Fenton reaction‐induced renal carcinogenesis in Mutyh ‐deficient mice exhibits less chromosomal aberrations than the rat model

Oxidative stress including iron excess has been associated with carcinogenesis. The level of 8‐oxoguanine, a major oxidatively modified base in DNA, is maintained very low by three distinct enzymes, encoded by OGG1 , MUTYH and MTH1 . Germline biallelic inactivation of MUTYH represents a familial cancer syndrome called MUTYH‐associated polyposis. Here, we used Mutyh ‐deficient mice to evaluate renal carcinogenesis induced by ferric nitrilotriacetate (Fe‐NTA). Although the C57BL/6 background is cancer‐resistant, a repeated intraperitoneal administration of Fe‐NTA induced a high incidence of renal cell carcinoma (RCC; 26.7%) in Mutyh ‐deficient mice in comparison to wild‐type mice (7.1%). Fe‐NTA treatment also induced renal malignant lymphoma, which did not occur without the Fe‐NTA treatment in both the genotypes. Renal tumor‐free survival after Fe‐NTA treatment was marginally different ( P  = 0.157) between the two genotypes. Array‐based comparative genome hybridization analyses revealed, in RCC, the loss of heterozygosity in chromosomes 4 and 12 without p16 INK [4][Toyokuni S., 2009] A inactivation; these results were confirmed by a methylation analysis and showed no significant difference between the genotypes. Lymphomas showed a preference for genomic amplifications. Dlk1 inactivation by promoter methylation may be involved in carcinogenesis in both tumors. Fe‐NTA‐induced murine RCCs revealed significantly less genomic aberrations than those in rats, demonstrating a marked species difference.