Pathogenic germline variants in BRCA1/2 are associated with a decreased number of hypomethylated rDNA copies

Abstract Background Little is known about the phenotypic impact of the enormous rDNA copy number (CN) variation among individuals. The rDNA CN appears to be stable across different tissues of the same individual, whereas many tumors exhibit consistent rDNA CN changes, compared to healthy tissue. Herein, we have analyzed rDNA CN in blood of healthy carriers of BRCA1 / 2 pathogenic variants (PV), who have a high risk of developing breast and ovarian cancer. Methods Using a combination of digital droplet PCR and deep bisulfite sequencing we have determined the absolute rDNA CN and the number of copies with a hypomethylated (≤ 10%) promoter region in healthy BRCA1 ( N = 90) and BRCA2 ( N = 71) PV carriers as well as in PV-negative controls ( N = 146). Results Absolute CN was comparable between groups. However, there was a significant and an almost significant difference, respectively, in hypomethylated rDNA CN between females carrying a BRCA1 ( P = 0.023) or BRCA2 PV ( P = 0.085), compared to controls. The effect appeared to be restricted primarily to younger women. PV carriers younger than 45 years (69 BRCA1 , 47 BRCA2 ) exhibited approximately 10 hypomethylated copies less ( P = 0.015 for BRCA1 and 0.150 for BRCA2 ) than age-matched controls ( N = 98). Conclusions Our results link germline BRCA1 / 2 PV to rDNA epigenetic regulation. We propose that the decreased number of hypomethylated, presumably active CN may contribute to cancer susceptibility in BRCA1 / 2 PV carriers, preceding tumor development.