Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer

Takashi Hirosawa, Masaharu Ishida, Kentaro Ishii, Keigo Kanehara, Katsuyoshi Kudo, Shinobu Ohnuma, Takashi Kamei, Fuyuhiko Motoi, Takeshi Naitoh, Florin Selaru, Michiaki Unno

Research output: Contribution to journalArticle

Abstract

Background BRCA-1 associated protein (BAP1) is a de-ubiquitinating enzyme that regulates gene expression. Recently, the BAP1 mutation and its involvement in cancer survival have been reported in a range of tumor types, including uveal melanoma, mesothelioma, renal cancers, and biliary tract cancers. However, the frequency of BAP1 mutation and down-regulation varies among tumor types, and little is known about the function of BAP1 silencing in cancer cells. Gallbladder carcinoma (GBC) is a type of biliary tract cancer with a poor prognosis. Few mutational studies have investigated the role of BAP1 in GBC, and no functional study in vitro-, or clinical studies about cancer survival have been done. Methods GBC cells were studied by following the small interfering RNA mediated silencing of BAP1 with regard to proliferation, migration, invasion, and drug sensitivity. We carried out genomic, epigenomic and immunohistochemical analyses to detect somatic BAP1 alterations in 47 GBC patients undergoing surgical resection. Results BAP1 depletion resulted in increased migration and invasion, but not proliferation, and also resulted in decreased sensitivity to bortezomib, a proteasome inhibitor. Suppressed expression of BAP1 occurred in 22 GBC cases (46.8%) and showed a strong trend toward a worse median survival time of 13.3 months (95% CI, 17.6–62.6) (p = 0.0034). Sanger sequencing revealed a loss-of-function mutation of BAP1 in 11 out of these 22 GBC cases (50%) with low BAP1 expression, whereas 2 out of 25 GBC cases (8%) were detected in cases with high BAP1 expression. Partial changes in methylation were observed in 6 out of 47 cases, but methylation did not show a strong relationship to BAP1 expression or to the prognosis. Conclusion Our findings showed that genetic mutations are involved in BAP1 down-regulation, leading to promotion of the invasive character of cancer cells and poor prognosis in GBC.

Original languageEnglish (US)
Article numbere0206643
JournalPLoS One
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2018

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Gallbladder Neoplasms
Methylation
gall bladder
Gallbladder
carcinoma
Tumors
Cells
Carcinoma
mutation
Mutation
Proteasome Inhibitors
neoplasms
Biliary Tract Neoplasms
Gene expression
Small Interfering RNA
biliary tract
prognosis
Neoplasms
Pharmaceutical Preparations
methylation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Hirosawa, T., Ishida, M., Ishii, K., Kanehara, K., Kudo, K., Ohnuma, S., ... Unno, M. (2018). Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer. PLoS One, 13(11), [e0206643]. https://doi.org/10.1371/journal.pone.0206643

Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer. / Hirosawa, Takashi; Ishida, Masaharu; Ishii, Kentaro; Kanehara, Keigo; Kudo, Katsuyoshi; Ohnuma, Shinobu; Kamei, Takashi; Motoi, Fuyuhiko; Naitoh, Takeshi; Selaru, Florin; Unno, Michiaki.

In: PLoS One, Vol. 13, No. 11, e0206643, 01.11.2018.

Research output: Contribution to journalArticle

Hirosawa, T, Ishida, M, Ishii, K, Kanehara, K, Kudo, K, Ohnuma, S, Kamei, T, Motoi, F, Naitoh, T, Selaru, F & Unno, M 2018, 'Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer', PLoS One, vol. 13, no. 11, e0206643. https://doi.org/10.1371/journal.pone.0206643
Hirosawa, Takashi ; Ishida, Masaharu ; Ishii, Kentaro ; Kanehara, Keigo ; Kudo, Katsuyoshi ; Ohnuma, Shinobu ; Kamei, Takashi ; Motoi, Fuyuhiko ; Naitoh, Takeshi ; Selaru, Florin ; Unno, Michiaki. / Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer. In: PLoS One. 2018 ; Vol. 13, No. 11.
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abstract = "Background BRCA-1 associated protein (BAP1) is a de-ubiquitinating enzyme that regulates gene expression. Recently, the BAP1 mutation and its involvement in cancer survival have been reported in a range of tumor types, including uveal melanoma, mesothelioma, renal cancers, and biliary tract cancers. However, the frequency of BAP1 mutation and down-regulation varies among tumor types, and little is known about the function of BAP1 silencing in cancer cells. Gallbladder carcinoma (GBC) is a type of biliary tract cancer with a poor prognosis. Few mutational studies have investigated the role of BAP1 in GBC, and no functional study in vitro-, or clinical studies about cancer survival have been done. Methods GBC cells were studied by following the small interfering RNA mediated silencing of BAP1 with regard to proliferation, migration, invasion, and drug sensitivity. We carried out genomic, epigenomic and immunohistochemical analyses to detect somatic BAP1 alterations in 47 GBC patients undergoing surgical resection. Results BAP1 depletion resulted in increased migration and invasion, but not proliferation, and also resulted in decreased sensitivity to bortezomib, a proteasome inhibitor. Suppressed expression of BAP1 occurred in 22 GBC cases (46.8{\%}) and showed a strong trend toward a worse median survival time of 13.3 months (95{\%} CI, 17.6–62.6) (p = 0.0034). Sanger sequencing revealed a loss-of-function mutation of BAP1 in 11 out of these 22 GBC cases (50{\%}) with low BAP1 expression, whereas 2 out of 25 GBC cases (8{\%}) were detected in cases with high BAP1 expression. Partial changes in methylation were observed in 6 out of 47 cases, but methylation did not show a strong relationship to BAP1 expression or to the prognosis. Conclusion Our findings showed that genetic mutations are involved in BAP1 down-regulation, leading to promotion of the invasive character of cancer cells and poor prognosis in GBC.",
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AU - Kudo, Katsuyoshi

AU - Ohnuma, Shinobu

AU - Kamei, Takashi

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