Mutagenicity of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N–OH-PhIP) in human TP53 knock-in (Hupki) mouse embryo fibroblasts

Hölzl-Armstrong, Lisa; Moody, Sarah; Kucab, Jill E.; Zwart, Edwin; Bellamri, Medjda; Luijten, Mirjam; Turesky, Robert J.; Stratton, Michael R.; Arlt, Volker M.; Phillips, David H.

doi:10.1016/j.fct.2020.111855

Cited by 6 publications

(4 citation statements)

References 52 publications

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“…dG-C8-PhIP, the principal adduct formed with PhIP, ,, induces C:G > A:T and C:G > T:A transversions and the C:G > G:C transition in rodents, transgenic target genes, mouse embryo fibroblasts, human-induced pluripotent stem cells, and site-specific mutagenesis studies. ,− The PhIP mutational signature shows similarity to COSMIC SBS4, SBS8, SBS18, and SBS29 mutational signatures found in several types of human tumors, including the prostate . However, these signatures are not unique to PhIP, and DNA adducts of other environmental, dietary, and endogenous genotoxicants are likely to contribute to these mutations. , Other components in red meat, such as heme iron, can damage organs through free radical formation, and LPO products formed in cooked meat also may form DNA adducts or serve as tumor promoters …”

Section: Discussionmentioning

confidence: 95%

“…144 However, these signatures are not unique to PhIP, and DNA adducts of other environmental, dietary, and endogenous genotoxicants are likely to contribute to these mutations. 142,143 Other components in red meat, such as heme iron, can damage organs through free radical formation, and LPO products formed in cooked meat also may form DNA adducts or serve as tumor promoters. 145 Inflammation and oxidative stress are features in PC development.…”

Section: ■ Discussionmentioning

confidence: 99%

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The Cooked Meat Carcinogen 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine Hair Dosimeter, DNA Adductomics Discovery, and Associations with Prostate Cancer Pathology Biomarkers

Guo

Koopmeiners

Walmsley

et al. 2022

Chem. Res. Toxicol.

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Well-done cooked red meat consumption is linked to aggressive prostate cancer (PC) risk. Identifying mutation-inducing DNA adducts in the prostate genome can advance our understanding of chemicals in meat that may contribute to PC. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic aromatic amine (HAA) formed in cooked meat, is a potential human prostate carcinogen. PhIP was measured in the hair of PC patients undergoing prostatectomy, bladder cancer patients under treatment for cystoprostatectomy, and patients treated for benign prostatic hyperplasia (BPH). PhIP hair levels were above the quantification limit in 123 of 205 subjects. When dichotomizing prostate pathology biomarkers, the geometric mean PhIP hair levels were higher in patients with intermediate and elevated-risk prostate-specific antigen values than lower-risk values <4 ng/mL (p = 0.03). PhIP hair levels were also higher in patients with intermediate and high-risk Gleason scores ≥7 compared to lower-risk Gleason score 6 and BPH patients (p = 0.02). PC patients undergoing prostatectomy had higher PhIP hair levels than cystoprostatectomy or BPH patients (p = 0.02). PhIP-DNA adducts were detected in 9.4% of the patients assayed; however, DNA adducts of other carcinogenic HAAs, and benzo[a]pyrene formed in cooked meat, were not detected. Prostate specimens were also screened for 10 oxidative stress-associated lipid peroxidation (LPO) DNA adducts. Acrolein 1,N 2-propano-2′-deoxyguanosine adducts were detected in 54.5% of the patients; other LPO adducts were infrequently detected. Acrolein adducts were not associated with prostate pathology biomarkers, although DNA adductomic profiles differed between PC patients with low and high-grade Gleason scores. Many DNA adducts are of unknown origin; however, dG adducts of formaldehyde and a series of purported 4-hydroxy-2-alkenals were detected at higher abundance in a subset of patients with elevated Gleason scores. The PhIP hair biomarker and DNA adductomics data support the paradigm of well-done cooked meat and oxidative stress in aggressive PC risk.

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Section: Discussionmentioning

confidence: 95%

Section: ■ Discussionmentioning

confidence: 99%

The Cooked Meat Carcinogen 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine Hair Dosimeter, DNA Adductomics Discovery, and Associations with Prostate Cancer Pathology Biomarkers

Guo

Koopmeiners

Walmsley

et al. 2022

Chem. Res. Toxicol.

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“…SBS4, a mutational signature attributed to tobacco smoke, was found in five tumor‐distal samples, although only two of these patients were smokers. The presence of SBS4 in nonsmokers therefore implies a different etiology, such as lifestyle‐associated exposures to benzo[a]pyrene from other sources (wood burning, grilled meat, diesel exhaust), glycamide (cooked starch‐rich foods) or 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP, cooked meat), all of which cause the SBS4 signature experimentally [ 49 , 50 , 51 ], or to other agents that primarily form guanine adducts [ 52 ]. Whatever the precise etiology, these signatures reflect the mutational processes involved in the normal tongue and the tumor and are in keeping with additional events occurring during malignancy initiation/progression that are reflected by additional mutational signatures only in the tumor.…”

Section: Discussionmentioning

confidence: 99%

Evidence for etiologic field changes in tongue distant from tumor in patients with squamous cell carcinoma of the oral tongue

Wang

Coates

et al. 2022

The Journal of Pathology

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Oral cancer is a paradigm of Slaughter's concept of field cancerization, where tumors are thought to originate within an area of cells containing genetic alterations that predispose to cancer development. The field size is unclear but may represent a large area of tissue, and the origin of mutations is also unclear. Here, we analyzed whole exome and transcriptome features in contralateral tumor-distal tongue (i.e. distant from the tumor, not tumor-adjacent) and corresponding tumor tissues of 15 patients with squamous cell carcinoma of the oral tongue. The number of point mutations ranged from 41 to 237 in tumors and from one to 78 in tumor-distal samples. Tumor-distal samples showed mainly clock-like (associated with aging) or tobacco smoking mutational signatures. Tumors additionally showed mutations that associate with cytidine deaminase AID/APOBEC enzyme activities or a UV-like signature. Importantly, no point mutations were shared between a tumor and the matched tumor-distal sample in any patient. TP53 was the most frequently mutated gene in tumors (67%), whereas a TP53 mutation was detected in only one tumor-distal sample, and this mutation was not shared with the matched tumor. Arm-level copy number variation (CNV) was found in 12 tumors, with loss of chromosome (Chr) 8p or gain of 8q being the most frequent events. Two tumor-distal samples showed a gain of Chr8, which was associated with increased expression of Chr8-located genes in these samples, although gene ontology did not show a role for these genes in oncogenic processes. In situ hybridization revealed a mixed pattern of Chr8 gain and neutral copy number in both tumor cells and adjacent nontumor epithelium in one patient. We conclude that distant field cancerization exists but does not present as tumor-related mutational events. The data are compatible with etiologic field effects, rather than classical monoclonal field cancerization theory.

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“…The human cell lines, A549 and NOK, were selected based on the relevance of tobaccoassociated tumorigenesis in the source tissue types. MEFs were included as a well-established experimental model system for mutational signatures analysis [33][34][35]40,41 . To establish how exposure levels affect cell fitness, we monitored cell viability and cell growth rates (Supplementary Figure 2).…”

Section: Nnkoac Induces a Characteristic Mutational Signature In Cell...mentioning

confidence: 99%

Human cancer genomes harbor the mutational signature of tobacco-specific nitrosamines NNN and NNK

Korenjak,

Temiz,

Keita

et al. 2024

Preprint

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Tobacco usage is linked to multiple cancer types and accounts for a quarter of all cancer-related deaths. Tobacco smoke contains various carcinogenic compounds, including polycyclic aromatic hydrocarbons (PAH), though the mutagenic potential of many tobacco-related chemicals remains largely unexplored. In particular, the highly carcinogenic tobacco-specific nitrosamines NNN and NNK form pre-mutagenic pyridyloxobutyl (POB) DNA adducts. In the study presented here, we identified genome-scale POB-induced mutational signatures in cell lines and rat tumors, while also investigating their role in human cancer. These signatures are characterized by T>N and C>T mutations forming from specific POB adducts damaging dT and dC residues. Analysis of 2,780 cancer genomes uncovered POB signatures in ∼180 tumors; from cancer types distinct from the ones linked to smoking-related signatures SBS4 and SBS92. This suggests that, unlike PAH compounds, the POB pathway may contribute uniquely to the mutational landscapes of certain hematological malignancies and cancers of the kidney, breast, prostate and pancreas.

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Mutagenicity of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N–OH-PhIP) in human TP53 knock-in (Hupki) mouse embryo fibroblasts

Cited by 6 publications

References 52 publications

The Cooked Meat Carcinogen 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine Hair Dosimeter, DNA Adductomics Discovery, and Associations with Prostate Cancer Pathology Biomarkers

The Cooked Meat Carcinogen 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine Hair Dosimeter, DNA Adductomics Discovery, and Associations with Prostate Cancer Pathology Biomarkers

Evidence for etiologic field changes in tongue distant from tumor in patients with squamous cell carcinoma of the oral tongue

Human cancer genomes harbor the mutational signature of tobacco-specific nitrosamines NNN and NNK

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