title: 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.
authors.affiliation: Departments of Medical Biophysics and Radiation Biology, Clinical Radiology, and Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Yohei
authors.initials: Y
authors.lastname: Tominaga
authors.forename: Kazumi
authors.initials: K
authors.lastname: Yamauchi
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Nakatsu
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Sakumi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yoshiyama
authors.forename: Akinori
authors.initials: A
authors.lastname: Egashira
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kura
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
authors.forename: Masazumi
authors.initials: M
authors.lastname: Tsuneyoshi
authors.forename: Hisaji
authors.initials: H
authors.lastname: Maki
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Tsuzuki
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D018384:Oxidative Stress
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase