In this issuep53 alteration in morphologically normal/benign breast luminal cells in BRCA carriers with or without history of breast cancer☆
Introduction
BRCA1 and BRCA2 are the tumor suppressor genes which regulate the process of DNA repair, cell cycle, and apoptosis [1], [2]. Germline mutations in BRCA1 or BRCA2 increase breast cancer risk; about 50% of BRCA mutation carriers will develop breast cancer by the age of 70 years compared to 7% in the general population [3]. However, even in these hereditary cases, the development of breast cancer is a multistep process, with somatic mutations in other genes playing an important role in the carcinogenesis process [4], [5], [6].
TP 53 gene alteration is the most common somatic change found in breast carcinomas and is most frequently seen in high-grade/basal-like/medullary carcinomas [7], [8], [9]. It is also often mutated in the breast cancers in BRCA1 carriers and less frequently in BRCA2 carriers [10]. Basic research has shown that germline mutations of BRCA1 or BRCA2 will cause cell cycle arrest by activating the p53-dependent checkpoint [11]. Thus, p53 alteration could be an obligatory step in the tumorigenesis in BRCA carriers. Loss of p53 checkpoint control may have occurred prior to the “second hit” in BRCA for BRCA−/− cells to overcome cell cycle arrest and accumulate further somatic genetic abnormalities necessary for tumorigenesis [6], [12].
Clinical observations have shown that p53 alteration is an early event in breast carcinogenesis, even before ductal carcinoma in situ (DCIS). Our previous study identified that p53 alteration is already present in the morphologically normal/benign breast luminal cells in the sporadic breast cancer patients [13]. We also found that this p53 alteration is not a random event in normal/benign breast tissue, as this finding correlates with the p53 status of the corresponding tumors in breast cancer patients. We therefore hypothesized the concept of “breast p53 signature,” identifying a precursor lesion as an early event in the development of triple-negative high-grade breast carcinoma.
To follow up on this concept, here we studied p53 status in the morphologically normal/benign luminal cells in 66 patients with germline BRCA1 or BRCA2 mutations with or without a history of breast cancer and compared the results with previously studied sporadic breast cancers and mammoplasty specimens.
Section snippets
Case selection
The study was approved by the Research Subjects Review Board at the University of Rochester. The pathology files from 2009 to 2015 were reviewed. Thirty-one breast carcinomas (including 3 DCIS only) from 29 BRCA carriers were identified. Fourteen of the 29 patients were with BRCA1 germline mutation, 13 had BRCA2, and 2 were BRCA carriers but not specified for BRCA1 or BRCA2. Twenty-four of the 29 patients had bilateral mastectomy, with 2 patients having bilateral breast cancers. Thirty-seven
Results
Twenty-eight of the 31 breast carcinomas from the BRCA carriers had ER/PR information; 16 were ER/PR positive (3 BRCA1, 10 BRCA2, 3 BRCA1/2 unspecified), and 12 were negative (9 BRCA1, 3 BRCA2). Twenty-six of the 31 tumors had Her2 information, but only 1 was Her2 positive (by fluorescence in situ hybridization); the others were all Her2 negative.
Valid p53 staining was obtained in 30 of the 31 breast carcinomas in BRCA carriers (tumor cells were cut through in 1 case); 25 were with invasive
Discussion
Our study showed that breast cancers in BRCA carriers were generally Her2 negative, as previously reported in the literature [14]. We also identified that cancers in BRCA1 carriers were mostly ER/PR/Her2 triple-negative and more frequently with a p53 alteration, whereas the cancers in BRCA2 carriers were mostly ER/PR positive/Her2 negative and less frequently with a p53 alteration, similar to what has been reported in other studies [15]. When we compared the p53 alteration rate in cancers in
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Disclosures: None.