41P HLA genotypes modify the age-related penetrance of BRCA1 pathogenic variants in breast cancer patients

Most female carriers of germline BRCA1 mutation 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) varies widely. This study aimed to evaluate whether the age-related likelihood of developing BC in BRCA1 mutation carriers is influenced by inherited variations in the host immune system. Next-generation sequencing was utilized 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 patients with BRCA1-associated BC with early (<39 years, n = 215) and late (>57 years, n=108) age at onset. Age thresholds corresponding to the youngest and oldest quartiles of women were determined by analyzing the age distribution in 771 consecutive female BC patients carrying BRCA1 pathogenic variants. 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%); adjusted OR 2.96 (95% CI 1.58 - 5.56), p < 0.001] and homozygous genotypes [3/108 (2.8%) vs. 0/215 (0%); OR 14.3 (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% vs. 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 young-onset and late-onset BC patients. The maximum degree of homozygosity detected in this study was 6 out of 7 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]. HLA-DQB1*06:03P is significantly overrepresented in late-onset versus young-onset BRCA1 heterozygous BC patients suggesting that this allele has a protective role. A reduced diversity of HLA class I alleles may contribute to the early manifestation of BC in BRCA1 mutation carriers.