title: Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer.
abstract: Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.
authors.affiliation: Department of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Akatsuka
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohara
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Liu
authors.forename: Masashi
authors.initials: M
authors.lastname: Izumiya
authors.forename: Koichiro
authors.initials: K
authors.lastname: Abe
authors.forename: Masako
authors.initials: M
authors.lastname: Ochiai
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Nagai
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Hideki
authors.initials: H
authors.lastname: Murakami
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Eri
authors.initials: E
authors.lastname: Arai
authors.forename: Yae
authors.initials: Y
authors.lastname: Kanai
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D002874:Chromosome Mapping / Q000379:methods; D055028:Comparative Genomic Hybridization; D017353:Gene Deletion; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D006801:Humans; D007501:Iron / Q000737:chemistry*; D007680:Kidney Neoplasms / Q000378:metabolism; D008956:Models, Chemical; D009369:Neoplasms / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D007501:Iron