Abstract
Background: Breast cancer (BrC) is the most frequent neoplasm in women. New biomarkers, including aberrant DNA methylation, may improve BrC management. Herein, we evaluated the detection and prognostic performance of seven genes’ promoter methylation (APC, BRCA1, CCND2, FOXA1, PSAT1, RASSF1A and SCGB3A1). Methods: Methylation levels were assessed in primary BrC tissues by quantitative methylation-specific polymerase chain reaction (QMSP) and in circulating cell-free DNA (ccfDNA) by multiplex QMSP from two independent cohorts of patients (Cohort #1, n = 137; and Cohort #2, n = 44). Receiver operating characteristic (ROC) curves were constructed, and log-rank test and Cox regression were performed to assess the prognostic value of genes’ methylation levels. Results: The gene-panel APC, FOXA1, RASSF1A, SCGB3A1 discriminated normal from cancerous tissue with high accuracy (95.55%). In multivariable analysis, high PSAT1-methylation levels [>percentile 75 (P75)] associated with longer disease-free survival, whereas higher FOXA1-methylation levels (>P75) associated with shorter disease-specific survival. The best performing panel in ccfDNA (APC, FOXA1 and RASSF1A) disclosed a sensitivity, specificity and accuracy over 70%. Conclusions: This approach enables BrC accurate diagnosis and prognostic stratification in tissue samples, and allows for early detection in liquid biopsies, thus suggesting a putative value for patient management.
Highlights
Breast cancer (BrC) is the most common and lethal cancer in women worldwide, corresponding to 25% of all cancers in females [1]
To assess cancer-specificity, promoters’ methylation levels of Adenomatosis polyposis coli (APC), BRCA1, Cyclin D2 (CCND2), Fork-head box A1 (FOXA1), Phosphoserine Aminotransferase 1 (PSAT1), Ras association domain family 1 isoform A (RASSF1A) and Secretoglobin family 3A member 1 (SCGB3A1) were evaluated in Cohort #1 (BrC and normal breast tissue (NBr) tissue samples)
BrC samples displayed higher APC, CCND2, FOXA1, PSAT1, RASSF1A, and SCGB3A1 methylation levels than NrB samples (p < 0.001 for all genes, Supplementary File 1—Table S5), whereas no differences were found for BRCA1, which was not further tested (Supplementary File 1—Table S5)
Summary
Breast cancer (BrC) is the most common and lethal cancer in women worldwide, corresponding to 25% of all cancers in females [1]. Implementation of mammography-based BrC screening increase the proportion of cancers detected at an early-stage, contributing to a decrease in BrC-related mortality [2]. This screening strategy is hampered by frequent false positive results, leading to overdiagnosis. Despite all improvements in early detection, patients’ stratification and treatment, BrC remains the foremost cause of cancer-related mortality among women, mostly due to disease recurrence and/or metastasis development [1]. Conclusions: This approach enables BrC accurate diagnosis and prognostic stratification in tissue samples, and allows for early detection in liquid biopsies, suggesting a putative value for patient management
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