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Loss of BRCA1 expression and morphological features associated with BRCA1 promoter methylation status in triple-negative breast cancer

Abstract

Aberrant DNA methylation in the BRCA1 promoter region causes epigenetic silencing of BRCA1 gene expression, which is critical for breast cancer development. However, how BRCA1 promoter methylation status alters histological features remains poorly understood. Here, we investigated the possibility to predict BRCA1 promoter methylation status based on the morphological and immunohistochemical features of triple-negative breast cancers (TNBCs). The morphological features of 53 TNBCs were evaluated with hematoxylin-eosin staining, with immunohistochemical staining of BRCA1, androgen receptor, p53, cytokeratin 5/6, and epidermal growth factor receptor. BRCA1 promoter methylation status was used to distinguish BRCA1 promoter-methylated tumors (BPMTs) from BRCA1 promoter-unmethylated tumors (BPUTs) dependent on pathological characteristics. BPMTs comprised approximately 26% of the TNBCs. Immunohistochemical analysis found that BRCA1 protein expression was significantly lower in BPMT compared with BPUT (p = 0.016). Morphologically, BPMTs were associated with high mitotic index (p = 0.017), pushing margin (p = 0.017), a circumscribed growth pattern (p = 0.014), and a syncytial growth pattern (p = 0.034) compared with BPUTs. We then assessed the potential of predicting BRCA1 promoter methylation status by using published score systems based on these morphological characteristics. A receiver operating characteristic analysis showed an area under the curve of 0.80. This study found that BRCA1 promoter methylation status could be derived from morphological features and lower BRCA1 expression of TNBCs, which may help identify suitable cases for target treatment with PARP inhibitors.

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Acknowledgements

We thank Aiko Nishimoto, Harumi Yamamura, and Kei Sakuma for their technical support. We are grateful to Dr. Reo Maruyama of the Cancer Institute of Japanese Foundation for Cancer Research for his helpful advice regarding the PCR products. We are indebted to Dr. Edward Barroga (https://orcid.org/0000–0002–8920–2607), Medical Editor, and Professor of Academic Writing at St. Luke’s International University, Tokyo, Japan, for reviewing and editing the manuscript. The authors acknowledge the assistance of Clear Science (www.clearscience.net) with the English language editing of this manuscript. Grants-in-aid supported this study for scientific research from the Japanese Foundation for Multidisciplinary Treatment of Cancer.

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Correspondence to Masahiko Tanabe.

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Morizono, A., Tanabe, M., Ikemura, M. et al. Loss of BRCA1 expression and morphological features associated with BRCA1 promoter methylation status in triple-negative breast cancer. J Hum Genet (2021). https://doi.org/10.1038/s10038-021-00911-3

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