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.
Scientific reports. 2022 May 20*** epublish ***
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
Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan., Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ., Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan., Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. .