A study led by PhD student Sara Oster Flayshman under the guidance of Rami Aqeilan and Yotam Drier from the Faculty of Medicine at Hebrew University in collaboration with City of Hope researchers Dr. Seewaldt and Dr. LaBarge, has revealed a previously unseen window into how breast cancer begins in women carrying BRCA1 or BRCA2 mutations.
The study, published in Cell Death & Disease, traces the earliest molecular events that set cells on the path toward malignancy, years before cancer is clinically detectable.
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.
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 tumour 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 favour oncogenic change.
Many of the genes identified as highly break-prone in BRCA mutation carriers are the same genes later found mutated in breast tumours. 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.
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 tumours 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.”
Flayshman said: “What is especially exciting is that we can now pinpoint specific regions in the genome that are repeatedly damaged long before a tumour appears.”
Drier said: “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.”
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.
The discovery marks an important stride toward deciphering the biological origins of cancer and turning that knowledge into predictive and preventive medicine.
Jim Cornall is editor of Deeptech Digest and publisher at Ayr Coastal Media. He is an award-winning writer, editor, photographer, broadcaster, designer and author. Contact Jim here.