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Increased, Insufficient repair or mis-repair of pro-mutagenic DNA adducts leads to Increased, Induced Mutations in Critical Genes
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|AFB1: Mutagenic Mode-of-Action leading to Hepatocellular Carcinoma (HCC)||adjacent||Moderate||Ted Simon (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
There is no direct information concerning insufficient or mis-repair of AFB1 promutagenic adducts leading directly to mutations in critical genes. It is well known, however, that in general when the repair of DNA adducts is either done incorrectly or is insufficient to remove the DNA adduct and correct the DNA sequence prior to DNA replication, a mutation at the site of the DNA adduct will result in the daughter cells upon DNA replication.
Evidence Collection Strategy
Evidence Supporting this KER
When DNA adducts are not repaired, mutations result if cell replication (and DNA synthesis) takes place.
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
1. Bedard LL, and Massey TE. Aflatoxin B1-induced DNA damage and its repair. Cancer Lett. 2006, Sep 28;241(2):174-83.
2. Bedard LL, Alessi M, Davey S, and Massey TE. Susceptibility to aflatoxin B1-induced carcinogenesis correlates with tissue-specific differences in DNA repair activity in mouse and in rat. Cancer Res. 2005, Feb 15;65(4):1265-70.
3. Smith BT, and Walker GC. Mutagenesis and more: umuDC and the Escherichia coli SOS response. Genetics. 1998, Apr;148(4):1599-610.
4. Bailey EA, Iyer RS, Stone MP, Harris TM, and Essigmann JM. Mutational properties of the primary aflatoxin B1-DNA adduct. Proc Natl Acad Sci U S A. 1996, Feb 20;93(4):1535-9.
5. Denissenko MF, Koudriakova TB, Smith L, O'Connor TR, Riggs AD, and Pfeifer GP. The p53 codon 249 mutational hotspot in hepatocellular carcinoma is not related to selective formation or persistence of aflatoxin B1 adducts. Oncogene. 1998, Dec 10;17(23):3007-14.
6. Banerjee S, Brown KL, Egli M, and Stone MP. Bypass of aflatoxin B1 adducts by the Sulfolobus solfataricus DNA polymerase IV. J Am Chem Soc. 2011, Aug 17;133(32):12556-68.
7. Guo Y, Breeden LL, Zarbl H, Preston BD, and Eaton DL. Expression of a human cytochrome p450 in yeast permits analysis of pathways for response to and repair of aflatoxin-induced DNA damage. Mol Cell Biol. 2005, Jul;25(14):5823-33.
8. Alekseyev YO, Hamm ML, and Essigmann JM. Aflatoxin B1 formamidopyrimidine adducts are preferentially repaired by the nucleotide excision repair pathway in vivo. Carcinogenesis. 2004, Jun;25(6):1045-51. 9. Kew MC. Aflatoxins as a cause of hepatocellular carcinoma. J Gastrointestin Liver Dis. 2013, Sep;22(3):305-10.
10. Mulder JE, Bondy GS, Mehta R, and Massey TE. Up-regulation of nucleotide excision repair in mouse lung and liver following chronic exposure to aflatoxin B₁ and its dependence on p53 genotype. Toxicol Appl Pharmacol. 2014, Mar 1;275(2):96-103.
11. Kirk GD, Turner PC, Gong Y, Lesi OA, Mendy M, Goedert JJ, et al. Hepatocellular carcinoma and polymorphisms in carcinogen-metabolizing and DNA repair enzymes in a population with aflatoxin exposure and hepatitis B virus endemicity. Cancer Epidemiol Biomarkers Prev. 2005, Feb;14(2):373-9.
12. Long XD, Ma Y, Wei YP, and Deng ZL. The polymorphisms of GSTM1, GSTT1, HYL1*2, and XRCC1, and aflatoxin B1-related hepatocellular carcinoma in Guangxi population, China. Hepatol Res. 2006, Sep;36(1):48-55.
13. Long XD, Ma Y, Qu de Y, Liu YG, Huang ZQ, Huang YZ, et al. The polymorphism of XRCC3 codon 241 and AFB1-related hepatocellular carcinoma in Guangxi population, China. Ann Epidemiol. 2008, Jul;18(7):572-8.
14. Long XD, Ma Y, Huang HD, Yao JG, Qu de Y, and Lu YL. Polymorphism of XRCC1 and the frequency of mutation in codon 249 of the p53 gene in hepatocellular carcinoma among Guangxi population, China. Mol Carcinog. 2008, Apr;47(4):295-300.
15. Long X-D, Ma Y, and Deng Z-L. GSTM1 and XRCC3 polymorphisms: Effects on levels of aflatoxin B1-DNA adducts. Chinese Journal of Cancer Research. 2009, Sep;21(3):177-184.
16. Besaratinia A, Kim SI, Hainaut P, and Pfeifer GP. In vitro recapitulating of TP53 mutagenesis in hepatocellular carcinoma associated with dietary aflatoxin B1 exposure. Gastroenterology. 2009, Sep;137(3):1127-37, 1137.e1-5.
17. Lin YC, Li L, Makarova AV, Burgers PM, Stone MP, and Lloyd RS. Error-prone Replication Bypass of the Primary Aflatoxin B1 DNA Adduct, AFB1-N7-Gua. J Biol Chem. 2014, May 16;
18. Lin YC, Li L, Makarova AV, Burgers PM, Stone MP, and Lloyd RS. Molecular basis of aflatoxin-induced mutagenesis--role of the aflatoxin B1-formamidopyrimidine adduct. Carcinogenesis. 2014, Feb 7;
19. Leung MC, Goldstone JV, Boyd WA, Freedman JH, and Meyer JN. Caenorhabditis elegans generates biologically relevant levels of genotoxic metabolites from aflatoxin B1 but not benzo[a]pyrene in vivo. Toxicol Sci. 2010, Dec;118(2):444-53.
20. Meier B, Cooke SL, Weiss J, Bailly AP, Alexandrov LB, Marshall J, et al. C. elegans whole genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency. Genome Res. 2014, Jul 16;
21. de Carvalho FM, de Almeida Pereira T, Gonçalves PL, Jarske RD, Pereira FE, and Louro ID. Hepatocellular carcinoma and liver cirrhosis TP53 mutation analysis reflects a moderate dietary exposure to aflatoxins in Espírito Santo State, Brazil. Mol Biol Rep. 2013, Aug;40(8):4883-7.
22. Gursoy-Yuzugullu O, Yuzugullu H, Yilmaz M, and Ozturk M. Aflatoxin genotoxicity is associated with a defective DNA damage response bypassing p53 activation. Liver Int. 2011, Apr;31(4):561-71.
23. Szymañska K, Chen JG, Cui Y, Gong YY, Turner PC, Villar S, et al. TP53 R249S mutations, exposure to aflatoxin, and occurrence of hepatocellular carcinoma in a cohort of chronic hepatitis B virus carriers from Qidong, China. Cancer Epidemiol Biomarkers Prev. 2009, May;18(5):1638-43.
24. Villar S, Le Roux-Goglin E, Gouas DA, Plymoth A, Ferro G, Boniol M, et al. Seasonal variation in TP53 R249S-mutated serum DNA with aflatoxin exposure and hepatitis B virus infection. Environ Health Perspect. 2011, Nov;119(11):1635-40.
25. Macé K, Aguilar F, Wang JS, Vautravers P, Gómez-Lechón M, Gonzalez FJ, et al. Aflatoxin B1-induced DNA adduct formation and p53 mutations in CYP450-expressing human liver cell lines. Carcinogenesis. 1997, Jul;18(7):1291-7.
26. Aguilar F, Hussain SP, and Cerutti P. Aflatoxin B1 induces the transversion of G-->T in codon 249 of the p53 tumor suppressor gene in human hepatocytes. Proc Natl Acad Sci U S A. 1993, Sep 15;90(18):8586-90.
27. Preston RJ, Williams GM. (2005). DNA-reactive carcinogens: mode of action and human cancer hazard. Crit Rev Toxicol, 35, 673–83
28. Pottenger, L.H., Andrews LS, Bachman AN, Boogaard PJ, Cadet J, Embry MR, Farmer PB, Himmelstein MW, Jarabek AM, Martin EA, Mauthe RJ, Persaud R, Preston RJ, Schoeny R, Skare J, Swenberg JA, Williams GM, Zeiger E, Zhang F, Kim JH. (2014). An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B1, tamoxifen and vinyl chloride. Crit. Rev. Toxicol. 44(4):348-391.
29. Puisieux A, Lim S, Groopman J, Ozturk M. (1991). Selective targeting of p53 gene mutational hotspots in human cancers by etiologically defined carcinogens. Cancer Res. 51(22):6185-6189.