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Normal Tissue Adjacent to Breast Tumors Also Exhibits Epigenetic Changes

NEW YORK (GenomeWeb) – Normal breast tissue of women with breast cancer harbors epigenetic changes that may be an indicator of disease susceptibility, according to a new study.

A University College London-led team of researchers analyzed nearly 670 breast tissue samples, including tumor and matched normal samples from women with breast cancer and samples from healthy women. As they reported in Nature Communications today, the normal breast tissue from women with cancer exhibited thousandsof epigenetic alterations similar to the changes in the matched tumor tissue. This signature, the team reported, was also linked to poorer prognosis and survivorship in breast cancer patients.

"These new data show how epigenetic alterations, if detected early enough, could be used to identify women at higher risk of developing breast cancer," first author Andrew Teschendorff, a UCL computational biologist, said in a statement. "Since epigenetic alterations are reversible, it offers the potential to design preventive strategies."

Teschendorff and his colleagues generated Illumina 450k DNA methylation data on a discovery set of 50 normal/benign samples from women without cancer, 42 matched normal-tumor samples, and a further 263 samples from women with breast cancer.

Rather than simply looking for differentially methylated regions, the researchers instead developed a feature selection algorithm called iEVORA that recognizes heterogeneity and differential variability, thus taking into consideration the stochastic and heterogeneity seen in normal cells at risk of transformation. Using that approach, they uncovered more than 7,300 differentially variable and differentially methylated CpGs (DVMC).

Most of these DVMCs were more variable and hypermethylated in the normal samples obtained from sites adjacent to breast cancers. Increased variance rather than an increase in the mean DNA methylation level is the main distinguishing feature of DVMCs, the researchers added.

The 42 normal samples from next to tumor samples showed marked differences in the overall number of epigenetic changes at hypervariable DVMC loci, the researchers reported. Only two samples showed changes at more than half the DVMC sites, and most DVMCs exhibited DNA methylation changes in only four or five of the normal-adjacent samples. This, the researchers noted, supports the notion that DNA methylation changes in the normal-adjacent tissue are mostly stochastic when viewed across unrelated individuals.

Teschendorff and his colleagues validated this finding of epigenetic changes in normal, but breast cancer-adjacent tissue in an independent set of normal breast tissue from women undergoing breast reduction surgery and normal samples collected from next to invasive breast cancers.

The adjacent tumors also harbored a number of these epigenetic changes, the researchers reported.

When they compared the DNA methylation levels of DVMCs within the 42 matched normal-tumor pairs, they found that DVMCs hypermethylated in the normal-adjacent tissue were also more highly methylated in the matched breast cancers. Up to a third of the hypervariable and hypermethylated DVMCs underwent further increases in DNA methylation in the tumors, while only about 2 percent underwent a reversal in DNA methylation.

In the tumors, however, these DNA methylation changes become more shared across cancers. This suggested to the researchers that although any two randomly chosen normal-adjacent samples may differ a bit in the loci with DNA methylation changes, any randomly chosen breast cancers would likely share more of those loci.

The researchers traced many of these epigenetic changes to transcription factors like EZH2 and SUZ12 that are important in to chromatin architecture. They further found that many of these epigenetic changes affected WNT and FGF signaling pathways, which have previously been linked to tumorigenesis.

Enrichment of these epigenetic changes was also linked with disease progression, tumor size, and outcomes. According to the researchers these alterations appear to mark pre-neoplastic normal cells that then transform and become enriched in cancer.

"We are working hard to understand the risk factors associated with epigenetic changes in normal breast tissue and how these predispose a woman to cancer," senior author Martin Widschwendter, the head of the women's cancer department at UCL, said in a statement. "The application of these altered epigenetic signatures holds the key developing new interventions that could 'switch off' this epigenetic defect and hold the key to preventing cancer development."