Kuligina Ekaterina S, Romanko Alexandr A, Jankevic Tatjana, Martianov Aleksandr S, Ivantsov Alexandr O, Sokolova Tatyana N, Trofimov Dmitry, Kashyap Aniruddh, Cybulski Cezary, Lubiński Jan, Imyanitov Evgeny N
N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Pesochny-2, St. Petersburg, Russia, 197758.
Breast Cancer Res Treat. 2025 Jan;209(2):341-354. doi: 10.1007/s10549-024-07497-2. Epub 2024 Sep 21.
Female carriers of germline BRCA1 mutations almost invariably develop breast cancer (BC); however, the age at onset is a subject of variation. We hypothesized that the age-related penetrance of BRCA1 mutations may depend on inherited variability in the host immune system.
Next-generation sequencing was utilized for genotyping of HLA class I/II genes (HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQB1, and HLA-DRB1/3/4/5) in patients with BRCA1-associated BC with early (< / = 38 years, n = 215) and late (> / = 58 years, n = 108) age at onset.
HLA-DQB1*06:03P prevalence was higher in the late-onset group due to the excess of allele carriers [25/108 (23.1%) vs. 22/215 (10.2%); OR 2.96, p < 0.001]. For all HLA-I loci, there was a trend toward an increase in the number of homozygotes in the early-onset group. This trend reached statistical significance for the HLA-A [14.4% vs. 6.5%, p = 0.037; OR 2.4, p = 0.042]. The frequencies of HLA-DPB1, HLA-DQB1, and HLA-DRB1/3/4/5 homozygous genotypes did not differ between young-onset and late-onset patients. The maximum degree of homozygosity detected in this study was 6 out of 7 HLA class I/II loci; all six carriers of these genotypes were diagnosed with BC at the age < / = 38 years [OR 6.97, p = 0.187].
HLA polymorphism may play a role in modifying the penetrance of BRCA1 pathogenic variants. Certain HLA alleles or HLA homozygosity may modify the risk of BC in BRCA1 carriers.
种系BRCA1突变的女性携带者几乎都会患乳腺癌（BC）；然而，发病年龄存在差异。我们推测BRCA1突变与年龄相关的外显率可能取决于宿主免疫系统的遗传变异性。
利用下一代测序技术对BRCA1相关BC的早发（< / = 38岁，n = 215）和晚发（> / = 58岁，n = 108）患者的HLA I/II类基因（HLA-A、HLA-B、HLA-C、HLA-DPB1、HLA-DQB1和HLA-DRB1/3/4/5）进行基因分型。
由于等位基因携带者过多，HLA-DQB1*06:03P在晚发组中的患病率更高[25/108（23.1%）对22/215（10.2%）；OR 2.96，p < 0.001]。对于所有HLA-I位点，早发组纯合子数量有增加趋势。HLA-A的这种趋势达到统计学意义[14.4%对6.5%，p = 0.037；OR 2.4，p = 0.042]。早发和晚发患者之间HLA-DPB1、HLA-DQB1和HLA-DRB1/3/4/5纯合基因型的频率没有差异。本研究中检测到的最大纯合度为7个HLA I/II位点中的6个；所有这些基因型的6名携带者在< / = 38岁时被诊断为BC[OR 6.97，p = 0.187]。
HLA多态性可能在改变BRCA1致病变异的外显率中起作用。某些HLA等位基因或HLA纯合性可能改变BRCA1携带者患BC的风险。
