Cancer-Causing Mutations Found in Healthy Breast Tissue

In a recent study, a global team used cutting-edge methods for decoding single-cell genes to examine the genomes of almost 48,000 individual breast cells from cancer-free women. Nearly all of the women had a small percentage of breast cells, roughly 3%, that possessed genetic changes frequently linked to cancer, even though the great majority of cells seemed normal.

According to the research, which was published in Nature Genetics, these uncommon genetic abnormalities might be among the first stages of a chain of events that could lead to the development of breast cancer.

It is striking to see cancer-like mutations happening silently and at low levels in the cells of perfectly healthy women. While harmless on their own, these changes could be the basic building blocks of breast cancer. With further research into how these mutations arise and accumulate, we could potentially develop new and lifesaving preventive strategies, therapeutic approaches, and routes for early detection.”

Dr. Samuel Aparicio, Professor and Study Lead Senior Author, University of British Columbia

Aparicio is also a distinguished scientist at BC Cancer and Canada Research Chair in Molecular Oncology.

Large DNA regions are lost or duplicated in the mutations, which are referred to as copy number changes. Usually, these alterations are fixed by the body's own DNA repair systems. However, the mutations may build up and eventually cause cancer if the body is unable to recognize these alterations or start the healing process.

The study's goal was to determine how common copy number changes are in healthy tissue. To this end, it used DLP+, a cutting-edge single-cell gene sequencing method created by experts from UBC and BC Cancer, to analyze tens of thousands of breast cells from 28 women.

Although the majority of the women in the study had very slight genetic changes, these changes were only found in the luminal cells lining the lobules and ducts where milk passes through the breast, not in the associated contractile cells.

Since luminal cells are believed to be the cells of origin of all of the major types of breast cancer, the fact that these genetic alterations specifically accumulate in luminal cells provides additional support for the hypothesis that these alterations may prime or predispose these cells to cancer development.”

Dr. Joan Brugge, Professor and Study Co-Senior Author, Harvard Medical School, University of British Columbia

Joan Brugge said, “This study is an important step in our collective quest as scientists to understand the earliest events in breast cancer development. These insights can inform our efforts to design new, more effective prevention and monitoring strategies for those at high risk for cancer.”

Since it is well known that several mutations are needed to develop into cancer, most altered cells only had one or two copy number changes. However, the researchers found a few “extreme” instances of cells containing six or more of these significant genetic alterations in some women with high-risk genetic variations of BRCA1 and BRCA2.

These extreme cells might indicate a possible transition pathway from normal cells to cancer-like cells in high-risk individuals, marking a step farther in the formation of cancer.

To study this phenomenon, we used a method originally developed to study genome instability in cancer, providing a comprehensive view of copy number alterations at the single-cell level. Our computational approaches further allowed us to identify and analyze these rare events that are not visible with standard sequencing assays.”

Dr. Sohrab Shah, Nicholls-Biondi Chair, Computational Oncology and Chief of Computational Oncology, Memorial Sloan Kettering Cancer Center

The finding, according to the researchers, presents significant new concerns regarding the nature of breast cancer development, such as how and over what timescale mutations accumulate and why they exclusively arise in luminal cells.

Additionally, it implies that studying copy number changes in other organs may provide insight into the genesis, progression, and risk factors of other types of cancer.

“Answering these questions could help further our understanding of cancer risk and how to better detect and manage cancer in people at high risk,” said Dr. Aparicio.