Exposure to asbestos fiber is central to mesothelial carcinogenesis. Recent sequencing studies on human and rodent malignant mesothelioma (MM) revealed frequently mutated genes, including CDKN2A, BAP1 and NF2. Crocidolite directly or indirectly catalyses the generation of hydroxyl radicals, which appears to be the major driving force for mesothelial mutations. DNA base modification is an oxidative DNA damage mechanism, where 8-hydroxy-2′-deoxyguanosine (8-OHdG) is the most abundant modification both physiologically and pathologically. Multiple distinct mechanisms work together to decrease the genomic level of 8-OHdG through the enzymatic activities of Mutyh, Ogg1 and Mth1. Knockout of one or multiple enzymes is not lethal but increases the incidence of tumors. Here, we used single knockout (KO) mice to test whether the deficiency of these three genes affects the incidence and prognosis of asbestos-induced MM. Intraperitoneal injection of 3 mg crocidolite induced MM at a fraction of 14.8% (4/27) in Mth1 KO, 41.4% (12/29) in Mutyh KO and 24.0% (6/25) in Ogg1 KO mice, whereas 31.7% (20/63) induction was observed in C57BL/6 wild-type (Wt) mice. The lifespan of female Mth1 KO mice was longer than that of female Wt mice (p = 0.0468). Whole genome scanning of MM with array-based comparative genomic hybridization revealed rare genomic alterations compared to MM in rats and humans. These results indicate that neither Mutyh deficiency nor Ogg1 deficiency promotes crocidolite-induced MM in mice, but the sanitizing nucleotide pool with Mth1 is advantageous in crocidolite-induced mesothelial carcinogenesis.

接触石棉纤维是间皮癌变的关键。最近对人类和啮齿动物恶性间皮瘤（MM）进行的测序研究表明，经常突变的基因包括CDKN2A，BAP1和NF2。青花石直接或间接催化羟基自由基的产生，这似乎是间皮突变的主要驱动力。DNA碱基修饰是一种氧化性DNA损伤机制，其中8-羟基-2'-脱氧鸟苷（8-OHdG）在生理和病理上都是最丰富的修饰。多种不同的机制共同作用，通过Mutyh，Ogg1和Mth1的酶促活性降低8-OHdG的基因组水平。敲除一种或多种酶不是致命的，但会增加肿瘤的发生率。在这里，我们使用单基因敲除（KO）小鼠来测试这三个基因的缺乏是否影响石棉诱发的MM的发生率和预后。腹膜内注射3mg的青石棉为14.8％（4/27）的馏分诱导MM的MTH1在KO，41.4％（12/29）MUTYH KO和24.0％（6/25）OGG1 KO小鼠，而31.7％（在C57BL / 6野生型（Wt）小鼠中观察到诱导（20/63）。Mth1 KO雌性小鼠的寿命比Wt雌性小鼠（p = 0.0468）。通过基于阵列的比较基因组杂交对MM进行全基因组扫描，发现与大鼠和人类中的MM相比，罕见的基因组改变。这些结果表明Mutyh缺乏症或Ogg1缺乏症都不会促进青石棉诱发的小鼠MM，但是用Mth1清除核苷酸库在青石棉诱发的间皮癌变中具有优势。