The overlooked DNA signal that might reshape breast cancer screening

Scientists have long known that inherited mutations in the BRCA1 gene, one of the body’s most important tumor suppressors, can dramatically increase the risk of breast and ovarian cancer. But genes are not controlled only by changes (or mutations) in DNA sequence. They can also be switched “on” or “off” through chemical tags added to DNA, a process known as DNA methylation.

In a new study in collaboration with the diagnostic biotech company GRAIL, JAX’s Francesca Menghi and JAX Professor and President Emeritus Edison Liu highlight how these methylation changes may help identify cancer risk and monitor disease using only a blood sample.

Recently published in JCO Precision Oncology, the study focuses on methylation of the BRCA1 gene. Since BRCA1 normally helps repair damaged DNA and suppress tumor formation, turning it off through DNA methylation, similarly to gene mutations, can increase the likelihood of cancer development.

Importantly, this methylation is not always confined to tumor tissue. Previous work had shown that some healthy people carry low levels of BRCA1 methylation in normal cells throughout the body, a condition referred to as constitutional methylation. These individuals do not inherit a mutation in the DNA sequence itself. Instead, they carry an increased level of DNA methylation that likely arose very early during embryonic development. Earlier studies suggested that women with constitutional BRCA1 methylation have an increased risk of developing triple-negative breast cancer and high-grade serous ovarian cancer.

A blood test that may reveal hidden cancer risk

The new study asked a critical question: can BRCA1 methylation be detected reliably in fragments of DNA shed into the bloodstream from tissues throughout the body? Menghi said this question matters because these fragments, known as circulating cell-free DNA (or cfDNA), have become one of the most promising tools in modern cancer medicine. Blood-based “liquid biopsies” that use cfDNA are increasingly being used to detect cancers, monitor tumor burden, and track treatment response without requiring invasive tissue biopsies.

Using a highly sensitive assay developed through the Circulating Cell-Free Genome Atlas (CCGA) study, the researchers analyzed blood samples from more than 5,600 individuals, including participants with and without cancer. The assay was sensitive enough to detect extremely small amounts of methylated BRCA1 DNA in plasma. Among individuals without cancer, BRCA1 methylation was detected in about 4.8% of women and 2.9% of men. This confirmed earlier evidence that constitutional BRCA1 methylation is relatively common in the general population and appears more frequently in females.

The signal became even stronger in specific cancer types. BRCA1 methylation was significantly enriched in women with triple-negative breast cancer and ovarian cancer, where approximately 14%–15% of patients tested positive. In these patients, the amount of methylated BRCA1 DNA also correlated with measures of tumor burden, suggesting that tumors themselves contribute additional methylated DNA into the bloodstream.

“The big picture of our work is public health, because we have identified a new risk factor that potentially accounts for about a quarter of two very aggressive types of female cancers,” Menghi said. 

One of the most important aspects of the study is that it demonstrates a single blood test can potentially capture two biologically distinct phenomena at once: an underlying constitutional cancer predisposition and the presence of tumor-derived DNA. This dual capability could eventually make BRCA1 methylation testing useful for both cancer risk assessment and for monitoring active disease, Menghi said.

An overlooked signal

Unlike genetic mutations, methylation changes are rarely assessed systematically in routine clinical practice. Part of the reason is technical: detecting low-level constitutional methylation requires highly sensitive sequencing approaches that have only recently become feasible at scale.

Another reason is conceptual. Cancer risk has traditionally been viewed through the lens of inherited DNA sequence changes, while epigenetic alterations, such as methylation, were often considered secondary events occurring only within established tumors. The growing evidence that constitutional BRCA1 methylation may arise early in embryonic development, and may predispose otherwise healthy individuals to cancer decades later, challenges that framework.

“Our study is therefore important not only because it introduces a sensitive blood-based method to detect BRCA1 methylation,” Menghi said, “but also because it helps elevate BRCA1 methylation to the status of a clinically meaningful biomarker alongside BRCA1 mutation testing, which transformed breast and ovarian cancer care beginning in the 1990s.”

The new research also raises an important caution. Because BRCA1 methylation can exist in healthy individuals, detecting methylated BRCA1 DNA in blood should not automatically be interpreted as evidence of cancer. Some of the methylated DNA may come from normal tissues rather than from a tumor. This distinction will be critical as liquid biopsy technologies continue to advance and move into clinical practice, Menghi said.

At the same time, Menghi notes that cfDNA may provide a powerful new window into constitutional methylation across the body. Unlike analyses restricted to white blood cells or individual tissues, cfDNA reflects contributions from many organs simultaneously. This could help researchers better understand how early changes in DNA methylation influence cancer risk over time.

The work also opens broader questions. Could similar constitutional methylation alterations exist in other cancer-related genes? Could blood-based methylation testing identify people at elevated cancer risk years before disease develops? And might these epigenetic patterns help guide treatment decisions, especially for cancers known to respond to therapies targeting BRCA1 deficiency such as PARP inhibitors?

More broadly, the work underscores a growing realization in cancer biology: some of the earliest events that predispose to cancer may occur long before a tumor forms, perhaps even during embryonic development, and traces of those events may remain detectable throughout life in a simple blood sample.

“While additional validation studies will be needed before these tests become routine in the clinic, our work represents an important step toward integrating DNA methylation biomarkers into precision medicine,” Menghi said. “It highlights how cancer risk may be written not only in our genes, but also in the molecular annotations layered on top of them.”

This research was supported by the National Cancer Institute (grants P30CA034196 and R01CA255705).

Other study authors are Margaret Antonio and Tracy Nance of GRAIL, Inc.

JAX media contact: Roberto Molar, [email protected], 202-765-5144

About The Jackson Laboratory
The Jackson Laboratory (JAX) is an independent, nonprofit biomedical research institution with a National Cancer Institute-designated Cancer Center. JAX leverages a unique combination of research, education, and resources to achieve its bold mission: to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health. Established in Bar Harbor, Maine in 1929, JAX is a global organization with nearly 3,000 employees worldwide and campuses and facilities in Maine, Connecticut, California, Florida, New York, and Japan. For more information, please visit www.jax.org.

Citation: Liu E.T., et al. Prevalence of BRCA1 Promoter Methylation in Cohorts of Individuals With and Without Cancer Assessed by Circulating Cell-Free DNA. (2026). DOI: 10.1200/PO-25-00854