TY - JOUR
T1 - Cancer genomic profiling identified dihydropyrimidine dehydrogenase deficiency in bladder cancer promotes sensitivity to gemcitabine
AU - Tsukahara, Shigehiro
AU - Shiota, Masaki
AU - Takamatsu, Dai
AU - Nagakawa, Shohei
AU - Matsumoto, Takashi
AU - Kiyokoba, Ryo
AU - Yagi, Mikako
AU - Setoyama, Daiki
AU - Noda, Nozomi
AU - Matsumoto, Shinya
AU - Hayashi, Tetsutaro
AU - Contreras-Sanz, Alberto
AU - Black, Peter C.
AU - Inokuchi, Junichi
AU - Kouhashi, Kenichi
AU - Oda, Yoshinao
AU - Uchiumi, Takeshi
AU - Eto, Masatoshi
AU - Kang, Dongchon
N1 - Funding Information:
This work was supported by a grant from the Clinical Research Promotion Foundation. The funder had no role in the study design, data collection, data analysis, interpretation, or writing of the report. We would like to thank Ms. Harumi Inoue, Ms. Hoshimi Izumi, Ms. Noriko Hakoda, Ms. Eriko Gunshima, Ms. Mami Nakamizo, and the Research Support Center, Research Center for Human Disease Modeling, Kyushu University Graduate School of Medical Science, for technical assistance. Finally, we thank H. Nikki March, PhD, from Edanz ( https://jp.edanz.com/ac ) for editing a draft of this manuscript.
Funding Information:
This work was supported by a grant from the Clinical Research Promotion Foundation. The funder had no role in the study design, data collection, data analysis, interpretation, or writing of the report. We would like to thank Ms. Harumi Inoue, Ms. Hoshimi Izumi, Ms. Noriko Hakoda, Ms. Eriko Gunshima, Ms. Mami Nakamizo, and the Research Support Center, Research Center for Human Disease Modeling, Kyushu University Graduate School of Medical Science, for technical assistance. Finally, we thank H. Nikki March, PhD, from Edanz (https://jp.edanz.com/ac ) for editing a draft of this manuscript.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). However, genomic alterations associated with chemotherapy sensitivity in MIBC have not been fully explored. This study aimed to investigate the genomic landscape of MIBC in association with the response to chemotherapy and to explore the biological role of genomic alterations. Genomic alterations in MIBC were sequenced by targeted exome sequencing of 409 genes. Gene expression in MIBC tissues was analyzed by western blotting, immunohistochemistry, and RNA microarray. Cellular sensitivity to gemcitabine and gemcitabine metabolite was examined in bladder cancer cells after modulation of candidate gene. Targeted exome sequencing in 20 cases with MIBC revealed various genomic alterations including pathogenic missense mutation of DPYD gene encoding dihydropyrimidine dehydrogenase (DPD). Conversely, high DPYD and DPD expression were associated with poor response to gemcitabine-containing chemotherapy among patients with MIBC, as well as gemcitabine resistance in bladder cancer cells. DPD suppression rendered cells sensitive to gemcitabine, while DPD overexpression made cells gemcitabine-resistant through reduced activity of the cytotoxic gemcitabine metabolite difluorodeoxycytidine diphosphate. This study revealed the novel role of DPD in gemcitabine metabolism. It has been suggested that DPYD genomic alterations and DPD expression are potential predictive biomarkers in gemcitabine treatment.
AB - Chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). However, genomic alterations associated with chemotherapy sensitivity in MIBC have not been fully explored. This study aimed to investigate the genomic landscape of MIBC in association with the response to chemotherapy and to explore the biological role of genomic alterations. Genomic alterations in MIBC were sequenced by targeted exome sequencing of 409 genes. Gene expression in MIBC tissues was analyzed by western blotting, immunohistochemistry, and RNA microarray. Cellular sensitivity to gemcitabine and gemcitabine metabolite was examined in bladder cancer cells after modulation of candidate gene. Targeted exome sequencing in 20 cases with MIBC revealed various genomic alterations including pathogenic missense mutation of DPYD gene encoding dihydropyrimidine dehydrogenase (DPD). Conversely, high DPYD and DPD expression were associated with poor response to gemcitabine-containing chemotherapy among patients with MIBC, as well as gemcitabine resistance in bladder cancer cells. DPD suppression rendered cells sensitive to gemcitabine, while DPD overexpression made cells gemcitabine-resistant through reduced activity of the cytotoxic gemcitabine metabolite difluorodeoxycytidine diphosphate. This study revealed the novel role of DPD in gemcitabine metabolism. It has been suggested that DPYD genomic alterations and DPD expression are potential predictive biomarkers in gemcitabine treatment.
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UR - http://www.scopus.com/inward/citedby.url?scp=85130414051&partnerID=8YFLogxK
U2 - 10.1038/s41598-022-12528-3
DO - 10.1038/s41598-022-12528-3
M3 - Article
C2 - 35595780
AN - SCOPUS:85130414051
SN - 2045-2322
VL - 12
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 8535
ER -
