Keywords
gene BRCA1
HLA-genotypes
hereditary mutations
age at onset
antitumor immunity
penetrance
How to Cite
Abstract
Introduction. Carriers of pathogenic BRCA1 variants exhibit significant variability in the age at onset of breast cancer (BC). Human leukocyte antigen (HLA) class I and II molecules are central to tumor antigen presentation. However, existing genome-wide association studies (GWAS) cannot adequately assess their role in penetrance modification due to the high polymorphism and structural complexity of the HLA region. Consequently, the contribution of HLA genotypes to the age-dependent realization of BRCA1-associated BC risk remains largely unknown.
Aim. To evaluate the association of HLA class I and II genotypes, as well as HLA homozygosity, with the age at BC onset in BRCA1 mutation carriers.
Materials and Methods. The study included 323 carriers of pathogenic BRCA1 alleles with confirmed BC from Russia and Poland, stratified into groups with early (≤ 39 years, n = 215) and late (≥ 57 years, n = 108) disease onset. High-resolution HLA typing of loci A, B, C, DPB1, DQB1, DRB1/3/4/5 was performed by next-generation sequencing (NGS). Allele frequencies and the proportion of homozygous genotypes were compared using the χ² test and Fisher’s exact test, with calculation of odds ratios (OR).
Results. The HLA-DQB1*06:03P allele was significantly more frequent in the late-onset BC group compared to the early-onset group (13.8 vs. 5.1 %; OR = 2.91, 95 % CI 1.62–5.22; p = 0.0001). The HLA-C*03:04P allele was associated with an increased risk of early onset (7.7 vs. 3.2 %; p = 0.027). Homozygosity at the HLA-A locus was significantly associated with BC development at a young age (14.4 vs. 6.5 %; OR = 2.4, 95 % CI 1.03–5.72; p = 0.037). A similar trend towards a higher frequency of homozygosity in early-onset patients was observed for the remaining HLA class I loci.
Conclusion. The HLA genotype may modify the age-dependent penetrance of pathogenic BRCA1 mutations. The presence of the HLA-DQB1*06:03P allele is associated with delayed BC development, whereas homozygosity at HLA class I loci is linked to earlier manifestation of cancer risk.
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Copyright (c) 2026 Арина Андреевна Перевалова, Александр Сергеевич Мартьянов, Екатерина Шотовна Кулигина, Александр Андреевич Романько, Татьяна Николаевна Соколова, Татьяна Эдуардовна Янкевич, Дмитрий Юрьевич Трофимов, Евгений Наумович Имянитов