Cancer genomic profiling identified dihydropyrimidine dehydrogenase deficiency in bladder cancer promotes sensitivity to gemcitabine

Shigehiro Tsukahara, Masaki Shiota, Dai Takamatsu, Shohei Nagakawa, Takashi Matsumoto, Ryo Kiyokoba, Mikako Yagi, Daiki Setoyama, Nozomi Noda, Shinya Matsumoto, Tetsutaro Hayashi, Alberto Contreras-Sanz, Peter C. Black, Junichi Inokuchi, Kenichi Kohashi, Yoshinao Oda, Takeshi Uchiumi, Masatoshi Eto, Dongchon Kang

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number8535
JournalScientific reports
Volume12
Issue number1
DOIs
Publication statusPublished - Dec 2022

All Science Journal Classification (ASJC) codes

  • General

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