P53 alteration in morphologically normal/benign breast luminal cells in BRCA carriers with or without history of breast cancer

Germ-line mutations in BRCA genes have been shown to predispose patients to breast cancer. Studies have suggested that p53 alteration is a necessary step in tumorigenesis in BRCA carriers. Our previous study showed p53 alteration in morphologically normal/benign breast luminal cells in sporadic breast cancer patients, the so-called “breast p53 signature”. Here, we studied p53 status in 66 BRCA1/2 carriers' breasts; 29 patients with breast carcinoma (2 patients with bilateral breast carcinomas) and 37 without. Seven of the 12 (58%) triple-negative breast carcinomas in BRCA carriers were positive for p53 alteration (immunohistochemical stain and/or sequencing), the same frequency as in sporadic triple-negative breast carcinomas. Focal p53 positivity in adjacent normal/benign luminal cells was identified in 4 of the 7 cases with p53 positive carcinomas but not in breasts with p53 negative carcinomas, indicating that p53 positivity in normal/benign breast luminal cells is not a random event. Further, in BRCA carriers' prophylactic mastectomies, twelve of the 94 (12.77%) breasts had focal p53 positivity in normal/benign luminal cells, with 2 cases in bilateral breasts, significantly higher than in previously studied mammoplasty specimens (0%). Our study suggests that germline BRCA genes mutations could result in genomic instability and an elevated gene mutation rate (such as p53 gene) in breast luminal cells compared with general population, predisposing BRCA carriers to develop p53 positive/triple-negative breast carcinomas.