Background: DKK3 and SOX17, antagonists of Wnt/β-catenin pathway, function as tumor suppressor genes. Promoter methylation of DKK3 and SOX17 genes has been shown in many cancers. Several epigenetic alterations as DNA methylation are reported to be associated with the risk of breast cancer in relatives of breast cancer patients.
Objective: This study aimed to explore the relationships between DKK3 and SOX17 gene methylation with family history and clinicopathological characters of breast cancer.
Subjects and Methods: A total of 90 females were selected, 30 with breast cancer, 60 age-matched
cancer-free subjects; 30 with (high risk group) and 30 without (control group) family history of breast cancer. Sybr green-based quantitative methylation-specific PCR was used for the determination of DKK3 and SOX17 methylation levels.
Results: Significant variations were observed within DKK3 and SOX17 methylation percentage between the breast cancer, high risk and control groups (p<0.001, p=0.002, respectively). Interestingly, SOX17 methylation was not related to any of tumor characteristics or family history of breast cancer, however, SOX17 methylation percentage had a positive correlation with the BMI(r=0.28, p=0.045) and a negative correlation with the age at diagnosis (r = -0.28, p=0.019). DKK3 methylation percentage was significantly higher in patients with postmenopausal state or negative progesterone receptor immunostaining (p=0.046, p=0.024, respectively). Through linear regression analysis, DKK3 methylation was associated with lymph node grade and negative progesterone receptor. Receiver operating characteristic curve analysis showed that DKK3 methylation had 61.7% specificity and 83.3% sensitivity at cutoff 68.8 % and area under the curve 0.803 (p<0.001, 95% CI=0.703 - 0.903), while, SOX17 methylation had the same sensitivity as DKK3, but higher specificity 76.6% at cutoff point 93.6% with area under curve 0.803 (p<0.001,95% CI =0.738 -0.925). Conclusion: DKK3 methylation shows a higher family history of breast cancer than SOX17 methylation. SOX17 methylation at a higher methylation percentage has better sensitivity for the diagnosis of breast cancer. These data suggest that methylation of the Wnt pathway antagonist may be associated with family history and clinicopathological characters of breast cancer. Analysis of DKK3 and SOX17 methylation in the breast tissue of females at risk of breast cancer could provide more information about relationships with risk factors of breast cancer. .