Linking environmental carcinogen exposure to TP53 mutations in human tumours using the human TP53 knock‐in (Hupki) mouse model

Abstract

TP53 is one of the most commonly mutated genes in human tumours. Variations in the types and frequencies of mutations at different tumour sites suggest that they may provide clues to the identity of the causative mutagenic agent. A useful model for studying human TP53 mutagenesis is the partial human TP53 knock‐in (Hupki) mouse containing exons 4–9 of human TP53 in place of the corresponding mouse exons. For an in vitro assay, embryo fibroblasts from the Hupki mouse can be examined for the generation and selection of TP53 mutations because mouse cells can be immortalized by mutation of Tp53 alone. Thus far, four environmental carcinogens have been examined using the Hupki embryo fibroblast immortalization assay: (a) UV light, which is linked to human skin cancer; (b) benzo[a]pyrene, which is associated with tobacco smoke‐induced lung cancer; (c) 3‐nitrobenzanthrone, a suspected human lung carcinogen linked to diesel exposure; and (d) aristolochic acid, which is linked to Balkan endemic nephropathy‐associated urothelial cancer. In each case, a unique TP53 mutation pattern was generated that corresponded to the pattern found in human tumours where exposure to these agents has been documented. Therefore, the Hupki embryo fibroblast immortalization assay has sufficient specificity to make it applicable to other environmental mutagens that putatively play a role in cancer aetiology. Despite the utility of the current Hupki embryo fibroblast immortalization assay, it has several limitations that could be addressed by future developments, in order to improve its sensitivity and selectivity.

Nutlin‐3a selects for cells harbouring TP53 mutations

“…However, silent mutations have been observed infrequently in previous HIMAs and were not found in the current study 5. It is also unclear whether other genetic alterations, particularly those affecting p53 pathway components, would impact the response of an immortal clone to Nutlin‐3a.…”

“…C > T and CC > TT mutations in head and neck squamous carcinomas, associated with ultraviolet (UV)‐radiation exposure; G > T mutations in smokers' lung cancers, associated with exposure to tobacco carcinogens, such as benzo[ a ]pyrene (BaP); A > T mutations in urothelial carcinomas, associated with exposure to aristolochic acid (AA) 2. Some of these signatures have been replicated experimentally using embryo fibroblasts from the partial human TP53 knock‐in (Hupki) mouse, in which exons 4–9 of human TP53 replace the corresponding exons of murine Trp53 5, 6, 7…”

Aristolochic Acid Induced Suicidal Erythrocyte Death

“…Causes of Aristolochic Acid intoxication include long-term intake of medicinal herbs containing Aristolochic Acid [16][17][18][19] or of flour obtained from wheat contaminated with seeds of Aristolochia clematitis [16]. Aristolochic Acid is considered to be at least partially effective by inducing DNA adduct formation and mutations [1,4,8,9,13,14]. Aristolochic acid nephropathy is associated with anemia [20][21][22][23][24][25][26][27][28][29][30][31].…”

“…Aristolochic Acid, a nephrotoxin and carcinogen [1] from plants of the genus Aristolochia [2], may lead to acute kidney injury [3], renal aristolochic acid nephropathy [4][5][6][7][8][9][10], Balkan endemic nephropathy [1, 7-9, 11, 12], and urothelial carcinoma [1,2,4,[6][7][8][9][10][13][14][15]. Causes of Aristolochic Acid intoxication include long-term intake of medicinal herbs containing Aristolochic Acid [16][17][18][19] or of flour obtained from wheat contaminated with seeds of Aristolochia clematitis [16].…”

DNA Repair Pathways and their Therapeutic Potential in Lung Cancer

“…Conversely, while G to A transitions have been observed in tumors from 47% of nonsmokers, only 29% of smokers display this alteration. Interestingly, these mutations are not randomly distributed across the TP53 gene, with hotspots existing in codons 157, 158, 245, 248, 249 and 273 [66,68,69]. While the cause of these mutations remain unknown, PAH diol epoxide metabolites found in cigarette smoke is known to favourably react at these hotspots in tobacco-related lung cancers [66,[68][69].…”