Background: Previously, we have examined the methylation status of SLC19A3 (solute carrier family 19, member 3) promoter and found that SLC19A3 was epigenetically down-regulated in gastric cancer. Here, we aim to develop a new biomarker for cancer diagnosis using methylated SLC19A3 DNA in plasma. Methods: SLC19A3 gene expression was examined by RT-qPCR. Methylation status of SLC19A3 promoter was evaluated by methylation-specific qPCR. A robust and simple methylation-sensitive restriction enzyme digestion and real-time quantitative PCR assay was developed to quantify SLC19A3 DNA methylation in plasma. Results: Expression of SLC19A3 was significantly down-regulated in 80% (12/15) of breast tumors (P < 0.005). Breast tumors had significant increase in methylation percentage when compared to adjacent non-tumor tissues (P < 0.05). A total of 155 independent plasma samples from participants including 60 breast cancer, 45 gastric cancer patients and 60 healthy subjects were analyzed. Plasma methylated SLC19A3 DNA yielded a ROC curve area of 77%, sensitivity of 82% and specificity of 60% in discriminating breast cancer from control subjects. This marker yielded a ROC curve area of 87%, sensitivity of 90.0% and specificity of 62% in discriminating gastric cancer from control subjects. Elevated level in plasma has been detected not only in advanced stages but also early stages of tumors. Intriguingly, of all DCIS cases from breast cancer patients this plasma marker generated a ROC value of 92%, sensitivity of 100% and specificity of 78% in discriminating DCIS cases from controls. Conclusions: These results suggested that aberrant SLC19A3 promoter hypermethylation in plasma may be a novel biomarker for early breast cancer diagnosis. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-01-02.
Background and Aims: Emerging evidence that microRNAs (miRNAs) play an important role in cancer development has opened up new opportunities for cancer diagnosis. Recent studies demonstrated that released exosomes which contain a subset of both cellular mRNA and miRNA could be a useful source of biomarkers for cancer detection. Here, we aim to develop a novel biomarker for breast cancer diagnosis using exosomal miRNAs in plasma. Methods: We have developed a rapid and novel isolation protocol to enrich tumor-associated exosomes from plasma samples by capturing tumor specific surface markers containing exosomes. After enrichment, we performed miRNA profiling on four sample sets; (1) Ep-CAM marker enriched plasma exosomes of breast cancer patients; (2) breast tumors of the same patients; (3) adjacent non-cancerous tissues of the same patients; (4) Ep-CAM marker enriched plasma exosomes of normal control subjects. Profiling is performed using PCR-based array with human microRNA panels that contain more than 700 miRNAs. Results: Our profiling data showed that 15 miRNAs are concordantly up-regulated and 13 miRNAs are concordantly down-regulated in both plasma exosomes and corresponding tumors. These account for ∼25% (up-regulation) and ∼15% (down-regulation) of all miRNAs detectable in plasma exosomes. Our findings demonstrate that miRNA profile in EpCAM-enriched plasma exosomes from breast cancer patients exhibit certain similar pattern to that in the corresponding tumors. Based on our profiling results, plasma signatures that differentiated breast cancer from control are generated and some of the well-known breast cancer related miRNAs such as miR-10b, miR-21, miR-155 and miR-145 are included in our panel list. The putative miRNA biomarkers are validated on plasma samples from an independent cohort from more than 100 cancer patients. Further validation of the selected markers is likely to offer an accurate, noninvasive and specific diagnostic assay for breast cancer. Conclusions: These results suggest that exosomal miRNAs in plasma may be a novel biomarker for breast cancer diagnosis. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-08-05.
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