Introduction: BRCA1 and BRCA2 are closely associated with hereditary breast and ovarian cancer. In clinical practice, these genes are part of genetic counselling, cancer prevention, and often difficult medical decisions.
But BRCA1 and BRCA2 are also DNA repair genes.
Blood formation is a lifelong process. Every day, blood stem and progenitor cells divide and produce enormous numbers of mature blood cells. During life, some of them can acquire somatic mutations. In some cases, a mutated blood cell population can expand and become detectable in the blood, even before there is any diagnosed hematological disease. This phenomenon is known as clonal hematopoiesis.
Our study1 started with a simple question: could inherited defects in DNA repair make it easier for blood cells to acquire or maintain somatic mutations?
From BRCA genes to blood stem cell clones
One of the most important acquired mutations in myeloproliferative neoplasms (MPNs) is JAK2V617F. MPNs are clonal blood disorders in which hematopoietic stem cells give rise to excessive production of mature blood cells, and JAK2V617F is one of their key driver mutations.
However, JAK2V617F is not restricted to patients with diagnosed MPNs. With sensitive molecular methods, it can also be detected at very low levels in people without a diagnosed hematological disease, as part of clonal hematopoiesis. Since BRCA1 and BRCA2 act at different steps of homologous recombination repair, we wondered whether carriers of germline BRCA1 and BRCA2 mutations would show the same pattern of JAK2V617F-positive blood cell clones or not.
This project extends our previous work, in which we described inherited DNA repair variants in young-onset and familial MPNs2-4 and demonstrated that these germline DNA repair mutations synergize with the somatic JAK2V617F mutation to change the behavior of blood cells.
Searching for low-level signals in blood
To address this question, we collaborated with colleagues in Aachen, Cologne, and Leipzig and analyzed peripheral blood samples from three cohorts: germline BRCA1/2 mutation carriers, BRCA-wildtype breast cancer patients who had undergone clinical BRCA testing, and healthy blood donors.
In total, the study included 568 BRCA1/2 mutation carriers, 567 non-carrier breast cancer patients, and 356 healthy blood donors.
Because the mutant cell frequency may be very low in blood, we used a highly-sensitive allele-specific quantitative PCR approach to detect and quantify JAK2V617F in genomic DNA from peripheral blood.
At this point, one might expect a simple comparison: BRCA carriers versus non-carriers.
But the first comparison did not capture the whole picture.
A result hidden in the subgroups
When we first looked at BRCA1/2 mutation carriers as a single group, the frequency of JAK2V617F positivity was the same as in BRCA-wildtype breast cancer patients: 4.2% in both groups.
This finding argued against a simple overall difference between BRCA carriers and non-carriers.
However, when we separated BRCA1 from BRCA2, the pattern changed.
JAK2V617F was detected more frequently in BRCA1 mutation carriers than in BRCA2 mutation carriers. The difference between BRCA carriers and healthy blood donors was also mainly driven by the BRCA1 subgroup, whereas BRCA2 carriers did not differ from healthy donors in the same way.
Among individuals who were JAK2V617F-positive, BRCA1 carriers also showed higher variant allele frequencies than BRCA2 carriers. This suggested that the difference might not only concern whether a clone is detectable, but potentially also the size or behavior of these clones.
For us, this was an important point of the study: clinically related groups can still contain biologically distinct subgroups. BRCA1 and BRCA2 are often placed in the same category, but separating them changed the interpretation of the data.
Why BRCA1 and BRCA2 may not be interchangeable
BRCA1 and BRCA2 are often discussed together because both are involved in homologous recombination repair and both are clinically important cancer predisposition genes.
Yet their biological roles are not identical.
BRCA1 is involved in early damage sensing and pathway regulation, while BRCA2 plays a more direct role in RAD51 loading and strand invasion. These differences may matter in blood stem and progenitor cells exposed to replicative stress, inflammation, aging, cancer, or treatment-related pressures.
In this context, germline BRCA1 haploinsufficiency could potentially influence the acquisition, persistence, or expansion of JAK2V617F-positive clones. At this stage, we cannot say which of these possibilities is most relevant. Still, the distinction between BRCA1 and BRCA2 appears biologically relevant.
Looking ahead
The observation opens several questions for future studies. Do BRCA1-associated JAK2V617F-positive clones behave differently over time? Are they influenced by inflammation, cancer-related factors, or treatment-related pressures? And could these observations eventually contribute to more personalized risk assessment or monitoring strategies in selected patients?
Answering these questions will require larger and longitudinal cohorts. Such studies will be essential to understand whether BRCA1 status influences the appearance, persistence, or expansion of these clones, and what clinical relevance this may have.
This project also reminds us that familiar clinical categories can sometimes hide important biological differences. BRCA1 and BRCA2 are often discussed together. Our data suggest that, at least in the context of JAK2V617F-positive clonal hematopoiesis, looking at them separately may matter.
On behalf of all coauthors, S. Koschmieder and J. Rodriguez
References
- Rodriguez MJ, Hauke J, Kayali M, et al. JAK2(V617F)-positive clonal hematopoiesis in germline BRCA1 versus BRCA2 mutation carriers. Leukemia. 2026.
- Elbracht M, Meyer R, Kricheldorf K, et al. Germline variants in DNA repair genes, including BRCA1/2, may cause familial myeloproliferative neoplasms. Blood Advances. 2021;5(17):3373-3376.
- Meyer R, Rodriguez MJ, Caduc M, et al. Frequent and clinically relevant germline DNA repair gene variants in young and familial myeloproliferative neoplasms. Blood Cancer Journal. 2026;16(1):2.
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Bermes M, Rodriguez MJ, Toledo MAS, et al. Exploiting Synthetic Lethality between Germline BRCA1 Haploinsufficien cy and PARP Inhibition in JAK2V617F-Positive Myeloproliferative Neoplasms. International Journal of Molecular Sciences. 2023;24(24):17560.