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Promoter hypermethylation of the tumor-suppressor genes ITIH5, DKK3, and RASSF1A as novel biomarkers for blood-based breast cancer screening.

Kloten V, Becker B, Winner K, Schrauder MG, Fasching PA, Anzeneder T, Veeck J, Hartmann A, Knüchel R, Dahl E - Breast Cancer Res. (2013)

Bottom Line: Based on the test set, we determined ITIH5 and DKK3 promoter methylation as candidate biomarkers with the best sensitivity and specificity.In both the test and validation set combined, ITIH5 and DKK3 methylation achieved 41% sensitivity with a specificity of 93% and 100% in healthy and benign disease controls, respectively.Combination of these genes with RASSF1A methylation increased the sensitivity to 67% with a specificity of 69% and 82% in healthy controls and benign disease controls, respectively.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: For early detection of breast cancer, the development of robust blood-based biomarkers that accurately reflect the host tumor is mandatory. We investigated DNA methylation in circulating free DNA (cfDNA) from blood of breast cancer patients and matched controls to establish a biomarker panel potentially useful for early detection of breast cancer.

Methods: We examined promoter methylation of seven putative tumor-suppressor genes (SFRP1, SFRP2, SFRP5, ITIH5, WIF1, DKK3, and RASSF1A) in cfDNA extracted from serum. Clinical performance was first determined in a test set (n = 261 sera). In an independent validation set (n = 343 sera), we validated the most promising genes for further use in early breast cancer detection. Sera from 59 benign breast disease and 58 colon cancer patients were included for additional specificity testing.

Results: Based on the test set, we determined ITIH5 and DKK3 promoter methylation as candidate biomarkers with the best sensitivity and specificity. In both the test and validation set combined, ITIH5 and DKK3 methylation achieved 41% sensitivity with a specificity of 93% and 100% in healthy and benign disease controls, respectively. Combination of these genes with RASSF1A methylation increased the sensitivity to 67% with a specificity of 69% and 82% in healthy controls and benign disease controls, respectively.

Conclusions: Tumor-specific methylation of the three-gene panel (ITIH5, DKK3, and RASSF1A) might be a valuable biomarker for the early detection of breast cancer.

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Related in: MedlinePlus

ROC-curve analysis of the three-gene panel in control samples including age-matched healthy and benign disease controls. ROC curves were established for different biomarker combinations to determine a cutoff value. A cutoff value of 0.085% methylation was defined for positive detection of disease; the specificity of the panel increased to 80.5% with a sensitivity of 51.4%. ROC analysis revealed an area under the curve (AUC) of 0.712 (95% CI, 0.653 to 0.770).
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Figure 3: ROC-curve analysis of the three-gene panel in control samples including age-matched healthy and benign disease controls. ROC curves were established for different biomarker combinations to determine a cutoff value. A cutoff value of 0.085% methylation was defined for positive detection of disease; the specificity of the panel increased to 80.5% with a sensitivity of 51.4%. ROC analysis revealed an area under the curve (AUC) of 0.712 (95% CI, 0.653 to 0.770).

Mentions: Next, we performed ROC curve analysis for multiple marker combinations to determine both sensitivity and specificity in breast cancer and control samples and to calculate the optimal threshold value for the three-marker panel (Figure 3). According to this analysis, the three-marker panel can discriminate between breast cancer patients and women without breast cancer with a sensitivity of 67% and a specificity of 69% (AUC, 0.697 (95% CI, 0.634 to 0.759)). Additionally, the three-marker panel allowed distinguishing breast cancer patients from women with a benign breast disease with high specificity (82%; AUC, 0.765 (95% CI, 0.692 to 0.839)). The combination of healthy and benign controls revealed a specificity of the three-marker panel of 72% (AUC, 0.712 (95% CI, 0.653 to 0.770)). Combinations of different markers were examined to maximize specificity and sensitivity. The best combination remained with all three genes (Table 5). Defining a cut-off value for the three-gene panel of 0.085% for positive detection of methylation (and thus disease), the panel distinguished between breast cancer and both healthy and benign controls with a sensitivity of 51.4% and a specificity of 80.5%.


Promoter hypermethylation of the tumor-suppressor genes ITIH5, DKK3, and RASSF1A as novel biomarkers for blood-based breast cancer screening.

Kloten V, Becker B, Winner K, Schrauder MG, Fasching PA, Anzeneder T, Veeck J, Hartmann A, Knüchel R, Dahl E - Breast Cancer Res. (2013)

ROC-curve analysis of the three-gene panel in control samples including age-matched healthy and benign disease controls. ROC curves were established for different biomarker combinations to determine a cutoff value. A cutoff value of 0.085% methylation was defined for positive detection of disease; the specificity of the panel increased to 80.5% with a sensitivity of 51.4%. ROC analysis revealed an area under the curve (AUC) of 0.712 (95% CI, 0.653 to 0.770).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672828&req=5

Figure 3: ROC-curve analysis of the three-gene panel in control samples including age-matched healthy and benign disease controls. ROC curves were established for different biomarker combinations to determine a cutoff value. A cutoff value of 0.085% methylation was defined for positive detection of disease; the specificity of the panel increased to 80.5% with a sensitivity of 51.4%. ROC analysis revealed an area under the curve (AUC) of 0.712 (95% CI, 0.653 to 0.770).
Mentions: Next, we performed ROC curve analysis for multiple marker combinations to determine both sensitivity and specificity in breast cancer and control samples and to calculate the optimal threshold value for the three-marker panel (Figure 3). According to this analysis, the three-marker panel can discriminate between breast cancer patients and women without breast cancer with a sensitivity of 67% and a specificity of 69% (AUC, 0.697 (95% CI, 0.634 to 0.759)). Additionally, the three-marker panel allowed distinguishing breast cancer patients from women with a benign breast disease with high specificity (82%; AUC, 0.765 (95% CI, 0.692 to 0.839)). The combination of healthy and benign controls revealed a specificity of the three-marker panel of 72% (AUC, 0.712 (95% CI, 0.653 to 0.770)). Combinations of different markers were examined to maximize specificity and sensitivity. The best combination remained with all three genes (Table 5). Defining a cut-off value for the three-gene panel of 0.085% for positive detection of methylation (and thus disease), the panel distinguished between breast cancer and both healthy and benign controls with a sensitivity of 51.4% and a specificity of 80.5%.

Bottom Line: Based on the test set, we determined ITIH5 and DKK3 promoter methylation as candidate biomarkers with the best sensitivity and specificity.In both the test and validation set combined, ITIH5 and DKK3 methylation achieved 41% sensitivity with a specificity of 93% and 100% in healthy and benign disease controls, respectively.Combination of these genes with RASSF1A methylation increased the sensitivity to 67% with a specificity of 69% and 82% in healthy controls and benign disease controls, respectively.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: For early detection of breast cancer, the development of robust blood-based biomarkers that accurately reflect the host tumor is mandatory. We investigated DNA methylation in circulating free DNA (cfDNA) from blood of breast cancer patients and matched controls to establish a biomarker panel potentially useful for early detection of breast cancer.

Methods: We examined promoter methylation of seven putative tumor-suppressor genes (SFRP1, SFRP2, SFRP5, ITIH5, WIF1, DKK3, and RASSF1A) in cfDNA extracted from serum. Clinical performance was first determined in a test set (n = 261 sera). In an independent validation set (n = 343 sera), we validated the most promising genes for further use in early breast cancer detection. Sera from 59 benign breast disease and 58 colon cancer patients were included for additional specificity testing.

Results: Based on the test set, we determined ITIH5 and DKK3 promoter methylation as candidate biomarkers with the best sensitivity and specificity. In both the test and validation set combined, ITIH5 and DKK3 methylation achieved 41% sensitivity with a specificity of 93% and 100% in healthy and benign disease controls, respectively. Combination of these genes with RASSF1A methylation increased the sensitivity to 67% with a specificity of 69% and 82% in healthy controls and benign disease controls, respectively.

Conclusions: Tumor-specific methylation of the three-gene panel (ITIH5, DKK3, and RASSF1A) might be a valuable biomarker for the early detection of breast cancer.

Show MeSH
Related in: MedlinePlus