byBritish Medical Journal

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Damaging variants in genes involved in a rapid immune response (innate immunity) are significantly linked to earlier breast cancer onset in carriers of the harmful BRCA1 genetic mutation, reveal preliminary findings published online in theJournal of Medical Genetics.

The strongest association was found for genes involved in theactivation of natural killer cells, which serve as the body's rapid first line defense against viruses and cancer.

The findings prompt the researchers to suggest that more refined, personalized risk prediction models may be needed for carriers of the mutant BRCA1 gene, as although this mutation strongly boosts their risk of breast cancer, age at diagnosis varies considerably.

Women harboring apathogenic variant of the BRCA1 genehave an estimated 60%–80% lifetime risk of developing breast cancer and a 30%–40% heightened risk of ovarian cancer, note the researchers.

Surgical removalof the breasts, fallopian tubes, and ovaries mitigates the risk, but because the age at which breast cancer develops in carriers is highly variable, even among those with the same genetic BRCA1 mutation, it's difficult to know when this life-changing procedure should be carried out, they explain.

But this variation in disease onset suggests that other modifying factors might be influential, including impaired immunity, because of the pivotal role the immune system has in the development and surveillance of cancer, they say.

To explore this further, they studied whole exome sequencing information from 321 Ashkenazi Jewish women, among whom the prevalence of BRCA1 mutations is around five to six times higher than it is among other ethnic groups worldwide.

Whole exome sequencing reads the most crucial 1–2% of a person's DNA—the exome— which contains around 85% of mutations known to cause specific medical conditions.

The women were all carrying the same BRCA1 mutation (185delAG) and 98 of them had been diagnosed with breast cancer. Their average age at diagnosis was 41.5, but ranged from 26 to 75.

The whole exome sequencing revealed that additional likely damaging mutations (missense variants) in genes involved in innate immunity were significantly associated with earlier onset of the disease.

Mutations in the genes involved in natural killer cell activation were most strongly associated with earlier disease onset, conferring a risk more than 3.5 times greater.

"It remains to be determined whether these preliminary findings can be replicated in independent, ethnically diverse, larger cohorts of carriers of heterogeneous [pathogenic variants] in BRCA1," caution the researchers.

But they suggest their findings "highlight a potential role forinnate immune pathwaysas modifiers of BRCA1 penetrance and may support the development of more refined, personalized BC risk prediction models for BRCA1 [pathogenic variant] carriers."

Publication details Damaging missense variants in innate immunity genes are associated with earlier age of breast cancer onset in BRCA1 185delAG carriers, Journal of Medical Genetics (2026). DOI: 10.1136/jmg-2025-111394 Journal information: Journal of Medical Genetics