Oxidative stress–induced DNA damage and its repair systems are related to cancer etiology; however, the molecular basis triggering tumorigenesis is not well understood. Here, we aimed to explore the causal relationship between oxidative stress, somatic mutations in pre-tumor-initiated normal tissues, and tumor incidence in the small intestines of MUTYH-proficient and MUTYH-deficient mice. MUTYH is a base excision repair enzyme associated with human colorectal cancer. Mice were administered different concentrations of potassium bromate (KBrO₃; an oxidizing agent)–containing water for 4 wk for mutagenesis studies or 16 wk for tumorigenesis studies. All Mutyh^−/− mice treated with >0.1% KBrO₃ developed multiple tumors, and the average tumor number increased dose dependently. Somatic mutation analysis of Mutyh^−/−/rpsL transgenic mice revealed that G:C > T:A transversion was the only mutation type correlated positively with KBrO₃ dose and tumor incidence. These mutations preferentially occurred at 5′G in GG and GAA sequences in rpsL. This characteristic mutation pattern was also observed in the genomic region of Mutyh^−/− tumors using whole-exome sequencing. It closely corresponded to signature 18 and SBS36, typically caused by 8-oxo-guanine (8-oxoG). 8-oxoG-induced mutations were sequence context dependent, yielding a biased amino acid change leading to missense and stop-gain mutations. These mutations frequently occurred in critical amino acid codons of known cancer drivers, Apc or Ctnnb1, known for activating Wnt signal pathway. Our results indicate that oxidative stress contributes to increased tumor incidence by elevating the likelihood of gaining driver mutations by increasing 8-oxoG-mediated mutagenesis, particularly under MUTYH-deficient conditions.

中文翻译：

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氧化应激通过增强 MUTYH 缺陷小鼠中 8-氧代鸟嘌呤介导的诱变加速肠道肿瘤发生

氧化应激引起的DNA损伤及其修复系统与癌症病因有关；然而，引发肿瘤发生的分子基础尚不清楚。在这里，我们的目的是探讨氧化应激、肿瘤前启动的正常组织中的体细胞突变以及 MUTYH 熟练和 MUTYH 缺陷小鼠小肠肿瘤发生率之间的因果关系。 MUTYH 是一种与人类结直肠癌相关的碱基切除修复酶。小鼠被给予不同浓度的含有溴酸钾（KBrO ₃；一种氧化剂）的水4周用于诱变研究或16周用于肿瘤发生研究。所有用 >0.1% KBrO _3治疗的Mutyh ^−/−小鼠均出现多个肿瘤，且平均肿瘤数量呈剂量依赖性增加。Mutyh ^−/− / rpsL转基因小鼠的体细胞突变分析表明，G:C > T:A 颠换是唯一与 KBrO ₃剂量和肿瘤发生率正相关的突变类型。这些突变优先发生在rpsL中 GG 和 GAA 序列的 5'G 处。使用全外显子组测序在Mutyh ^−/−肿瘤的基因组区域中也观察到了这种特征突变模式。它与特征 18 和 SBS36 密切对应，通常由 8-氧代鸟嘌呤 (8-oxoG) 引起。 8-oxoG 诱导的突变是序列背景依赖性的，产生偏向的氨基酸变化，导致错义和停止突变。这些突变经常发生在已知癌症驱动因素Apc或Ctnnb1的关键氨基酸密码子中，这些密码子以激活 Wnt 信号通路而闻名。我们的结果表明，氧化应激通过增加 8-oxoG 介导的诱变来提高获得驱动突变的可能性，从而导致肿瘤发病率增加，特别是在 MUTYH 缺陷的条件下。