Molecular profiling of breast cancer methylation pattern in triple negative versus non- triple negative breast cancer

Abstract

Epigenetic alterations, especially promotor methylation, have a significant impact on gene expression, molecular subtyping, prognosis, and outcome of breast cancer (BC). The methylation profile was assessed for 22 genes of the BC tissue using the EpiTect Methyl II PCR System in 40 triple-negative BC (TNBC) patients compared to 50 non-TNBC group. The data were corelated with the disease-free (DFS) and overall survival (OS) of the patients. Genes that were differentially hypermethylated in TNBC patients compared to those with non-TNBC included CCND2, CDKN2A, ESR1, CDH1, BRCA1, GSTP, RASSF1, SLIT2, MGMT, PTEN, TP73, and PRDM2. These panel achieved 95% sensitivity, 98% specificity, 97.44% positive predictive value (PPV), 94.23% negative predictive value (NPV), and AUC of 0.993. Hypermethylation of BRCA1, CDH1, CDKN2A, ESR1, GSTP, HIC1, MGMT, PRDM2, PTEN, PYCARDM, RASSF1M, THBS1, and TP73 associated significantly with worse OS and DFS in TNBC cohort. Meanwhile, CCNA1 and CDH1 hypermethylation demonstrated significant associations with poor DFS but did not show significant relationships with OS in TNBC patients. PTGS2 and TNFRSF10C methylation were associated with better DFS and OS rates in TNBC patients. On multivariate Cox regression, CCND2 and PTEN hypermethylation were independent predictors of DFS in the overall BC patients. The hypermethylation of BRCA1 and GSTP were independent predictors of DFS, while PTEN hypermethylation was an independent predictor of OS in the TNBC cohort. The identification of hypermethylated genes, such as BRCA1, CCND2, CDH1, ESR1, GSTP, RASSF1, SLIT2, MGMT, and PTEN may serve as potential biomarkers or therapeutic targets for TNBC.