BACKGROUND AND AIMS
Most female carriers of germline BRCA1 mutations develop breast and/or ovarian cancer. However, the penetrance of BRCA1 pathogenic variants does not reach 100%, and the age at onset for BRCA1-associated breast cancer (BC) is a subject of variation.1 This study aimed to evaluate whether the age-related likelihood of developing BC in carriers of the BRCA1 mutation is influenced by inherited variations in the host immune system, namely, human leukocyte antigen (HLA) Classes I and II genes polymorphism. The search for modifiers of BRCA1 penetrance is complicated by the need to identify a large number of healthy individuals who remain cancer-free in late adulthood despite carrying a pathogenic variant. Here, the authors utilised a different approach, where they included in the study only patients with BRCA1-driven BC, and compared the distribution of HLA genotypes in young-onset versus late-onset cases. The authors reasoned that young-onset patients are likely to be enriched by genetic variants, which increase the penetrance of BRCA1 pathogenic alleles.
MATERIALS AND METHODS
Next-generation sequencing was utilised for genotyping of HLA Class I and II genes (HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQB1, and HLA-DRB1/3/4/5) in Slavic patients with BRCA1-associated BC with early (≤38 years; n=215) and late (≥58 years; n=108) age at onset. The age thresholds corresponding to the youngest and oldest quartiles of females were determined by analysing the age distribution in 771 consecutive female patients with BC carrying BRCA1 mutations.
RESULTS
The HLA-DQB1*06:03P prevalence was higher in the late-onset group due to the excess of allele carriers (25/108 [23.1%] versus 22/215 [10.2%]; adjusted odds ratio [OR]: 2.96; 95% confidence interval [CI]: 1.58–5.56; p<0.001) and homozygous genotypes (3/108 [2.8%] versus 0/215 [0.0%]; OR: 14.30; 95% CI: 0.73–279.27; p=0.08). For all HLA-I loci, there was a trend toward an increase in the number of homozygous genotypes in the early-onset group. For the HLA-A locus this prevalence was significant (14.4% versus 6.5%; p=0.037; OR: 2.4; 95% CI: 1.03–5.72; p=0.042). The frequencies of HLA-DPB1, HLA-DQB1, and HLA-DRB3/4/5 homozygous genotypes did not differ between patients with young-onset and late-onset BC. There was a trend towards the increased frequency of DRB1 homozygotes in the young versus senior patients (11.7% versus 6.5%; p=0.144). The maximum degree of homozygosity detected in this study was six out of seven HLA Class I/II loci; all six female carriers of these genotypes were diagnosed with BC before the age of 39 years (OR: 6.97; 95% CI: 0.39–125.01; p=0.187).
CONCLUSION
This study demonstrates that HLA polymorphism may play a role in modifying the penetrance of BRCA1 pathogenic variants. The authors revealed that HLA-DQB1*06:03P is overrepresented in patients with late-onset versus young-onset BRCA1 heterozygous BC, suggesting that this allele has a protective role. In addition, the authors observed a trend towards the role of the reduced HLA genotype diversity (homozygosity) in modifying age-related BRCA1 penetrance. Genetic variations in the immune system were not previously considered in studies of BRCA1/2-associated cancer risks. The obtained data warrant international multicentre studies aimed to test whether particular HLA alleles or HLA homozygosity, or variations in some other immune-related genes, may increase the risk of cancer disease in carriers of the BRCA1/2 mutation.
