnostic and/or primary prevention strategies are urgently required. The ideal risk-predictive test should: integrate the effects of both genetic and nongenetic factors and aim to capture these effects using an approach that is both biologically stable and technically reproducible; derive a score from easily accessible biological samples that acts as a surrogate for the organ in question; and enable the effectiveness of risk-reducing measures to be monitored. Substantial evidence has accumulated suggesting that the epigenome and, in particular, DNA methylation-based tests meet all of these requirements. However, the development and implementation of DNA methylation-based risk-prediction tests poses considerable challenges. In particular, the cell type specificity of DNA methylation and the extensive cellular heterogeneity of the easily accessible surrogate cells that might contain information relevant to less accessible tissues necessitates the use of novel methods in order to account for these confounding issues. Furthermore, the engagement of the scientific community with health-care professionals, policymakers and the public is required in order to identify and address the organizational, ethical, legal, social and economic challenges associated with the routine use of epigenetic testing.
- MeSH
- epigenomika trendy MeSH
- genom lidský genetika MeSH
- hodnocení rizik * MeSH
- lidé MeSH
- metylace DNA genetika MeSH
- nádory epidemiologie genetika MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
