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

• Published in: Scientific reports Vol. 12; no. 1; p. 8535
• Main Authors: Tsukahara, Shigehiro, Shiota, Masaki, Takamatsu, Dai, Nagakawa, Shohei, Matsumoto, Takashi, Kiyokoba, Ryo, Yagi, Mikako, Setoyama, Daiki, Noda, Nozomi, Matsumoto, Shinya, Hayashi, Tetsutaro, Contreras-Sanz, Alberto, Black, Peter C., Inokuchi, Junichi, Kohashi, Kenichi, Oda, Yoshinao, Uchiumi, Takeshi, Eto, Masatoshi, Kang, Dongchon
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20-05-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67; 692/4025; 692/4028; Bladder cancer; Cancer; Cancer therapies; Chemotherapy; Cytotoxicity; Dehydrogenase; Dehydrogenases; DNA microarrays; Gemcitabine; Gene expression; Genomics; Humanities and Social Sciences; Immunohistochemistry; Invasiveness; Metabolites; Missense mutation; multidisciplinary; Science; Science (multidisciplinary); Western blotting
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-12528-3

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.