Elsevier

Human Pathology

Volume 68, October 2017, Pages 22-25
Human Pathology

In this issue
p53 alteration in morphologically normal/benign breast luminal cells in BRCA carriers with or without history of breast cancer

https://doi.org/10.1016/j.humpath.2017.04.007Get rights and content

Highlights

  • Previously published “breast p53 signature” in general population.

  • p53 alteration frequency in triple-negative breast carcinomas is the same in BRCA carriers and noncarriers.

  • In BRCA carriers, focal p53 positivity in normal/benign luminal cells:

    • o

      Correlates with p53 status in corresponding tumors

    • o

      Same frequency between prophylactic mastectomies and mastectomies for breast cancers

    • o

      Frequency much higher in prophylactic mastectomy than mammoplasty from general population

  • We explain why BRCA carriers have much higher risk of developing breast carcinomas, especially p53-positive carcinomas.

Summary

Germline 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. Furthermore, in BRCA carriers' prophylactic mastectomies, 12 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 gene mutations could result in genomic instability and an elevated gene mutation rate (such as the p53 gene) in breast luminal cells compared with the general population, predisposing BRCA carriers to develop p53-positive/triple-negative breast carcinomas.

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

References (17)

There are more references available in the full text version of this article.

Cited by (8)

  • Interaction of p53 with BRC analogs: A comparative design assisted by ZDOCK and CABS-Dock simulation

    2023, Journal of Molecular Structure
    Citation Excerpt :

    Mutations in these regions can lead to defective cell division and cancer development. In BRCA-associated cancers, a mutation in the BRCA2 gene is strongly correlated with a p53 mutation [5]. It has been reported that the interaction between BRCA2 and p53 plays an essential role in DNA repair pathways, polypeptides can promote the release of the p53 protein, and induce cell cycle arrest and apoptosis.

  • Characterizing TP53 mutations in ovarian carcinomas with and without concurrent BRCA1 or BRCA2 mutations

    2021, Gynecologic Oncology
    Citation Excerpt :

    Our study is one of the largest prospective cohorts specifically examining the distribution of co-occurrent mutations in these two driver pathways and findings were further replicated using TCGA and PanCancer Atlas data. In ovarian and breast carcinoma, p53 IHC analyses have previously demonstrated more frequent aberrant expression reflective of missense mutations in BRCA-mutation carriers [6,25–27]. Our data suggest that TP53 mutations may be a pre-requisite in most BRCA-associated carcinogenesis.

  • Exploring Ductal Carcinoma In-Situ to Invasive Ductal Carcinoma Transitions Using Energy Minimization Principles

    2022, Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
View all citing articles on Scopus

Disclosures: None.

View full text