Damaging variants in genes involved in a rapid immune response (innate immunity) are significantly linked to earlier breast cancer onset in carriers of the BRCA1 genetic mutation, according to preliminary findings published by Shemesh et al in the Journal of Medical Genetics.
The strongest association was found for genes involved in the activation of natural killer cells, which serve as the body’s rapid first-line defense against viruses and cancer.
The findings prompted 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 a pathogenic variant of the BRCA1 gene have an estimated 60% to 80% lifetime risk of developing breast cancer and a 30% to 40% heightened risk of ovarian cancer, noted the researchers.
Surgical removal of the breasts, fallopian tubes, and ovaries mitigates the risk, but because the age at which breast cancer develops in carriers is highly variable, even amongst those with the same genetic BRCA1 mutation, it’s difficult to know when this procedure should be carried out, they explained. 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.
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% to 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 years, but onset ranged from 26 years to 75 years.
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,” cautioned the researchers.
But they suggested their findings “highlight a potential role for innate immune pathways as modifiers of BRCA1 penetrance and may support the development of more refined, personalized breast cancer risk prediction models for BRCA1 [pathogenic variant] carriers.”
DISCLOSURE: For full disclosures of the study authors, visit jmg.bmj.com.
