title: Genomic Landscape of Experimental Bladder Cancer in Rodents and Its Application to Human Bladder Cancer: Gene Amplification and Potential Overexpression of Cyp2a5/CYP2A6 Are Associated with the Invasive Phenotype.
abstract: Non-muscle invasive (superficial) bladder cancer is a low-grade malignancy with good prognosis, while muscle invasive (invasive) bladder cancer is a high-grade malignancy with poor prognosis. N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) induces superficial bladder cancers with papillary morphology in rats and invasive bladder cancers with infiltrating phenotype in mice. In this study, we analyzed genomic landscapes of rodent BBN-induced bladder cancers using array-based comparative genomic hybridization (array CGH). While no significant copy number alterations were detected in superficial bladder tumors in rats, copy number gains in chromosomal regions 2D-E1, 7qA3, 9F2, and 11C-D were detected in invasive bladder tumors in mice. Amplification of representative genes located on 2D-E1 and 7qA3 chromosomal regions was confirmed by quantitative PCR. Cyp2a22 and Cyp2a5 genes but not Cyp2g1, Cyp2a12, and Rab4b genes on mouse chromosome 7qA3 were amplified in invasive bladder cancers. Although the human ortholog gene of Cyp2a22 has not been confirmed, the mouse Cyp2a5 gene is the ortholog of the human CYP2A6 gene located in chromosomal region 19q13.2, and CYP2A6 was identified by database search as one of the closest human homolog to mouse Cyp2a22. Considering a possibility that this region may be related to mouse 7qA3, we analyzed CYP2A6 copy number and expression in human bladder cancer using cell lines and resected tumor specimens. Although only one of eight cell lines showed more than one copy increase of the CYP2A6 gene, CYP2A6 amplification was detected in six out of 18 primary bladder tumors where it was associated with the invasive phenotype. Immunohistochemical analyses of 118 primary bladder tumors revealed that CYP2A6 protein expression was also higher in invasive tumors, especially in those of the scattered type. Together, these findings indicate that the amplification and overexpression of the CYP2A6 gene are characteristic of human bladder cancers with increased malignancy and that CYP2A6 can be a candidate prognostic biomarker in this type of cancer.
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan.|Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kanemoto
authors.affiliation: Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Fukuta
authors.affiliation: Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Kawai
authors.affiliation: Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tozawa
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Ochiai
authors.affiliation: Division of Cancer Differentiation, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Ohnami
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yae
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: Department of Omics Network, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Katoh
authors.affiliation: Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yasui
authors.affiliation: Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kohri
authors.affiliation: National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Kakizoe
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D045744:Cell Line, Tumor; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics*; D000072467:Cytochrome P450 Family 2 / Q000235:genetics*; D005784:Gene Amplification; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D010641:Phenotype; D051381:Rats; D026801:Synteny; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2