Abstract
Mammography is the gold standard for early breast cancer detection, but shows important limitations. Blood-based approaches on basis of cell-free DNA (cfDNA) provide minimally invasive screening tools to characterize epigenetic alterations of tumor suppressor genes and could serve as a liquid biopsy, complementing mammography. Potential biomarkers were identified from The Cancer Genome Atlas (TCGA), using HumanMethylation450-BeadChip data. Promoter methylation status was evaluated quantitatively by pyrosequencing in a serum test cohort (n = 103), a serum validation cohort (n = 368) and a plasma cohort (n = 125). SPAG6, NKX2-6 and PER1 were identified as novel biomarker candidates. ITIH5 was included on basis of our previous work. In the serum test cohort, a panel of SPAG6 and ITIH5 showed 63% sensitivity for DCIS and 51% sensitivity for early invasive tumor (pT1, pN0) detection at 80% specificity. The serum validation cohort revealed 50% sensitivity for DCIS detection on basis of NKX2-6 and ITIH5. Furthermore, an inverse correlation between methylation frequency and cfDNA concentration was uncovered. Therefore, markers were tested in a plasma cohort, achieving a 64% sensitivity for breast cancer detection using SPAG6, PER1 and ITIH5. Although liquid biopsy remains challenging, a combination of SPAG6, NKX2-6, ITIH5 and PER1 (SNiPER) provides a promising tool for blood-based breast cancer detection.
Highlights
Mammography is the gold standard for early breast cancer detection, but shows important limitations
Based on The Cancer Genome Atlas (TCGA) analysis and the defined criteria, we identified ten potential candidate genes of which SPAG6, PER1 and NKX2-6 proved suitable for early breast cancer detection after an initial validation in breast cancer cell lines and a small cryoconserved tissue cohort (Supplementary Figure 1)
ITIH5 was included on basis of previous promising data by our group [29]
Summary
Mammography is the gold standard for early breast cancer detection, but shows important limitations. The current gold standard for early breast cancer detection is mammography [4]. Mammography is able to detect small invasive breast tumors before they become palpable and is the most effective tool for detection of micro calcifications and DCIS [5]. Mammography causes personal discomfort, resulting in insufficient compliance rates [6, 7]. It has poor accuracy in women with dense breast tissue, causing a decrease in sensitivity from 70–91% to 30–48% [5, 6, 8,9,10], and is less sensitive for the detection of small or diffuse tumors [11]. We are in need of a minimally invasive tool to increase compliance and improve non-invasive screening
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