Innate immune gene variants linked to earlier breast cancer in BRCA1 carriers

Preliminary genomic analysis has linked defects in natural killer cell pathways to earlier breast cancer diagnosis in women with BRCA1 mutations, raising the prospect of more precise risk prediction models

An observational study has reported that damaging genetic variants affecting innate immune function have been significantly associated with the earlier onset of breast cancer in women who carry pathogenic variants of the BRCA1 gene. The preliminary findings point to particular to genes involved in activation of natural killer cells as key contributors.

Pathogenic variants in BRCA1 have long been recognised to confer elevated lifetime risk of both breast and ovarian cancers. Estimates have suggested that women who carry these genes face a 60 to 80 per cent probability of developing breast cancer in their lifetimes. Additionally, they also face a 30 to 40 per cent risk of ovarian cancers.

Despite this high penetrance – which is how often a particular genetic variant actually produces its associated trait in the carrier – the age at which breast cancer presents varies widely. This remains true even among individuals who carry the same mutation. That variability has posed a substantial clinical challenge, particularly in decisions about timing of preventive interventions such as risk-reducing mastectomy or salpingo-oophorectomy – the surgical procedure that removes ovaries and fallopian tubes.

The study sought to investigate this variability through the lens of host immunity. The team proposed that additional genetic factors, particularly those that influence the innate immune system, may modify cancer surveillance capacity and thereby alter the timing of tumour emergence.

Innate immunity constitutes the body’s rapid-response defence mechanism and includes cellular components such as natural killer cells which are capable of identifying and eliminating virally infected or transformed cells without prior sensitisation.

To examine this hypothesis, the researchers analysed whole exome sequencing data from 321 women of Ashkenazi Jewish ancestry, a population in which the prevalence of specific BRCA1 mutations is estimated to be between five and six times higher than in many other groups. All participants carried the same founder mutation – known as 185delAG – which allowed the study to isolate the effects of additional genetic variation without the confounding influence of heterogeneous primary mutations.

Whole exome sequencing focuses on the protein-coding regions of the genome, which comprise approximately one to two per cent of total DNA yet contain around 85 per cent of known disease-causing mutations. Within this cohort, 98 women had received a diagnosis of breast cancer. The average age at diagnosis was 41.5 years – although the range extended from 26 to 75 years – underscoring the heterogeneity in disease onset.

Analysis of the sequencing data revealed that carriers who also harboured likely deleterious missense variants in genes associated with innate immune pathways experienced significantly earlier onset of breast cancer. The most pronounced association emerged in relation to genes that regulate activation of natural killer cells. Variants within these pathways were linked to a more than 250 per cent increase in the likelihood of earlier disease manifestation compared with carriers who did not possess such additional mutations.

These findings have important implications for risk stratification. Current clinical models that estimate cancer risk in BRCA1 carriers have largely focused on the presence or absence of the primary pathogenic variant, with limited incorporation of modifying genetic or biological factors. The identification of innate immune gene variants as potential modifiers of penetrance suggests that more granular approaches may be required to predict not only whether cancer will develop but also when it is most likely to arise.

“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,” the researchers said.

“Our findings highlight a potential role for innate immune pathways as modifiers of BRCA1 penetrance and may support development of more refined, personalised breast cancer risk prediction models for BRCA1 pathogenic variant carriers,” they added.

If confirmed, the work could contribute to a shift in clinical management of hereditary breast cancer risk. More precise estimation of age-specific risk may allow clinicians to tailor surveillance strategies and preventive interventions with greater confidence, thereby balancing the benefits of early risk reduction against the physical and psychological burden of major prophylactic surgery. In that context, integration of immunogenetic data into predictive models represents a plausible next step in efforts to personalise cancer prevention.

For further reading please visit: 10.1136/jmg-2025-111394