A new study has demonstrated that in women with BRCA1 or BRCA2 mutations, breast cells already carry a clear pattern of DNA ‘damage spots’ long before any tumor appears. These weak points tend to sit on important cancer-related genes and look very similar to what is later seen in actual breast cancer. Based on this finding, new approaches can be developed to detect cancer much earlier and maybe even stop it before it starts.
The study led by Ph.D. student Sara Oster Flayshman under the guidance of Professor Rami Aqeilan, MD, the Jacob M. Eisenberg and Thomas W. Baylek Chair for Medical Research in the field of Genetic Engineering, and Yotam Drier, Ph.D. from the Faculty of Medicine at Hebrew University in Jerusalem, Israel, in collaboration with Victoria L. Seewaldt, MD, and Mark LaBarge, Ph.D. at City of Hope Comprehensive Cancer Center, Duarte, CA, USA, for the first time, revealed a previously unseen window into how breast cancer begins in women carrying BRCA1 or BRCA2 mutations.
The study outcomes, published in Cell Death & Disease, trace the earliest molecular events that set cells on the path toward malignancy, years before cancer is clinically detectable.[1]
Compromising Repair
For decades, scientists have known that mutations in BRCA1 and BRCA2 compromise a cell’s ability to repair DNA double-strand breaks (DSBs), one of the most dangerous forms of genetic damage. But how this chronic damage transforms healthy breast tissue into cancer has remained a mystery.
The team used next-generation sequencing to map DNA breaks across the genomes of primary mammary epithelial cells from non-malignant BRCA mutation carriers. These women are classified as high-risk patients, yet their cells have not undergone malignant transformation. This provided a rare opportunity to study carcinogenesis at its inception.
A Distinctive Pattern of DNA Breakage
The researchers discovered that the DSB landscape in BRCA-mutated cells is fundamentally different from that of healthy controls, and, strikingly, resembles the pattern seen in breast cancer cells.
Key cancer genes, including both proto-oncogenes and tumor suppressors, showed a significantly higher number of breaks in BRCA mutation carriers. Moreover, genes that experience more breaks tended to be more highly expressed, making them both active and vulnerable, conditions that favor oncogenic change.
Early Damage Predicts Future Mutations
Many of the genes identified as highly prone to breakage in BRCA mutation carriers are subsequently found mutated in breast tumors. This reveals a direct molecular bridge between early DNA repair deficiencies and the mutations that drive breast cancer progression.
The study also shows that these high-breakage genes strongly correlate with homologous recombination (HR) repair pathways, reinforcing the central role of BRCA-driven HR loss in cancer initiation.
New Avenues for Early Detection
By charting where and how DNA breaks accumulate before cancer emerges, the research opens the door to future tools for early cancer detection, potentially years before tumors become visible by imaging or symptomatic.
“This work provides critical insight into the earliest molecular changes that take place in breast cells of BRCA mutation carriers,” Aqeilan said.
“Understanding these initial events allows us to envision new strategies for identifying cancer at its earliest, most treatable stages,” he added.
“What is especially exciting,” noted Sara Oster Flayshman, “is that we can now pinpoint specific regions in the genome that are repeatedly damaged long before a tumor appears.
“These patterns could one day help us develop more precise biomarkers, so that high-risk women are not only monitored more effectively, but also offered interventions based on the actual biology of their cells,” added Drier
A Step Toward Prevention
With breast cancer remaining the most common cancer in women worldwide, these findings represent an important advance in understanding cancer risk in BRCA mutation carriers, those who often face difficult decisions about surveillance and preventive surgery.
This discovery marks an important step toward elucidating the biological origins of cancer and translating that knowledge into predictive and preventive medicine.
Reference
[1] Oster Flayshman S, Hidmi O, Alva-Ornelas JA, Monin J, LaBarge MA, Seewaldt VL, Drier Y, Aqeilan RI. The breakome of BRCA1 and BRCA2 pathway mutation carriers reveals early processes in breast oncogenesis. Cell Death Dis. 2025 Dec 5;16(1):891. doi: 10.1038/s41419-025-08235-2. PMID: 41350536; PMCID: PMC12717187.
Featured image: A break in a chromosome and the surrounding ‘map’ of the DNA region. By combining information on chromatin organization with precise mapping of break sites, genomic regions that are more fragile can be identified. This approach helps researchers understand why certain genes are more susceptible to damage in diseases such as cancer and may guide more effective strategies to protect the genome. Photo courtesy © 2026 Aqeilan Lab. Used with permission.
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