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Researchers ID Copy Number Changes Associated With Cancer in Normal Cells

NEW YORK (GenomeWeb) – Researchers from Uppsala University in Sweden have identified copy number alterations typically associated with cancer in normal cells of breast cancer patients, suggesting that the mutations could be early indicators of disease. 

Reporting their work recently in Genome Research, the researchers aimed to look for markers that predict a risk for breast cancer in individuals without a hereditary risk. Approximately 10 percent of women in developed countries get non-familial breast cancer, also called sporadic breast cancer. The disease is heterogeneous and individuals differ in clinical manifestation, radiologic appearance, prognosis, and outcome. Yet, there are no good markers to predict a woman's risk for developing the disease.

Mammography is used to screen older women, yet it has a limited sensitivity and often only identifies disease once a tumor poses a significant mortality risk, the authors wrote.

In order to look for potential markers that could predict risk of disease at an earlier stage, the researchers studied 282 female sporadic breast cancer patients who underwent mastectomy. From each patient, they evaluated primary tumor tissue, several normal-looking tissue samples at various distances from the tumor, and normal blood or skin samples.

The team characterized all the samples via microarrays and three with low-coverage whole-genome sequencing. From 1,162 non-tumor breast tissue, 183 samples from 108 patients had at least one aberration. The researchers noted that the more sites they sampled from a patient, the more likely they were to find one containing an aberration, suggesting that the identified aberrations may represent only a part of all aberrations that might exist in the studied individuals.

Twenty-seven samples had highly aberrant genomes, affecting over 39 percent of the genomes. Alterations spanned large regions, even whole chromosomes, and there were differences between individual cells, suggesting heterogeneity.

Next, they stratified the remaining 157 tissue samples by mutation load. Because the goal was to identify the earliest markers of breast cancer, they first looked at the samples with a low mutation load.

Copy number gains were the most frequent alteration observed, suggesting that "oncogenic activation (up-regulation) of genes via increased copy number might be a pre-dominant mechanism for initiation of the SBC disease process," the authors wrote.

The authors confirmed that the genomic alterations identified in the normal breast tissue were also found in the primary tumor, with two exceptions. In one case, the team identified a deletion to a tumor suppressor gene that was not present in the tumor, and in another case, the researchers found eight alterations in the normal tissue, only four of which were in the primary tumor.

The most common event in samples with low mutational loads was a copy number gain of ERBB2, which was also the third most common event among all samples. The researchers also found this event in patients' epithelial and mesenchymal cells, demonstrating that "early predisposing genetic signatures are present in normal breast parenchyma as an expression of field cancerization and are not likely to be derived from migrating tumor cells," the authors wrote.

Recurrent gains to receptor genes were also found in EGFR, FGFR1, IGF1R, NGFR, and LIFR.

"Our analysis represents a snapshot picture of a progressive process that is likely going on for many years, if not decades," the authors wrote.

The findings raise important questions about tumor resection and point to a new method of early detection, although further validation studies are needed to determine their clinical significance.

For instance, tumor resection in breast cancer patients is a well-established standard of care; however, there is debate about how much tissue should be removed to ensure all cancer cells are taken. The authors reported that their study provides some evidence for altered cells "sometimes located at unexpected distances" from primary tumors. If those cells are left behind, they "may represent the source of local recurrence," the authors wrote.

In addition, if the findings are confirmed, they could point the way toward better and earlier diagnostics. For instance, in the future, researchers could potentially design imaging tests to detect the proteins located on the cell surface of breast cells that are encoded by cancer genes that have copy number gains.

"Such tests could detect an ongoing disease process much earlier (years, possibly even decades) compared to mammography," the authors wrote.