Abstract
Background: DNA methylation is a common event in the early development of various tumors, including breast cancer (BRCA), which has been studies as potential tumor biomarkers. Although previous studies have reported a cluster of aberrant promoter methylation changes in BRCA, none of these research groups have proved the specificity of these DNA methylation changes. Here we aimed to identify specific DNA methylation signatures in BRCA which can be used as diagnostic and prognostic markers.Methods: Differentially methylated sites were identified using the Cancer Genome Atlas (TCGA) BRCA data set. We screened for BRCA-differential methylation by comparing methylation profiles of BRCA patients, healthy breast biopsies and blood samples. These differential methylated sites were compared to nine main cancer samples to identify BRCA specific methylated sites. A BayesNet model was built to distinguish BRCA patients from healthy donors. The model was validated using three Gene Expression Omnibus (GEO) independent data sets. In addition, we also carried out the Cox regression analysis to identify DNA methylation markers which are significantly related to the overall survival (OS) rate of BRCA patients and verified them in the validation cohort.Results: We identified seven differentially methylated sites (DMSs) that were highly correlated with cell cycle as potential specific diagnostic biomarkers for BRCA patients. The combination of 7 DMSs achieved ~94% sensitivity in predicting BRCA, ~95% specificity comparing healthy vs. cancer samples, and ~88% specificity in excluding other cancers. The 7 DMSs were highly correlated with cell cycle. We also identified 6 methylation sites that are highly correlated with the OS of BRCA patients and can be used to accurately predict the survival of BRCA patients (training cohort: likelihood ratio = 70.25, p = 3.633 × 10−13, area under the curve (AUC) = 0.784; validation cohort: AUC = 0.734). Stratification analysis by age, clinical stage, Tumor types, and chemotherapy retained statistical significance.Conclusion: In summary, our study demonstrated the role of methylation profiles in the diagnosis and prognosis of BRCA. This signature is superior to currently published methylation markers for diagnosis and prognosis for BRCA patients. It can be used as promising biomarkers for early diagnosis and prognosis of BRCA.
Highlights
Breast cancer (BRCA) is currently the most common malignant cancer in women (Bray et al, 2018)
DNA methylation of 790 breast cancer (BRCA) tumor samples and 98 adjacent normal tissue samples obtained from Cancer Genome Atlas (TCGA) were used for differential methylation analysis
Pearson correlation test was performed on these differentially methylated site (DMS) to find the DMSs that can drive gene expression (| r |> 0.3, p < 0.05) (Supplementary Table 6)
Summary
Breast cancer (BRCA) is currently the most common malignant cancer in women (Bray et al, 2018). Detection of BRCA can significantly increase the chance of effective treatment and has a very important role in improving survival. Early detection of BRCA can increase the chance of effective treatment and has a very important role in improving survival. BSP (sensitivity 88.9%, specificity 96.1%) and OPN (sensitivity 95.0%, specificity 84.5%) can achieve a high accuracy rate for the diagnosis of breast cancer. Their diagnostic threshold is very close to other tumors. It is very important to find specific diagnostic markers for breast cancer. DNA methylation is a common event in the early development of various tumors, including breast cancer (BRCA), which has been studies as potential tumor biomarkers. We aimed to identify specific DNA methylation signatures in BRCA which can be used as diagnostic and prognostic markers
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