Elsevier

Human Pathology

Volume 71, January 2018, Pages 135-144
Human Pathology

Original contribution
BRCA1 and BRCA2 expression patterns and prognostic significance in digestive system cancers,☆☆

https://doi.org/10.1016/j.humpath.2017.10.032Get rights and content

Highlights

  • Evaluation of BRCA1/2 by IHC may provide prognostic information for four digestive system cancers.

  • BRCA1/2 is commonly associated with tumor stages in digestive system cancers.

  • Expression patterns and subcellular localization of BRCA1/2 are similar in digestive system cancers.

Summary

The role of BRCA1 and BRCA2 genes is mainly to maintain genome integrity in response to DNA damage through different mechanisms. Deregulation of BRCA1 and BRCA2 is associated with the development of tumor and altered sensitivity to chemotherapeutic agents. In this study, we determined protein expression of BRCA1 and BRCA2 in 4 digestive system cancers (gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer) by immunohistochemistry on tissue microarrays. A total of 1546 samples of 4 types of cancer tissues, their matched adjacent nontumor tissues, and corresponding benign tissues were studied, respectively. Immunohistochemistry expression patterns of the 2 proteins and their correlation with patients' clinical parameters and overall survival were analyzed. The results showed that low expression of cytoplasmic BRCA1 and BRCA2 was commonly associated with advanced tumor–lymph node–metastasis stage, whereas high expression of nuclear BRCA1 was generally correlated with advanced tumor stages in these cancers. High expression of cytoplasmic BRCA1 and BRCA2 had significantly favorable overall survival in digestive system cancers; in contrast, BRCA1 nuclear expression usually predicted poor outcomes. We conclude that BRCA1 and BRCA2 could be used as clinicopathological biomarkers to evaluate the prognosis of digestive system cancers.

Introduction

Digestive system tumors, such as gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), and pancreatic cancer (PC), have become the most terrible threats to human health. GC, CRC, and HCC are highly prevalent, ranking among the top causes of cancer-related mortality worldwide [1]. During the past years, comprehensive treatment strategies including surgery, chemotherapy, radiotherapy, and targeted therapy have been applied to digestive system cancers, but still yielding disappointing outcomes. Therefore, it is crucial to identify prognostic markers to obtain additional prognostic information and guide more effective clinical therapy for patients with digestive system cancers.

BRCA1 and BRCA2 are 2 major breast and ovarian cancer susceptibility genes. They are tumor suppressor genes, and their protein products are ubiquitously expressed and involved in fundamental cellular processes. Both of the proteins are essential for the preservation of genome integrity by repairing damaged DNA, especially double-stranded break (DSB), yet acting through distinct mechanisms [2], [3]. DSB is the most threatening form of DNA damage within the cell, which could arise from exogenous agents (eg, ionizing radiation) and endogenously generated reactive oxygen species but predominately from DNA replication during cell division. The improper repair of important DSBs impairs the chromosomal stability, and the loss of genetic stability due to failure of DNA repair may augment cancer susceptibility. It has been well recognized that deficiency in DNA damage repair is a fundamental etiological factor of various human cancers. Germline mutations in 1 copy of either gene of BRCA1 and BRCA2 can cause hereditary breast and ovarian cancer syndrome, which is characterized by not only early onset breast cancer but also an increased risk of developing cancer in ovary, pancreas, stomach, laryngeal, fallopian tube, and prostate [4], [5], [6], [7], [8], [9]. Given their omnipresent expression and association with tumorigenesis, numerous studies have investigated the association of mutations in BRCA1 and BRCA2 with cancer prognosis. However, prognostic values of BRCA1 or BRCA2 protein expression in cancers have not been extensively evaluated.

Immunolocalization of BRCA proteins by immunohistochemistry (IHC) has been reported in limited human carcinomas including breast cancer, epithelial ovarian carcinoma, and prostate cancer and may be a promising prognostic biomarker for them [10], [11], [12]. IHC is an easy and inexpensive routine test that is available to most pathologists. It is worthy of noting that some factors can influence the comparability of the results between different studies. So far, few researches have been conducted on determining prognostic values of BRCA protein expression in multiple cancer types under the same IHC conditions. With this in mind, we carried out this study using IHC on tissue microarrays to assess the protein expression patterns and prognostic values of BRCA1 and BRCA2 in digestive system tumors including gastric, colorectal, liver, and pancreatic cancers.

Section snippets

Human tissue specimens and patient clinical information

We retrieved all tissue blocks (formalin-fixed, paraffin-embedded tissue samples) from the Department of Pathology, Affiliated Hospital of Nantong University, between 2003 and 2012. We have a total of 627 tissues for GC study, comprising 14 tissues from chronic gastritis, 16 intestinal metaplasias, 26 low-grade intraepithelial neoplasias (LGINs), 14 high-grade intraepithelial neoplasias (HGINs), 478 gastric cancers, and 79 surgical margins. A total of 442 tissues were collected for CRC study,

BRCA1 and BRCA2 expression in normal, benign, and cancer tissues

BRCA1 stained in the cytoplasm and nuclei of glandular epithelium and tumor cells to different extents, whereas BRCA2 was only detected in the cytoplasm of normal and cancerous cells. Moreover, neither of the 2 markers was visualized in stromal cells (Fig. 1, Fig. 2, Fig. 3, Fig. 4). IHC distributions of BRCA1 and BRCA2 in different cancers are summarized in the Table. We used cutoff values to dichotomize IHC staining scores of the 2 markers. The cutoff points for BRCA1 (cytoplasm and nucleus)

Discussion

BRCA1 and BRCA2 play versatile roles in several DNA repair pathways (eg, homologous recombination, nonhomologous end joining, and single-strand annealing) and in checkpoint regulation. During homologous recombination, BRCA1 is like a signaling mediator, acting as a linkage between the sensors that detect DNA damage and effectors that execute proper DSBs repair [18]. BRCA2 primarily functions through interaction with RAD51 to trigger DSB repair [19]. When the homologous recombination pathway is

Supplementary data

The following are the Supplementary data to this article.

Supplementary tables

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    Competing interests: none.

    ☆☆

    Funding/Support: This study was supported by research grants from the Elite Program of Affiliated Hospital of Nantong University, the 226 Talent Training Program of Nantong City, Nantong, Jiangsu, PRC, and the National Natural Science Foundation of China (81702086).

    1

    Gui-Hua Wang and Chun-Mei Zhao contributed equally to the manuscript.

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