J Cancer 2022; 13(1):88-101. doi:10.7150/jca.65574 This issue

Research Paper

Somatic mutation and expression of BAP1 in hepatocellular carcinoma: an indicator for ferroptosis and immune checkpoint inhibitor therapies

Yu-Chuan Yan1, Guang-Xiao Meng1, Zi-Niu Ding1, Yan-Feng Liu1, Zhi-Qiang Chen1, Lun-Jie Yan1, Ya-Fei yang1, Hui Liu1, Chun-Cheng Yang1, Zhao-Ru Dong1, Jian-Guo Hong1✉, Tao Li1,2✉

1. Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
2. Department of hepatobiliary surgery, The second Hospital of Shandong University, Jinan 250012, P.R. China.

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Citation:
Yan YC, Meng GX, Ding ZN, Liu YF, Chen ZQ, Yan LJ, yang YF, Liu H, Yang CC, Dong ZR, Hong JG, Li T. Somatic mutation and expression of BAP1 in hepatocellular carcinoma: an indicator for ferroptosis and immune checkpoint inhibitor therapies. J Cancer 2022; 13(1):88-101. doi:10.7150/jca.65574. Available from https://www.jcancer.org/v13p0088.htm

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Abstract

Graphic abstract

BRCA1-Associated Protein 1 (BAP1) is a deubiquitylase that is found associated with multiprotein complexes that regulate key cellular pathways, and subsequent researches have revealed that BAP1 acts independently as a tumor suppressor. Somatic BAP1 mutations occur in various malignancies, but malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. Whether somatic mutation or expression alteration of BAP1 in hepatocellular carcinoma (HCC) influence carcinogenesis or immunogenicity is still unknown. In this study, we analyzed RNA expression, immune infiltration, survival and mutation data of HCC from The Cancer Genome Atlas databases. The association between BAP1 and clinicopathological features was further investigated by immunohistochemistry on tissue microarray. We found that the prognosis of patients with high BAP1 expression was significantly worse than that of patients with low BAP1 expression, and multivariate analyses revealed that BAP1 expression was an independent prognostic factor for poor prognosis. HCC with high BAP1 expression was associated with low ESTIMATE Score, recruitment of more tumor-infiltrating macrophage, and elevated levels of tumor mutation burden, microsatellite instability, neoantigen count, as well as programmed death-ligand1 in HCC. In addition, BAP1 mutated HCC showed reduced ability to promote ferroptosis and high BAP1 expression was correlated with ferroptosis. In conclusion, high BAP1 expression reflects immunosuppression and ferroptosis in HCC. BAP1 is a promising prognostic marker for survival of HCC and may act as a complementary indicator for patients to receive ferroptosis-promoting therapy or immunotherapy.

Keywords: hepatocellular carcinoma, BAP1, ferroptosis, mutation, immune checkpoint inhibitors