Understanding the earliest genetic changes involved in breast cancer development is key to improving prevention, early detection, and targeted treatment. A recent BCRF-supported study published in Nature Genetics has provided new insights into these early changes, laying the foundation for new strategies to manage breast cancer.
The work represents a collaboration across three laboratories, each led by a BCRF investigator: Dr. Samuel Aparicio of University of British Columbia and BC Cancer, Dr. Joan Brugge of Harvard Medical School, and Dr. Sohrab Shah of Memorial Sloan Kettering Cancer Center. Together, they investigated the genetic profiles of thousands of breast cells to uncover the initial steps that may lead to breast cancer.
We know that breast cancer does not emerge overnight. Instead, it evolves over time as genetic changes accumulate in certain cells. How and which cells evolve to grow uncontrollably and form tumors are questions that this research team sought to understand. Their strategy involved closely examining genetic changes in individual breast cells.
To accomplish this, they used a new approach to single-cell sequencing previously developed by Drs. Shah, Aparicio, and colleagues. This method, Direct Library Preparation+ (DLP+), integrates automation, advanced microscope technology, and sophisticated computational techniques to provide an unprecedented level of resolution.
Imagine looking at a sample of thousands of cells at one time, plucking one out of the sample for microscopic imaging, and then sequencing the whole genome of that one cell. Until DLP+, this wasn’t possible. Now, this technology enables researchers to link how a cell appears (morphology) with properties of its genome (DNA).
Originally developed to study genomic instability in cancer, DLP+ allows scientists to see the first mutations that give rise to tumors. Additionally, DLP+ can capture rare genetic events that occur in small subpopulations of cells, providing a clearer and more detailed understanding of cancer initiation.
The team sequenced the genes in more than 48,000 individual breast cells isolated from 28 women without breast cancer. This group included 19 individuals with inherited BRCA1 and BRCA2 gene mutations, which are known to significantly increase breast cancer risk. By studying samples from healthy women, the team hoped to pinpoint the genetic changes that might make up the earliest steps in tumor formation.
They discovered that about three percent of all cells carried specific genetic alterations called copy number alterations (CNAs). CNAs are caused by the duplication or loss of large DNA segments and occur over a person’s lifetime. While relatively rare and harmless on their own, they can accumulate and potentially lead to cancer if left uncorrected by the body’s natural DNA repair mechanisms.
In their study, the team consistently found cancer-like mutations across almost all individuals. Many of the CNAs reported in this study are frequently observed in breast cancers, suggesting they play a role in how normal cells become cancer cells. However, more research is needed to directly determine if and how these CNAs boost the ability of a normal cell to grow, divide, or resist stress—attributes of a cancer cell.
Interestingly, the CNAs were primarily found in luminal cells, which line the breast ducts and lobules and are believed to be the origin of most breast cancers. These alterations were largely absent from basal cells, which are found in the glandular tissue of the breast.
“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. Brugge said. “This study is an important step on our collective quest as scientists to understand the earliest events in breast cancer development.”
The team also closely examined CNAs in breast cells harboring inherited BRCA mutations, as investigating the accumulation of large genetic changes may clarify the genetic origins of BRCA-mutated cancer. The team found that some cells harboring BRCA mutations had far more CNAs than cells without BRCA mutations, and they had also lost a copy of the tumor suppressor gene TP53.
This pattern may represent a series of events that cause breast cancer to develop and progress in high-risk individuals. Further studies with larger groups are necessary to confirm whether individuals with BRCA mutations are more likely to acquire CNAs.
“We only have a partial understanding of how breast cancers begin, and if we knew more about the factors that influence that beginning, we might be able to delay or prevent it,” Dr. Aparicio said. This research represents a step forward in that pursuit and highlights the importance of using advanced technologies to study the genetic makeup of normal tissue in the breast and other organs.
“BCRF’s funding has been crucial in applying innovative approaches to studying patterns of mutation and how they relate to established breast cancers,” Dr. Aparicio said. “With ongoing support, we are excited about how these findings might be applied.”
By striving to understand the fundamental biology that drives cancer, scientists are building the foundation to create better risk assessment tools, detect the disease at its earliest stage, and develop personalized interception and treatment strategies.
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