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GSTs polymorphisms are associated with epigenetic silencing of CDKN2A gene in esophageal squamous cell carcinoma

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Abstract

Esophageal cancer is the eighth most common cancer and the sixth most frequent cause of cancer mortality worldwide. Exposure to polycyclic aromatic hydrocarbons formed by incomplete combustion of organic matter is an important risk factor. Genetic polymorphisms in genes encoding PAH-metabolizing enzymes like glutathione S-transferases (GSTM1, GSTP1, GSTT1) which conjugate glutathione to PAHs for reduction of oxidative stress may affect an individual’s response to PAH exposure. Genomic DNA from 50 esophageal squamous cell carcinoma patients extracted from peripheral blood. PCR-RFLP technique was employed to determine GSTM1, GSTT1, and GSTP1 polymorphisms. Aberrant promoter methylation of CDKN2A was applied by methylation-specific PCR technique. Concentration of urinary 1-hydroxypyrene was determined using a HPLC system. About 38.7% showed the null GSTM1 genotype (54% cases and 13% controls), 23.7% showed GSTT1 null genotype (30% cases and 13% controls), and 62.5% were GSTP1 A/A genotype (66% cases and 56% controls). Polymorphic variants of GSTM1 and GSTT1 were significantly associated with aberrant methylation of CDKN2A gene. The null state of GSTT1 was significantly associated with high concentrations of 1-OHP in urea (p < 0.01). There was significant association between methylated states of CDKN2A and high concentrations of 1-OHP in urine (p < 0.01). We identified significant association between polymorphism of GSTs genes and epigenetic silencing of tumor suppressor gene CDKN2A in esophageal squamous cell carcinoma.

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Acknowledgments

The authors gratefully acknowledge the scientific and technical supports of colleagues at the Division of Human Genetics, Immunology Research Center, and Avicenna Research Institute (Mashhad University of Medical Sciences).

Funding

This study was supported by a grant from the Vice Chancellor for Research at Mashhad University of Medical Sciences (no. 85032) and was part of a M.Sc. student’s dissertation.

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Author notes

  1. Mohammad Mahdi Forghanifard and Azadeh Aarabi contributed equally to this work.

Authors and Affiliations

  1. Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran

    Mohammad Mahdi Forghanifard

  2. Immunology research center, Mashhad University of Medical Sciences, Mashhad, Iran

    Azadeh Aarabi

  3. Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Maryam Nasiri Aghdam & Mohammad Reza Abbaszadegan

  4. Department of Pathology, Omeed Hospital, Mashhad University of Medical Sciences, Mashhad, 9196773117, Iran

    Bahram Memar

  5. Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Mohammad Hasanzadeh Khayat

  6. School of Systems Biology, George Mason University, Manassas, VA, USA

    Ezzat Dadkhah

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  1. Mohammad Mahdi Forghanifard
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  3. Maryam Nasiri Aghdam
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  7. Mohammad Reza Abbaszadegan
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Correspondence to Mohammad Reza Abbaszadegan.

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This study was approved by ethic committee of Mashhad University of Medical Science.

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Forghanifard, M.M., Aarabi, A., Nasiri Aghdam, M. et al. GSTs polymorphisms are associated with epigenetic silencing of CDKN2A gene in esophageal squamous cell carcinoma. Environ Sci Pollut Res 27, 31269–31277 (2020). https://doi.org/10.1007/s11356-020-09408-6

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