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.

• MeSH
• dospělí MeSH
• epigeneze genetická * MeSH
• epigenomika * metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace DNA * MeSH
• nádory prsu * genetika   diagnóza   MeSH
• studie případů a kontrol MeSH
• ústní sliznice metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

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

• Klíčová slova
• CDK4/6 blokátor, studie MONALEESA-1, studie MONARCH, CDK4/6 abemaciclib, multidisciplinární přístup,
• MeSH
• androstadieny MeSH
• chemorezistence MeSH
• farmakoterapie ekonomika   metody   trendy   MeSH
• hormonální protinádorové látky terapeutické užití   MeSH
• imunoterapie MeSH
• inhibitory aromatasy MeSH
• karcinom * farmakoterapie   terapie   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• metastázy nádorů farmakoterapie   terapie   MeSH
• nádory prsu * farmakoterapie   terapie   MeSH
• piperaziny MeSH
• přežití bez známek nemoci MeSH
• protinádorové látky terapeutické užití   MeSH
• pyridiny MeSH
• receptor erbB-2 MeSH
• sirolimus analogy a deriváty   MeSH
• výběr pacientů MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• rozhovory MeSH