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Abstract
Introduction. Hereditary defects in BRCA1/2 are the most common cause of inherited breast cancer (BC). However, not all carriers of pathogenic variants in these genes develop cancer during their lifetime. BRCA1-associated tumors are characterized by chromosomal instability and a consequent high neoantigen load, rendering them highly immunogenic. We hypothesized that germline genetic variation in immune response pathways may modify BC risk in BRCA1 mutation carriers, potentially accelerating or delaying disease onset.
Aim. To identify germline variants in immune response genes that influence the age at onset of BRCA1-associated BC.
Materials and Methods. The search for hereditary risk-modifying variants was performed via targeted sequencing of 353 immune response genes in 42 patients with young-onset (<39 years) and 35 patients with late-onset (>57 years) BRCA1-associated BC. Molecular epidemiological validation of candidate variants was subsequently performed on a pilot cohort consisting of 90 young-onset and 90 late-onset cases, utilizing high-resolution melting PCR (HRM-PCR) and Sanger sequencing. The PRF1 p.Ala91Val missense variant was analyzed in expanded cohorts (young-onset, n=164; late-onset, n=218) using allele-specific PCR (AS-PCR).
Results. Targeted sequencing identified 22 potentially significant variants associated with unusually young or late disease onset. Among these, the PRF1 p.Ala91Val variant was detected in 9.6% of young-onset patients but was absent in the late-onset group (7/73 vs. 0/78, p = 0.005). This association was confirmed in an independent cohort of Russian patients (5/50 vs. 2/117, p = 0.026). A pooled analysis of Russian and Polish patients showed a consistent trend (15/164 vs. 9/218, p = 0.055).
Conclusion. Germline variants in immune response genes, such as PRF1 p.Ala91Val, may modulate the age-dependent penetrance of BRCA1 mutations. Exome-wide screening of cancer-free carriers and affected individuals with BRCA1/2 pathogenic variants, as well as BRCA1/2-associated BC patients with young and late onset, could reveal novel genetic modifiers of BC risk.
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