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.
Highlights
Human cancers develop because of genetic and epigenetic changes induced by environmental and hereditary factors [1, 2]
In mice continuously receiving 0.05% BBN, hyperplasia, dysplasia, carcinoma in situ (CIS), and invasive tumors chronologically appeared in the bladder 4, 8, 12, and 20 weeks, respectively, after the start of the treatment (Fig 1B)
Histological examination revealed that superficial tumors in rats and invasive tumors in mice were of a mixed type containing urothelial carcinomas and squamous cell carcinomas (Fig 1)
Summary
Human cancers develop because of genetic and epigenetic changes induced by environmental and hereditary factors [1, 2]. Sampson et al have recently reported the estimation of the heritability of bladder cancer and its proportion attributable to cigarette smoking based on genome-wide association studies (GWASs) [9]. Cigarette smoking as well as occupational exposure to paint components, polycyclic aromatic hydrocarbons, and aromatic amines are known as environmental risk factors of bladder cancer [10, 11]. Using candidate-gene approach, a previous study has demonstrated the association between an increased risk of bladder cancer and deletion of the GSTM1 gene on human chromosome 1p13.3, which is involved in the metabolism of carcinogens [12]. Many GWASs revealed a correlation between an increased risk of bladder cancer and single nucleotide polymorphisms (SNPs) [13,14,15,16,17,18]
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