MUTYH-Null Mice Are Susceptible to Spontaneous and Oxidative Stress–Induced Intestinal Tumorigenesis

Abstract

MUTYH is a mammalian DNA glycosylase that initiates base excision repair by excising adenine opposite 8-oxoguanine and 2-hydroxyadenine opposite guanine, thereby preventing G:C to T:A transversion caused by oxidative stress. Recently, biallelic germ-line mutations of MUTYH have been found in patients predisposed to a recessive form of hereditary multiple colorectal adenoma and carcinoma with an increased incidence of G:C to T:A somatic mutations in the APC gene. In the present study, a systematic histologic examination revealed that more spontaneous tumors had developed in MUTYH-null mice (72 of 121; 59.5%) than in the wild type (38 of 109; 34.9%). The increased incidence of intestinal tumors in MUTYH-null mice (11 tumors in 10 of 121 mice) was statistically significant compared with the wild type (no intestinal tumors in 109 mice). Two adenomas and seven adenocarcinomas were observed in the small intestines, and two adenomas but no carcinomas were found in the colons. In MUTYH-null mice treated with KBrO 3 , the occurrence of small intestinal tumors dramatically increased. The mean number of polyps induced in the small intestines of these mice was 61.88 (males, 72.75; females, 51.00), whereas it was 0.85 (males, 0.50; females, 1.00) in wild-type mice. The tumors developed predominantly in the duodenum and in the upper region of the (jejunum) small intestines. We conclude that MUTYH suppresses spontaneous tumorigenesis in mammals, thus providing experimental evidence for the association between biallelic germ-line MUTYH mutations and a recessive form of human hereditary colorectal adenoma and carcinoma. [Cancer Res 2007;67(14):6599-604]

Effects of base excision repair proteins on mutagenesis by 8-oxo-7,8-dihydroguanine (8-hydroxyguanine) paired with cytosine and adenine

“…The four DNA glycosylases each function in the suppression of mutations by 8-oxo-Gua in DNA. The overlapped recognition of 8-oxo-Gua could explain the fact that single knock-out mice deficient in OGG1, MUTYH, NTH1, and NEIL1 show few tumor phenotypes [57,[65][66][67][68][69][70][71]. In contrast, there is evidence to support the view that polymorphisms in these DNA glycosylases are associated with human carcinogenesis (reviewed in 72).…”

Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

“…As discussed earlier, mutations in MutY have been associated with human colorectal cancer and autosomal recessive familial adenomatous polyposis, characterized by the development of multiple colorectal adenomas [Al-Tassan et al, 2002;Parker et al, 2002;Chow et al, 2004;Isidro et al, 2004;Dallosso et al, 2008;Casorelli et al, 2010;Kundu et al 2010;Oka and Nakabeppu, 2011;Mazzei et al, 2013]. Similarly, MutY 2/2 mice are prone to intestinal tumors and display greater sensitivity to potassium bromate induced tumorigenesis [Sakamoto et al 2007], unlike Ogg1 2/2 mice that are largely immune to the carcinogenic effects of potassium bromate [Arai et al, 2006]. Compound deletion of MUTY in an OGG1-deficient background resulted in increased tumor incidence in multiple tissues, including liver, lung, colon, heart, spleen, and kidney, resulting in a significant effect on mortality, relative to WT controls [Xie et al, 2004].…”

Tumour–stroma interactions in colorectal cancer: converging on β-catenin activation and cancer stemness

“…In fact, Cleven et al (2007), showed that expression of HIF1a in the stromal compartment correlates with poor prognosis in colorectal cancer. Moreover, loss of MUTYH function, a DNA glycogylase involved in base excision repair caused by oxidative stress, results in increased susceptibility to spontaneous and oxidative stressinduced (by the oxidative reagent KbrO3) intestinal tumorigenesis (Sakamoto et al, 2007). These data indicate that hypoxia and oxidative stress play a pivotal role in colorectal cancer progression.…”