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Detection of hypermethylated circulating serum DNA in metastatic breast cancer and confirmation by the cMethDNA assay

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, discovered through whole genome methylation array analysis of serum DNA. Cancer-specific methylated DNA was detected in training and test sets of recurrent Stage 4 patient sera with a sensitivity of >90% and a specificity of >96%. A core methylation signature was retained in serum, primary and metastatic tissues throughout the course of the disease, and the cMethDNA assay levels reflected patient response to chemotherapy. Together, our data suggest that the cMethDNA assay can provide a sensitive tool to detect minute levels of tumor DNA present in a vast excess of normal DNA in serum.

ORGANISM(S): Homo sapiens

PROVIDER: GSE52621 | GEO | 2014/03/01

SECONDARY ACCESSION(S): PRJNA229490

REPOSITORIES: GEO

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Project description:Abstract Background: Promoter hypermethylation coupled with loss of heterozygosity at the same locus results in loss of gene function in many tumor cells. The “rules” governing which genes are methylated during the pathogenesis of individual cancers, how specific methylation profiles are initially established, or what determines tumor-type specific methylation are unknown. However, DNA methylation markers that are highly specific and sensitive for common tumors would be useful for the early detection of cancer, and those required for the malignant phenotype identify pathways important as therapeutic targets. Methods and Findings: In an effort to identify new cancer-specific methylation markers, we employed a high throughput global expression profiling approach in lung cancer cells. We identified 132 genes that have 5’ CpG islands, are induced from undetectable levels by 5-aza-2’-deoxycytidine (5-aza) in multiple non-small cell lung cancer cell lines, and are expressed in immortalized human bronchial epithelial cells. As expected, these genes were also expressed in normal lung, but often not in companion primary lung cancers. Methylation analysis of a subset (45/132) of these promoter regions in primary lung cancer (N=20) and adjacent non-malignant tissue showed that 31 genes had acquired methylation in the tumors, but did not show methylation in normal lung or lymphocytes. We studied the eight most frequently and specifically methylated genes from our lung cancer data set in breast cancer (N=37), colon cancer (N=24), and prostate cancer (N=24) along with counterpart non-malignant tissues. We found that seven loci were frequently methylated in both breast and lung cancers, with four showing extensive methylation in all four epithelial tumors. Conclusions: By using a systematic biological screen we identified multiple genes that are methylated with high penetrance in primary lung, breast, colon, and prostate cancers. The cross-tumor methylation pattern we observed for these novel markers suggests that we have identified a partial promoter hypermethylation signature for these common malignancies. These data suggest that while tumors in different tissues vary substantially with respect to gene expression, there may be commonalities in their promoter methylation profiles that represent potential targets for early detection screening or therapeutic intervention. Keywords: Cell line comparison

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Detection of hypermethylated circulating serum DNA in metastatic breast cancer and confirmation by the cMethDNA assay

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