Researchers at the University of North Carolina at Chapel Hill have identified a particular gene expression pattern in normal-appearing breast tissue around tumors that was linked to lower 10-year survival rates for women with estrogen receptor-positive breast cancer.
[Photo: Dr. Melissa Troester]
Based on the finding, they believe they could use gene expression patterns – identified using genomic sequencing – in normal, adjacent tissue to predict survival for patients with that type of breast cancer. This is significant because, according to the National Cancer Institute, approximately 70 percent of breast cancers are estrogen receptor-positive.
Dr. Melissa Troester, associate professor of epidemiology at the UNC Gillings School of Global Public Health and member of UNC Lineberger Comprehensive Cancer Center, is first author of the study, “DNA defects, epigenetics, and gene expression in cancer-adjacent breast: a study from The Cancer Genome Atlas,” published online May 4 in npj Breast Cancer, a Nature Partner Journal.
“Most studies that have tried to develop predictive biomarkers for cancer progression have focused on tumor cells themselves,” Dr. Troester said. “This suggests that other factors in the micro-environment of the tumor may be important in predicting prognosis.”
The findings were drawn from what researchers say is the most comprehensive genetic and molecular analysis to-date of normal-appearing tissue surrounding breast cancer tumors. Advances in large-scale, faster sequencing of DNA and RNA made the study possible, they said.
Researchers analyzed multiple genomic characteristics of normal-appearing tissue, including DNA mutations, repeat copies of genes, DNA methylation and miRNA and gene expression patterns. The samples were drawn from The Cancer Genome Atlas, a multi-institution, collaborative effort backed by federal research dollars to map genomic and epigenomic alterations driving cancer.
Dr. Katherine Hoadley, professor of genetics in the UNC School of Medicine, UNC Lineberger member and study co-author, noted that normal tissues do not receive the same scientific attention as tumor samples. Their analysis allowed the researchers to determine whether normal-appearing tissues actually were normal at the molecular level. In many samples, Dr. Hoadley said, the researchers found evidence of tumor or tissue changes.
“It is interesting,” she said, “that no single genomic analysis consistently identified defects in the adjacent breast tissue, highlighting the difficulty in finding these alterations.”
Of the samples examined by multiple genomic methods, about 40 percent had some type of DNA or RNA defect in the normal tissue outside the tumor margin. Researchers believe that using genomic methods, they identified cancer cells or defective normal cells that were undetected using the microscope. However, the presence of cells with defects was not linked to better or worse survival for patients.
“Breast cancer researchers have recognized that breast-conserving therapy likely leaves behind tissue or cells that are either partially or fully transformed,” said Dr. Troester. “But these cells are targeted by therapy after surgery, keeping recurrence rates low for breast-conserving therapy.”
Dr. Troester said that this finding highlights the benefit of radiation therapy, which has been shown to lower recurrence rates for women who chose breast-conserving surgery. It also reaffirms studies that found no benefit to wider surgical margins during surgery, as the study found cells with genetic defects as far away as 4 centimeters from the tumor.
“This says it’s not sufficient only to excise the tumor with the wider margin – those mutations are still present at even farther distances from the tumor,” Dr. Troester said. “Radiotherapy and adjuvant chemotherapy are effective in eliminating cells with those DNA defects.”
The researchers also analyzed the gene expression patterns of the normal tissue outside tumor margins. Based on an analysis of mRNA and microRNA expression patterns, they found two different subtypes of tissue near the tumor. In women with estrogen receptor-positive cancer, one of the subtypes was linked to significantly lower 10-year survival rates.
“Gene expression subtypes of the surrounding tissue may reflect the composition and biological activity of the breast tissue in those patients,” Dr. Troester said. People with the subtype linked to the worse overall survival may have more fat in their tissue, or have higher cancer-driving signaling.
“This suggests that it may be possible to add information from the tumor micro-environment to standard clinical information to predict prognosis for patients,” Dr. Troester said.
The project was supported by funds from the National Institutes of Health (NIH). Individual researchers were supported by a National Institute for Environmental Health Sciences/National Cancer Institute Breast Cancer and the Environment Research Program grant, the NIH, NCI and the California Breast Cancer Research Program Translational Research Award.