Novel methylated biomarkers and a robust assay to detect circulating tumor dna in metastatic breast cancer Journal Article
| Authors: | Fackler, M. J.; Bujanda, Z. L.; Umbricht, C.; Teo, W. W.; Cho, S.; Zhang, Z.; Visvanathan, K.; Jeter, S.; Argani, P.; Wang, C.; Lyman, J. P.; De Brot, M.; Ingle, J. N.; Boughey, J.; Mcguire, K.; King, T. A.; Carey, L. A.; Cope, L.; Wolff, A. C.; Sukumar, S. |
| Article Title: | Novel methylated biomarkers and a robust assay to detect circulating tumor dna in metastatic breast cancer |
| Abstract: | The ability to consistently detect cell-free tumor-specific DNA in peripheral blood of patients with metastatic breast cancer provides the opportunity to detect changes in tumor burden and to monitor response to treatment. We developed cMethDNA, a quantitative multiplexed methylation-specific PCR assay for a panel of ten genes, consisting of novel and known breast cancer hypermethylated markers identified by mining our previously reported study of DNA methylation patterns in breast tissue (103 cancer, 21 normal on the Illumina Human- Methylation27 Beadchip) and then validating the 10-gene panel in The Cancer Genome Atlas project breast cancer methylome database. For cMethDNA, a fixed physiologic level (50 copies) of artificially constructed, standard nonhuman reference DNA specific for each gene is introduced in a constant volume of serum (300 mL) before purification of the DNA, facilitating a sensitive, specific, robust, and quantitative assay of tumor DNA, with broad dynamic range. Cancer-specific methylated DNA was detected in training (28 normal, 24 cancer) and test (27 normal, 33 cancer) sets of recurrent stage IV patient sera with a sensitivity of 91% and a specificity of 96% in the test set. In a pilot study, cMethDNA assay faithfully reflected patient response to chemotherapy (N = 29). A core methylation signature present in the primary breast cancer was retained in serum and metastatic tissues collected at autopsy two to 11 years after diagnosis of the disease. Together, our data suggest that the cMethDNA assay can detect advanced breast cancer, and monitor tumor burden and treatment response in women with metastatic breast cancer. © 2014 American Association for Cancer Research. |
| Keywords: | adult; cancer chemotherapy; controlled study; human tissue; treatment response; aged; case report; advanced cancer; sensitivity and specificity; reproducibility; breast cancer; tumor volume; tumor biopsy; dna methylation; prediction; distant metastasis; genome analysis; dna; pilot study; autopsy; breast metastasis; tumor gene; dna extraction; marker gene; clinical trial (topic); multiplex polymerase chain reaction; human; female; priority journal; article |
| Journal Title: | Cancer Research |
| Volume: | 74 |
| Issue: | 8 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2014-04-15 |
| Start Page: | 2160 |
| End Page: | 2170 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-13-3392 |
| PROVIDER: | scopus |
| PUBMED: | 24737128 |
| PMCID: | PMC4327879 |
| DOI/URL: | |
| Notes: | Cancer Res. -- Export Date: 2 June 2014 -- CODEN: CNREA -- Source: Scopus |
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