Researchers from the University of British Columbia (UBC), BC Cancer, Harvard Medical School, and Memorial Sloan Kettering Cancer Center (MSK) have discovered potential early genetic indicators of breast cancer—mutations resembling cancerous changes found in the cells of healthy women.
In a groundbreaking study published today in Nature Genetics, the international team analyzed the genomes of over 48,000 individual breast cells from women without cancer, employing innovative techniques to decode the genes of single cells. While most cells appeared normal, nearly all women studied exhibited a small fraction—approximately 3 percent—of breast cells with genetic alterations typically associated with cancer.
“It’s striking to see cancer-like mutations occurring silently and at low levels in the cells of perfectly healthy women,” said Dr. Samuel Aparicio, the lead senior author and a professor of pathology and laboratory medicine at UBC. “While these mutations are harmless on their own, they could serve as foundational elements in the progression toward breast cancer. Further research into the origins and accumulation of these mutations may lead to new preventive strategies, therapeutic approaches, and methods for early detection.”
The identified mutations, known as copy number alterations, involve the duplication or loss of large segments of DNA. Typically, the body’s natural DNA repair mechanisms correct these changes. However, if these mechanisms fail, the mutations can accumulate over time, potentially leading to cancer.
To assess the prevalence of copy number alterations in normal tissue, researchers examined tens of thousands of breast cells from 28 women using a cutting-edge single-cell gene sequencing technology called DLP+, developed by UBC and BC Cancer.
While genetic alterations were found at very low levels across most participants, they were specifically detected in luminal cells, which line the lobules and ducts of the breast, rather than in related contractile cells.
“Since luminal cells are believed to be the origin of all major types of breast cancer, the accumulation of these genetic alterations in luminal cells supports the hypothesis that they may predispose these cells to cancer development,” noted Dr. Joan Brugge, co-senior author and professor of cell biology at Harvard Medical School. “This study is a crucial step in our ongoing efforts to understand the earliest events in breast cancer development and could inform strategies for prevention and monitoring in high-risk populations.”
Most of the mutated cells contained only one or two copy number alterations, while cancer formation typically requires multiple mutations. However, in women with high-risk genetic variants of BRCA1 and BRCA2, researchers observed some cells exhibiting six or more significant genetic changes. These extreme cases may indicate a further progression in the cancer development process, suggesting a potential pathway from normal to cancer-like cells in high-risk individuals.
“To investigate this phenomenon, we utilized a method originally designed to study genome instability in cancer, allowing for a comprehensive view of copy number alterations at the single-cell level,” explained Dr. Sohrab Shah, the Nicholls-Biondi Chair in Computational Oncology and Chief of Computational Oncology at MSK. “Our computational techniques enabled us to identify and analyze these rare events that standard sequencing methods might miss.”
The study raises important questions about breast cancer development, including the mechanisms behind mutation accumulation, the timescales involved, and the specific occurrence of mutations in luminal cells. It also suggests that investigating copy number alterations in other tissues could provide insights into the development and progression of various cancers and their associated risk factors.
“Addressing these questions could enhance our understanding of cancer risk and improve detection and management strategies for individuals at high risk,” Dr. Aparicio added.
The study’s first authors include Vinci Au, who led the single-cell genome sequencing in the Aparicio Lab; Dr. Michael Oliphant, who oversaw cell isolation in the Brugge Lab; and Dr. Marc Williams, who conducted computational genome analysis in the Shah Lab.
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