Monitoring genotoxicity in patients receiving chemotherapy for cancer: application of the PIG-A assay

Horibata, Katsuyoshi; Ukai, Akiko; Ishikawa, Shinya; Sugano, Akira; Honma, Masamitsu

doi:10.1016/j.mrgentox.2016.08.002

Cited by 17 publications

(13 citation statements)

References 31 publications

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“…The frequency of the loss of GPIa containing proteins on the cell surface has been developed as a genotoxic biomarker by cloning and by flow cytometry methods in both humans and animals (PIG-A and Pig-a assays, respectively) (Dertinger et al, , 2014Dertinger and Heflich, 2011;Dobrovolsky et al, 2011Dobrovolsky et al, , 2013Horibata et al, 2013Horibata et al, , 2016Kimoto et al, 2013;Gollapudi et al, 2015;Heflich et al, 2015). Cloning assays detect mutants by their resistance to the drug aerolysin while flow cytometry uses antibodies targeting GPIa cell surface proteins.…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis of glycosylphosphatidylinositol anchor deficient aerolysin resistant isolates in gulf war i veterans exposed to depleted uranium

Nicklas

Vacek

Carter

et al. 2019

Environ and Mol Mutagen

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During the First Gulf War (1991) over 100 servicemen sustained depleted uranium (DU) exposure through wound contamination, inhalation, and shrapnel. The Department of Veterans Affairs has a surveillance program for these Veterans which has included genotoxicity assays. The frequencies of glycosylphosphatidylinositol anchor (GPIa) negative (aerolysin resistant) cells determined by cloning assays for these Veterans are reported in Albertini RJ et al. (2019: Environ Mol Mutagen). Molecular analyses of the GPIa biosynthesis class A (PIGA) gene was performed on 862 aerolysin‐resistant T‐lymphocyte recovered isolates. The frequencies of different types of PIGA mutations were compared between high and low DU exposure groups. Additional molecular studies were performed on mutants that produced no PIGA mRNA or with deletions of all or part of the PIGA gene to determine deletion size and breakpoint sequence. One mutant appeared to be the result of a chromothriptic event. A significant percentage (>30%) of the aerolysin resistant isolates, which varied by sample year and Veteran, had wild‐type PIGA cDNA (no mutation). As described in Albertini RJ et al. (2019: Environ Mol Mutagen), TCR gene rearrangement analysis of these isolates indicated most arose from multiple T‐cell progenitors (hence the inability to find a mutation). It is likely that these isolates were the result of failure of complete selection against nonmutant cells in the cloning assays. Real‐time studies of GPIa resistant isolates with no PIGA mutation but with a single TCR gene rearrangement found one clone with a PIGV deletion and several others with decreased levels of GPIa pathway gene mRNAs implying mutation in other GPIa pathway genes. Environ. Mol. Mutagen. 60:470–493, 2019. © 2019 Wiley Periodicals, Inc.

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Section: Introductionmentioning

confidence: 99%

Molecular analysis of glycosylphosphatidylinositol anchor deficient aerolysin resistant isolates in gulf war i veterans exposed to depleted uranium

Nicklas

Vacek

Carter

et al. 2019

Environ and Mol Mutagen

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“…Therefore, it is necessary to assess the genotoxicity of anticancer drugs. Up to now, there are a variety of in vivo and in vitro genotoxic tests for monitoring the genotoxicity in patients receiving chemotherapy, such as the PIG-A assay [58]. …”

Section: Genetic Toxicology In Cancer Cells and Chemotherapymentioning

confidence: 99%

The various aspects of genetic and epigenetic toxicology: testing methods and clinical applications

et al. 2017

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Genotoxicity refers to the ability of harmful substances to damage genetic information in cells. Being exposed to chemical and biological agents can result in genomic instabilities and/or epigenetic alterations, which translate into a variety of diseases, cancer included. This concise review discusses, from both a genetic and epigenetic point of view, the current detection methods of different agents’ genotoxicity, along with their basic and clinical relation to human cancer, chemotherapy, germ cells and stem cells.

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“…However, only a few human PIG‐A studies have been conducted. Most of the studies were on self‐identified healthy subjects (Dobrovolsky et al ; Rondelli et al ; Dertinger et al ; Cao et al ), and on the patients diagnosed with various types of cancer and treated by combination chemotherapy and/or radiation (Haboubi et al ; Horibata et al ). There is still a lack of human data demonstrating whether PIG‐A mutant frequencies (MFs) respond to mutagen exposures.…”

Section: Introductionmentioning

confidence: 99%

The potential application of human PIG‐A assay on azathioprine‐treated inflammatory bowel disease patients

Cao

Wang²,

Liu

et al. 2019

Environ and Mol Mutagen

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The rodent Pig-a assay has been used extensively as a potential regulatory assay for evaluating the in vivo mutagenicity of test substances. Although the assay can be conducted in different mammalian species, there have been only a few reports describing its use in humans, and rarely in genotoxicant-exposed human populations. In this study, PIG-A mutation frequencies (MFs) were evaluated in 36 azathioprine (AZA; human carcinogen)-treated inflammatory bowel disease (IBD) patients and 36 healthy volunteers. IBD patients exhibited a slight but statistically higher MF (6.10 AE 4.44 × 10 −6 ) than healthy volunteers (4.97 AE 2.74 × 10 −6 ) (P = 0.0489). The estimated relative risk for the exposed patients was 1.22 which indicated that AZA is a risk factor for inducing PIG-A mutation. However, the PIG-A MF showed no associations with AZA treatment duration or total AZA exposure. In addition, we performed the cytokinesis-block micronucleus test on the same samples. The frequencies of micronuclei (MN) and nuclear buds (NBUD) in IBD patients (MN: 4.70 AE 2.86‰; NBUD: 1.89 AE 0.95‰) were significantly higher than in healthy volunteers (MN: 1.47 AE 0.77‰, P < 0.001; NBUD: 0.90 AE 0.58‰, P = 0.004). MN frequency also had significant correlations with AZA treatment duration (P = 0.011) and total AZA exposure (P = 0.018).Our findings indicate that AZA-treated IBD patients have only a marginally significant increase in PIG-A MF; in contrast, a much stronger AZA-associated increase in genotoxicity was detected with the lymphocyte MN assay. Environ. Mol. Mutagen. 61:456-464, 2020.

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Monitoring genotoxicity in patients receiving chemotherapy for cancer: application of the PIG-A assay

Cited by 17 publications

References 31 publications

Molecular analysis of glycosylphosphatidylinositol anchor deficient aerolysin resistant isolates in gulf war i veterans exposed to depleted uranium

Molecular analysis of glycosylphosphatidylinositol anchor deficient aerolysin resistant isolates in gulf war i veterans exposed to depleted uranium

The various aspects of genetic and epigenetic toxicology: testing methods and clinical applications

The potential application of human PIG‐A assay on azathioprine‐treated inflammatory bowel disease patients

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