The effect of dietary folate on Apc and p53 mutations in the dimethylhydrazine rat model of colorectal cancer

被引:22
作者
Sohn, KJ
Puchyr, M
Salomon, RN
Graeme-Cook, F
Fung, L
Choi, SW
Mason, JB
Medline, A
Kim, YI
机构
[1] St Michaels Hosp, Dept Med, Div Gastroenterol, Toronto, ON M5S 1A8, Canada
[2] Univ Toronto, Toronto, ON M5S 1A8, Canada
[3] Tufts Univ, Vitamin Metab Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, Medford, MA 02155 USA
[4] Tufts Univ, Sch Med, New England Med Ctr, Dept Pathol, Medford, MA 02155 USA
[5] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Cambridge, MA 02138 USA
[6] Tufts Univ, Sch Med, New England Med Ctr, Dept Internal Med,Div Gastroenterol, Boston, MA 02111 USA
[7] Tufts Univ, Sch Med, New England Med Ctr, Dept Internal Med,Div Clin Nutr, Boston, MA 02111 USA
[8] Univ Toronto, Dept Pathol, Toronto, ON, Canada
关键词
D O I
10.1093/carcin/20.12.2345
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Dietary inadequacy of folate enhances and folate supplementation suppresses colorectal carcinogenesis in the dimethylhydrazine rat model. Folate is an essential factor for DNA methylation and the de novo biosynthesis of nucleotides, aberrations of which play important roles in mutagenesis, This study investigated whether the mutational hot spots of the Ape and p53 genes for human colorectal cancer are mutated in dimethylhydrazine-induced colorectal neoplasms and whether dietary folate can modulate mutations in these regions. Rats were fed diets containing 0, 2 (basal requirement), 8 or 40 mg folate/ kg diet. Five weeks after diet initiation, dimethylhydrazine was injected weekly for 15 weeks. Mutations were determined by direct sequencing in 11 low and seven high grade dysplasias and 13 invasive adenocarcinomas. A total of six Ape mutations were found in four dysplastic and carcinomatous lesions: two in two low grade dysplasias, two in one high grade dysplasia and two in one adenocarcinoma. All mutations were single base substitutions, four of which were A:T-->G:C transitions. Five of the six mutations were located upstream from the region corresponding to the human APC mutation cluster region. Dietary folate had no effect on the frequency and type of Ape mutations. No mutations were detected in exons 5-9 of the p53 gene in neoplastic lesions. These data suggest that in the dimethylhydrazine rat model of colorectal cancer, the Ape gene is mutated in early stages, albeit to a lesser degree than observed in human colorectal cancer, whereas the mutational hot spot of the p53 gene for human colorectal cancer is not commonly mutated. Although the low frequency of Ape mutations and the small number of neoplasms studied in this study might have precluded our ability to observe modulatory effects of folate, dietary folate appears to have no significant effect on Ape and p53 mutations.
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收藏
页码:2345 / 2350
页数:6
相关论文
共 47 条
[31]   NO ALLELIC LOSS AT THE P53 LOCUS IN 1,2-DIMETHYLHYDRAZINE-INDUCED MOUSE COLON TUMORS - PCR SSCP ANALYSIS WITH SEQUENCE-TAGGED MICROSATELLITE SITE PRIMERS [J].
OKAMOTO, M ;
OHTSU, H ;
MIYAKI, M ;
YONEKAWA, H .
CARCINOGENESIS, 1993, 14 (07) :1483-1486
[32]   MSH2 DEFICIENT MICE ARE VIABLE AND SUSCEPTIBLE TO LYMPHOID TUMORS [J].
REITMAIR, AH ;
SCHMITS, R ;
EWEL, A ;
BAPAT, B ;
REDSTON, M ;
MITRI, A ;
WATERHOUSE, P ;
MITTRUCKER, HW ;
WAKEHAM, A ;
LIU, B ;
THOMASON, A ;
GRIESSER, H ;
GALLINGER, S ;
BALLHAUSEN, WG ;
FISHEL, R ;
MAK, TW .
NATURE GENETICS, 1995, 11 (01) :64-70
[33]   DYSPLASIA IN INFLAMMATORY BOWEL-DISEASE - STANDARDIZED CLASSIFICATION WITH PROVISIONAL CLINICAL-APPLICATIONS [J].
RIDDELL, RH ;
GOLDMAN, H ;
RANSOHOFF, DF ;
APPELMAN, HD ;
FENOGLIO, CM ;
HAGGITT, RC ;
AHREN, C ;
CORREA, P ;
HAMILTON, SR ;
MORSON, BC ;
SOMMERS, SC ;
YARDLEY, JH .
HUMAN PATHOLOGY, 1983, 14 (11) :931-968
[34]   5-METHYLCYTOSINE AS AN ENDOGENOUS MUTAGEN IN THE HUMAN LDL RECEPTOR AND P53 GENES [J].
RIDEOUT, WM ;
COETZEE, GA ;
OLUMI, AF ;
JONES, PA .
SCIENCE, 1990, 249 (4974) :1288-1290
[35]  
SHANE F, 1995, FOLATE HLTH DIS, P1
[36]   HIGH-FREQUENCY MUTAGENESIS BY A DNA METHYLTRANSFERASE [J].
SHEN, JC ;
RIDEOUT, WM ;
JONES, PA .
CELL, 1992, 71 (07) :1073-1080
[37]   ABSENCE OF P53 GENE-MUTATIONS IN RAT COLON CARCINOMAS INDUCED BY AZOXYMETHANE [J].
SHIVAPURKAR, N ;
BELINSKY, SA ;
WOLF, DC ;
TANG, ZC ;
ALABASTER, O .
CANCER LETTERS, 1995, 96 (01) :63-70
[38]   Absence of p53 gene mutations in rat colon carcinomas induced through the synergistic interaction between methylazoxymethanol and X-irradiation [J].
Shivapurkar, N ;
Nikula, KJ ;
Tanaka, T ;
Tang, ZC ;
Alabaster, O .
CANCER LETTERS, 1997, 113 (1-2) :9-16
[39]   Loss of Apc and the entire chromosome 18 but absence of mutations at the Ras and Tp53 genes in intestinal tumors from Apc1638N, a mouse model for Apc-driven carcinogenesis [J].
Smits, R ;
Kartheuser, A ;
JagmohanChangur, S ;
Leblanc, V ;
Breukel, C ;
deVries, A ;
vanKranen, H ;
vanKrieken, JH ;
Williamson, S ;
Edelmann, W ;
Kucherlapati, R ;
Kan, PM ;
Fodde, R .
CARCINOGENESIS, 1997, 18 (02) :321-327
[40]  
Suzui M, 1997, MOL CARCINOGEN, V20, P389, DOI 10.1002/(SICI)1098-2744(199712)20:4<389::AID-MC8>3.3.CO