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Abstract
Introduction Natural killer (NK) cells are a fundamental component of cancer immunosurveillance. The transcriptomic profile of NK cells remains to be fully elucidated in BRCA1 mutation carriers who are disproportionately affected by tissue-specific carcinogenesis. Loss of BRCA1 is implicated with centrosomal aberrations affecting an immunological synapse via disruption of microtubule and actin dynamics. Previous work demonstrates NK cell activity to be differential in carriers specifically during the follicular phase.
Methods Peripheral blood NK cell profiles were compared between age-matched premenopausal BRCA1 mutation carriers and non-carriers (n = 8). Donors were aged 21 to 44 years with no prior risk-reducing surgery or concurrent hormone use and in good general health. Negatively selected CD3-CD56+ NK cells from the ‘early follicular’ (EF) phase (2 to 5 days following cessation of menstruation) had RNA extracted for library preparation (Illumina) mapped to human reference (GRCh38) with functional annotation analysis of genes (p-value <0.05).
Results 41 DEGs were identified in resting NK cells from cancer-free BRCA1 mutation carriers (figure 1) which had dysregulated pathways (REACTOME) linked to immunological processes (vesicle transport, signalling, cell-cycle). Ingenuity® Pathway Analysis identified processes linked to cellular growth, hereditary disorders, inflammation, cancer, and tumour morphology. Based on the current literature proposed immunobiological associations of identifiable genes are shown (figure 2).
Conclusion/Implications These novel findings reflect a dysregulated transcriptomic profile in otherwise healthy BRCA1 mutation carriers. Cumulative effects across the reproductive lifecycle may have detrimental pro-cancerous effects. Further work to ascertain the functional implications of these genomic alterations and the development of non-surgical adjuncts aimed at enhanced immune surveillance is needed.
