Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan;
Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
Genome Res. 2024 Feb 7;34(1):47-56. doi: 10.1101/gr.278326.123.
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 (KBrO; an oxidizing agent)-containing water for 4 wk for mutagenesis studies or 16 wk for tumorigenesis studies. All mice treated with >0.1% KBrO developed multiple tumors, and the average tumor number increased dose dependently. Somatic mutation analysis of / transgenic mice revealed that G:C > T:A transversion was the only mutation type correlated positively with KBrO dose and tumor incidence. These mutations preferentially occurred at 5'G in GG and GAA sequences in This characteristic mutation pattern was also observed in the genomic region of 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, or , 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.
氧化应激诱导的 DNA 损伤及其修复系统与癌症的发生有关；然而，触发肿瘤发生的分子基础尚不清楚。在这里，我们旨在探讨氧化应激、肿瘤起始前正常组织中的体细胞突变与 MUTYH 功能正常和缺失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。将小鼠用不同浓度的含溴酸钾（KBrO；一种氧化剂）的水进行 4 周的诱变研究或 16 周的肿瘤发生研究。所有用 >0.1% KBrO 处理的小鼠均发展出多个肿瘤，并且肿瘤数量与剂量呈依赖性增加。/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 剂量和肿瘤发生率呈正相关的突变类型。这些突变优先发生在 GG 和 GAA 序列的 5'G 中，在 肿瘤的全外显子测序中也观察到这种特征性的突变模式。它与特征性 18 和 SBS36 密切对应，通常由 8-氧鸟嘌呤（8-oxoG）引起。8-oxoG 诱导的突变是序列上下文依赖性的，导致偏向性氨基酸变化，导致错义和无义突变。这些突变经常发生在已知的癌症驱动基因，如 或 ，已知的激活 Wnt 信号通路的关键氨基酸密码子中。我们的结果表明，氧化应激通过增加 8-oxoG 介导的诱变导致获得驱动突变的可能性，从而增加肿瘤发生率，特别是在 MUTYH 缺失的情况下。
