Department of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
PLoS One. 2012;7(8):e43403. doi: 10.1371/journal.pone.0043403. Epub 2012 Aug 29.
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.
铁过载与人类致癌有关。铁氮三乙酸腹腔内给药会在啮齿动物的肾近端小管中引发芬顿反应，最终导致反复治疗后肾细胞癌（RCC）的发病率很高。我们进行了高分辨率微阵列比较基因组杂交，以确定这种氧化应激诱导的大鼠 RCC 基因组特征。结果显示广泛的大规模基因组改变，偏爱缺失。缺失和扩增很多，有时还会发生片段化，表明芬顿反应是体内发生这种基因组改变的原因。频率图表明，两个最常改变的基因座对应于 Cdkn2a/2b 缺失和 Met 扩增。肿瘤大小与 Met 表达和/或扩增呈比例相关，聚类分析证实了我们的结果。此外，我们开发了一种基于染色体同线性关系比较不同物种全基因组拷贝数改变模式的方法。大鼠 RCC 的模式与五种人类癌症中的人类 RCC 最为相似，其次是人类恶性间皮瘤，这是一种与铁过载相关的癌症。因此，铁依赖性芬顿化学反应在致癌过程中会导致大规模的基因组改变，这可能导致不同的基因组特征。基于人类癌症中广泛的基因组改变特征，我们的结果表明，这种化学反应可能在人类致癌过程中起主要作用。
