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A collaborative study by researchers from the University of British Columbia (UBC), BC Cancer, Harvard Medical School, and Memorial Sloan Kettering Cancer Center (MSK) has identified genetic mutations in normal breast cells that may represent early steps in breast cancer development. Published in Nature Genetics, the findings highlight the potential significance of cancer-associated mutations detected in healthy women.
Pinpointing Genetic Alterations in Normal Breast Cells
The study analyzed over 48,000 individual breast cells from women without cancer using single-cell sequencing technology. Researchers identified a small subset—approximately 3%—of luminal breast cells that harbored mutations known as copy number alterations (CNAs). These changes involve the duplication or loss of large DNA segments and are commonly associated with cancer.
"These changes could be the basic building blocks of breast cancer," said Samuel Aparicio, a professor of pathology and molecular oncology at UBC and BC Cancer. “With further research into how these mutations arise and accumulate, we could potentially develop new preventive strategies, therapeutic approaches, and routes for early detection.”
The study focused on CNAs in breast tissue, revealing their presence exclusively in luminal cells. These cells, which line the ducts and lobules of the breast, are thought to be the origin of most major types of breast cancer. Mutations were not found in the contractile cells associated with these tissues, emphasizing the luminal cells' unique vulnerability.
Advanced Techniques Reveal Rare Mutations
The team employed DLP+, an advanced single-cell sequencing technique developed at UBC and BC Cancer, to analyze breast cells from 28 women. This method provides high-resolution insights into genomic instability, enabling the detection of rare mutations that standard sequencing methods might overlook.
“Our computational approaches further allowed us to identify and analyze these rare events that are not visible with standard sequencing assays,” said Sohrab Shah, Chief of Computational Oncology at MSK. This technique provides a comprehensive view of copy number alterations and helps trace the potential progression of normal cells toward cancer-like states.
The majority of mutated cells carried only one or two CNAs. However, in women with high-risk genetic variants such as BRCA1 or BRCA2, researchers observed some cells with six or more CNAs. These "extreme" cases may represent advanced steps in a pathway leading from normal to cancerous cells, particularly in individuals with a predisposition to breast cancer.
Implications for Cancer Research and Prevention
While the body’s DNA repair mechanisms typically correct CNAs, their accumulation in luminal cells raises questions about the timescale and triggers for these mutations. According to Joan Brugge, a professor of cell biology at Harvard Medical School, “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.” The research also points to broader applications for studying CNAs in other tissues. Investigating similar mutations across organs may provide insights into the mechanisms underlying various cancer types.
Next Steps in Understanding Cancer Risk
The study highlights the importance of exploring how genetic mutations develop in luminal cells and the factors contributing to cancer risk. Researchers believe these findings could lead to improved monitoring and prevention strategies, especially for individuals at higher risk due to genetic predispositions. "This work raises important questions about how mutations accumulate, why they target luminal cells, and how they relate to cancer risk," Aparicio said.
Publication Details
Williams, M.J., Oliphant, M.U.J., Au, V. et al. Luminal breast epithelial cells of BRCA1 or BRCA2 mutation carriers and noncarriers harbor common breast cancer copy number alterations. Nat Genet (2024). https://doi.org/10.1038/s41588-024-01988-0
Pinpointing Genetic Alterations in Normal Breast Cells
The study analyzed over 48,000 individual breast cells from women without cancer using single-cell sequencing technology. Researchers identified a small subset—approximately 3%—of luminal breast cells that harbored mutations known as copy number alterations (CNAs). These changes involve the duplication or loss of large DNA segments and are commonly associated with cancer.
"These changes could be the basic building blocks of breast cancer," said Samuel Aparicio, a professor of pathology and molecular oncology at UBC and BC Cancer. “With further research into how these mutations arise and accumulate, we could potentially develop new preventive strategies, therapeutic approaches, and routes for early detection.”
The study focused on CNAs in breast tissue, revealing their presence exclusively in luminal cells. These cells, which line the ducts and lobules of the breast, are thought to be the origin of most major types of breast cancer. Mutations were not found in the contractile cells associated with these tissues, emphasizing the luminal cells' unique vulnerability.
Advanced Techniques Reveal Rare Mutations
The team employed DLP+, an advanced single-cell sequencing technique developed at UBC and BC Cancer, to analyze breast cells from 28 women. This method provides high-resolution insights into genomic instability, enabling the detection of rare mutations that standard sequencing methods might overlook.
“Our computational approaches further allowed us to identify and analyze these rare events that are not visible with standard sequencing assays,” said Sohrab Shah, Chief of Computational Oncology at MSK. This technique provides a comprehensive view of copy number alterations and helps trace the potential progression of normal cells toward cancer-like states.
The majority of mutated cells carried only one or two CNAs. However, in women with high-risk genetic variants such as BRCA1 or BRCA2, researchers observed some cells with six or more CNAs. These "extreme" cases may represent advanced steps in a pathway leading from normal to cancerous cells, particularly in individuals with a predisposition to breast cancer.
Implications for Cancer Research and Prevention
While the body’s DNA repair mechanisms typically correct CNAs, their accumulation in luminal cells raises questions about the timescale and triggers for these mutations. According to Joan Brugge, a professor of cell biology at Harvard Medical School, “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.” The research also points to broader applications for studying CNAs in other tissues. Investigating similar mutations across organs may provide insights into the mechanisms underlying various cancer types.
Next Steps in Understanding Cancer Risk
The study highlights the importance of exploring how genetic mutations develop in luminal cells and the factors contributing to cancer risk. Researchers believe these findings could lead to improved monitoring and prevention strategies, especially for individuals at higher risk due to genetic predispositions. "This work raises important questions about how mutations accumulate, why they target luminal cells, and how they relate to cancer risk," Aparicio said.
Publication Details
Williams, M.J., Oliphant, M.U.J., Au, V. et al. Luminal breast epithelial cells of BRCA1 or BRCA2 mutation carriers and noncarriers harbor common breast cancer copy number alterations. Nat Genet (2024). https://doi.org/10.1038/s41588-024-01988-0