Researchers study how epigenetic alterations contribute to age-related increases in breast cancer risk

Age is a key risk factor for breast cancer. A recent study by researchers from the Dartmouth-Hitchcock Norris Cotton Cancer Center (NCCC), "Age-related DNA methylation in normal breast tissue and its relationship with invasive breast tumor methylation," examines the connection between cancer and the aging process to see if epigenetic DNA alterations might contribute to age-related increases in breast cancer risk. (Epigenetics is the study of changes in gene function such as gene expression or gene expression potential - heritable changes passed during cell division - that occur without changes in DNA sequence.) The study is available online and will appear in the February 2014 issue of Epigenetics.

"In this work we are trying to gain a clearer understanding of the relationship between aging and epigenetic changes in cancer-free breast tissue," said Brock C. Christensen, PhD, assistant professor of Community and Family Medicine and of Pharmacology and Toxicology at Geisel and a researcher at the Norris Cotton Cancer Center. "This will help focus our search for early age-related molecular events that may contribute to increased risk of developing breast cancer."

The NCCC researchers analyzed publicly available genome-wide DNA methylation data from disease-free breast tissues and identified consistent methylation alterations associated with aging across multiple groups of subjects. (DNA methylation is an epigenetic mark that can occur on cytosine residues that are followed by guanine, also known as CpG dinucleotides, and contribute to regulation of gene expression.) They then compared levels of methylation in normal tissues to breast tumor tissues and confirmed that age-related changes present in normal breast tissues were present and more prominently altered in breast tumors. The NCCC study suggests that there may be common genomic regions that are particularly susceptible to age-related changes in DNA methylation over time in disease-free breast tissue and contribute to development of cancer.

"Our approach here is somewhat distinct from conventional cancer epigenome-wide studies in that we are focused first on characterizing age-related patterns of DNA methylation in disease-free tissue rather than tumors," said Christensen. "The profound changes in DNA methylation observed in breast tumors compared with disease-free breasts make it difficult to determine which DNA methylation alterations occur early in carcinogenesis. We think that our approach is one way to step toward identifying early molecular changes that truly contribute to tumor formation."

The NCCC researchers are currently working on a larger study of DNA methylation in cancer-free breast tissues where they hope to more completely characterize age-related methylation in normal breast tissue. They will also assess whether other important breast cancer risk modifiers (such as family history of disease and reproductive history) are related to DNA methylation patterns in normal breast tissue.