Skip to main content

Advertisement

Log in

CDKN1A (p21 gene) polymorphisms correlates with age in esophageal cancer

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

CDKN1A gene encoding p21 is an important tumour supressor involved in the pathogenesis of cancers. A few studies have been devoted to the association between CDKN1A single nucleotide polymorphisms (SNPs) and esophageal cancer (EC) in China, India and Iran. The aim of this case–control study was to investigate the association of CDKN1A polymorphisms with EC risk in the Turkey population for the first time.

Methods

In the present study, CDKN1A SNPs (rs1801270 C > T, rs1059234 C > A and rs3176352 C > G) were genotyped with the use of TaqMan SNP genotyping assays in 102 patients and 119 controls.

Results

The genotypes and alleles of CDKN1A SNPs were not significantly different among patients and controls. However, TT-genotype and T-allele of the rs1059234, the rs1801270 CC-genotype and rs3176352 G-allele were significantly associated with EC risk for ≤ 55 age (p < 0.05). In those over 55 age, CC-genotype and C-allele of the rs1059234 was significantly associated with EC (p < 0.05). The rs1059234 T-carriers had a higher risk of high globulin level (p = 0.017) and low albumin/globulin ratio (p = 0.019) when compared to non-T carriers (CC). The rs3176352 CC-genotype carriers had a higher risk of esophageal adenocarcinoma (EAC) subtype when compared to CG-genotype carriers and CG-genotype carriers had a higher risk of squamous cell carcinoma (ESCC) subtype (OR/95% CI = 4.00/1.06–15.08, p = 0.04). The rs3176352 CC-genotype is also a risk factor for the higher BMI (p = 0.04) and the higher CA-19–9 level (p = 0.009).

Conclusion

Our study suggests that the CDKN1A polymorphisms may play an important role in EC risk in relation to age. Future studies are needed to validate our findings.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

EC:

Esophageal cancer

qPCR:

Real time polymerase chain reaction

SNP:

Single nucleotide polymorphism

ESCC:

Esophageal squamous cell carcinoma

EAC:

Esophageal adenocarcinoma

EDTA:

Ethylenediamine tetra acetic acid

CA-19–9:

Carbohydrate antigen 19–9

CEA:

Carcinoembryogenic antigen

BMI:

Body mass index

References

  1. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Pineros M, Znaor A, Bray F (2019) Estimating the global cancer incidence and mortality in 2018: globocan sources and methods. Int J Cancer 144:1941–1953

    Article  CAS  Google Scholar 

  2. Arnold M, Soerjomataram I, Ferlay J, Forman D (2015) Global incidence of oesophageal cancer by histological subtype in 2012. Gut 64:381–387

    Article  Google Scholar 

  3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    Article  Google Scholar 

  4. Brown LM, Devesa SS (2002) Epidemiologic trends in esophageal and gastric cancer in the United States. Surg Oncol Clin N Am 11:235–256

    Article  Google Scholar 

  5. Eroğlu A, Aydın Y, Altuntaş B, Gündoğdu B, Yılmaz Ö (2016) The increasing incidence of esophageal squamous cell carcinoma in women in Turkey. Turk J Med Sci 46(5):1443–1448. https://doi.org/10.3906/sag-1504-154

    Article  PubMed  Google Scholar 

  6. Ilhan M, Erbaydar T, Akdeniz N, Arslan S (2005) Palmoplantar keratoderma is associated with esophagus squamous cell cancer in Van region of Turkey: a case control study. BMC Cancer 5:90. https://doi.org/10.1186/1471-2407-5-90

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lagergren J, Bottai M, Giola S (2021) Patients age and survival after surgery for esophageal cancer. Ann Surg Oncol 28(1):159–166. https://doi.org/10.1245/s10434-020-08653-w

    Article  PubMed  Google Scholar 

  8. Tian J, Liu C, Liu G, Zuo C, Chen H (2019) Cumulative evidence gor association between genetic polymorphisms and esophageal cancer susceptibility: a review with evidence frım meta-analaysis and genome-wide association studies. Cancer Med 8(3):1289–1305. https://doi.org/10.1002/cam4.1972

    Article  PubMed  PubMed Central  Google Scholar 

  9. Abnet CC, Arnold M, Wei WQ (2018) Epidemiology of esophageal squamous cell carcinoma. Gastroenterology 154(2):360–373

    Article  Google Scholar 

  10. Blagosklonny MV (2002) Are p27 and p21 cytoplasmic oncoproteins? Cell Cycle 1(6):391–393

    Article  CAS  Google Scholar 

  11. Cazzalini O, Donà F, Savio M, Tillhon M, Maccario C, Perucca P et al (2010) p21CDKN1A participates in base excision repair by regulating the activity of poly (ADP-ribose) polymerase-1. DNA Repair Amst 9(6):627–635

    Article  CAS  Google Scholar 

  12. Cmielová J, Rezácˇová M (2011) p21Cip1/Waf1 protein and its function based on a subcellular localization. J Cell Biochem 112(12):3502–3526. https://doi.org/10.1002/jcb.23296

    Article  CAS  PubMed  Google Scholar 

  13. Georgakilas AG, Martin OA, Bonner WM (2017) p21: a two-faced genome guardian. Trends Mol Med 23(4):310–319. https://doi.org/10.1016/j.molmed.2017.02.001

    Article  CAS  PubMed  Google Scholar 

  14. Li G et al (2005) Genetic polymorphisms of p21 are associated with risk of squamous cell carcinoma of the head and neck. Carcinogenesis 26:1596–1602

    Article  CAS  Google Scholar 

  15. Chedid M, Michieli P, Lengel C, Huppi K, Givol D (1994) A single nucleotide substitution at codon 31 (Ser/Arg) defines a polymorphism in a highly conserved region of the p53-inducible gene WAF1/CIP1. Oncogene 9(10):3021–3024

    CAS  PubMed  Google Scholar 

  16. Zheng L, Tang W, Shi Y, Chen S et al (2014) p21 rs3176352 G>C and p73 rs1801173 C>T polymorphisms are associated with an increased risk of esophageal cancer in a Chinese population. PLoS ONE 9(5):e96958. https://doi.org/10.1371/journal.pone.0096958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Taghavi N, Biramijamal F, Abbaszadegan MR et al (2010) P21(waf1/cip1) gene polymorphisms and possible interaction with cigarette smoking in esophageal squamous cell carcinoma in northeastern iran: a preliminary study. Arch Iran Med 13(3):235–242

    CAS  PubMed  Google Scholar 

  18. Bosman FT, Carneiro F, Hruban RH, Theise N (2010) WHO classification of tumours of the digestive system. WHO classification of tumours, vol 3, 4th edn. World Health Organization, Lyon

    Google Scholar 

  19. Gartel AL, Tyner AL (1999) Transcriptional regulation of the p21((WAF1/CIP1)) gene. Exp Cell Res 246:280–289

    Article  CAS  Google Scholar 

  20. El-Deiry WS et al (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–25

    Article  CAS  Google Scholar 

  21. Purnomosari D, Raharjo C, Kalim AS, Herviastuti R, Yushan M, Fajar RA, Harris KK, Wahyono A (2019) p21 Ser31Arg and FGFR2 rs2981582 polymorhisms as risk factors for early onset of breast cancer in Yogyakarta, Indonesia. Asian Pac J Cancer Prev 20(11):3305–3309. https://doi.org/10.31557/APJCP.2019.20.11.3305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang W, Li Y, Ning T, Cai H, Chen Z, Dong Y, Ke Y (2016) Polymorphisms in the 5’ upstream regulatory region of p21 (WAF1/CIP1) and susceptibility to oesophageal squamous cell carcinoma. Sci Rep 6:22564. https://doi.org/10.1038/srep22564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee CH, Wu DC, Lee JM, Wu IC, Goan YG, Kao EL, Huang HL, Chan TF, Chou SH, Chou YP (2007) Carcinogenetic impact of alcohol intake on squamous cell carcinoma risk of the oesophagus in relation to tobacco smoking. Eur J Cancer 43:1188–1199

    Article  CAS  Google Scholar 

  24. Taylor PR, Qiao YL, Abnet CC, Wen W, Dawsey SM, Yang CS, Gunter E, Blot WJ, Dong ZW, Mark SD (2003) Prospective study of serum vitamin E levels and esophageal and gastric cancers. J Natl Cancer Inst 95(18):1414–1416. https://doi.org/10.1093/jnci/djg044

    Article  PubMed  Google Scholar 

  25. Abnet CC, Lai B, Qiao YL, Vogt S, Luo XM, Taylor PR, Dong ZW, Mark SD, Dawsey SM (2005) Zinc concentration in esophageal biopsy specimens measured by x-ray fluorescence and esophageal cancer risk. J Natl Cancer Inst 97:301–306

    Article  CAS  Google Scholar 

  26. Kaya Z, Almali N, Karan BM, Gorgisen G (2021) Evaluation of TP53 codon 72 polymorphism in esophageal cancer susceptibility in Eastern Anatolia Region of Turkey. East J Med 26(3):388–395

    Article  Google Scholar 

  27. Celik S, Yılmaz EM, Özden F et al (2015) The relationship between eating and lifestyle habits and cancer in Van Lake region: another endemic region for esophageal and gastric cancers. J Cancer Epidemiol 201:254823

    Google Scholar 

  28. Watanabe M, Otake R, Kozuki R, Toihata T, Takahashi K, Okamura A, Imamura Y (2020) Recent progress in multidisiplinary treatment for patients with esophageal cancer. Surg Today 50(1):12–20. https://doi.org/10.1007/s00595-019-01878-7

    Article  PubMed  Google Scholar 

  29. Jie L, Zhenzhen L, Quancheng K, Suke S, Yidong L, Suyun W (2015) Association of p21 3’UTR gene polymorphism with cancer risk: evidence from a meta-analysis. Sci Rep 5:13189

    Article  Google Scholar 

  30. Wen J, Ye F, Li S, Huang X, Yang L, Xiao X, Xie X (2015) The practicability of a novel prognostic index (PI) model and comparison with nottingham prognostic index (NPI) in stage I-III breast cancer patients undergoing surgical treatment. PLoS ONE 10(11):e0143537

    Article  Google Scholar 

  31. Li Q, Meng X, Liang L, Xu Y, Cai G, Cai S (2015) High preoperative serum globulin in rectal cancer treated with neoadjunctive chemoradiation therapy is a risk factor for poor outcome. Am J Cancer Res 5(9):2856–2864

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang Y, Zhu JY, Zhou LN, Tang M, Chen MB, Tao M (2020) Predicting the prognosis of gastric cancer by albumin/globulin ratio and the prognostic nutritional index. Nutr Cancer 72(4):635–644

    Article  CAS  Google Scholar 

  33. Chi J, Xie Q, Jia J, Liu X, Sun J, Chen J, Yi L (2018) Prognostic value of albumin/globulin ratio in survival and lymph node metastasis in patients with cancer: a systematic review and meta-analysis. J Cancer 9(13):2341–2348. https://doi.org/10.7150/jca.24889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hiro J, Kobayashi M, Ohi M, Araki T, Inoue Y, Mohri Y, Kusunoki M (2017) Clinical burden of preoperative albumin-globulin ratio in esophageal cancer patients. Am J Surg 214(5):891–898

    Article  Google Scholar 

  35. Scarpa M, Noaro G, Saadeh L, Cavallin F, Cagol M, Alfieri R, Plebani M, Castoro C (2015) Esophageal cancer management: preoperative CA19.9 and CEA serum levels may identify occult advanced adenocarcinoma. World J Surg 39(2):424–432

    Article  Google Scholar 

  36. van der Kaaij RT, Voncken FEM, van Dieren JM, Snaebjornsson P, Korse CM, Grootscholten C, Aleman BMP, van Sandick JW (2019) Elevated pretreatment CEA and CA19-9 levels are related to early treatment failure in esophageal adenocarcinoma. Am J Clin Oncol 42(4):345–350

    Article  Google Scholar 

  37. Dai MH, Zhao YP, Cai LX, Zhu Y (2003) Combined detection of K-ras mutation and CA 19–9 level in plasma of patients with pancreatic cancer. Zhonghua Wai Ke Za Zhi 41(5):332–335

    PubMed  Google Scholar 

  38. He M, Wu C, Xu J, Guo H, Yang H, Zhang X, Sun J, Yu D, Zhou L, Peng T, He Y, Gao Y, Yuan J, Deng Q, Dai X, Tan A, Feng Y, Zhang H, Min X, Yang X, Zhu J, Zhai K, Chang J, Qin X, Tan W, Hu Y, Lang M, Tao S, Li Y, Li Y, Feng J, Li D, Kim ST, Zhang S, Zhang H, Zheng SL, Gui L, Wang Y, Wei S, Wang F, Fang W, Liang Y, Zhai Y, Chen W, Miao X, Zhou G, Hu FB, Lin D, Mo Z, Wu T (2014) A genome wide association study of genetic loci that influence tumour biomarkers cancer antigen 19–9, carcinoembryonic antigen and α fetoprotein and their associations with cancer risk. Gut 63(1):143–151

    Article  CAS  Google Scholar 

  39. Fang X, Wei J, He X, Lian J, Han D, An P, Zhou T, Liu S, Wang F, Min J (2018) Quantitative association between body mass index and the risk of cancer: A global Meta-analysis of prospective cohort studies. Int J Cancer 143(7):1595–1603

    Article  CAS  Google Scholar 

  40. Lin YC, Hour TC, Tsai YC, Huang SP, Wu WJ, Chen CH, Pu YS, Chung SD, Huang CY (2017) Preliminary evidence of polymorphisms of cell cycle regulatory genes and their roles in urinary tract urothelial cancer susceptibility and prognosis in a Taiwan population. Urol Oncol 35(9):543.e7-543.e16. https://doi.org/10.1016/j.urolonc.2016.08.001

    Article  CAS  Google Scholar 

  41. Chen R, Liu S, Ye H, Li J, Du Y, Chen L, Liu X, Ding Y, Li Q, Mao Y, Ai S, Zhang P, Ma W, Yang H (2015) Association of p53 rs1042522, MDM2 rs2279744, and p21 rs1801270 polymorphisms with retinoblastoma risk and invasion in a Chinese population. Sci Rep 5:13300. https://doi.org/10.1038/srep13300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang X, Lin Y, Lan F, Yu Y, Ouyang X, Liu W, Xie F, Wang X, Huang Q (2014) BAX and CDKN1A polymorphisms correlated with clinical outcomes of gastric cancer patients treated with postoperative chemotherapy. Med Oncol 31(11):249. https://doi.org/10.1007/s12032-014-0249-4

    Article  CAS  PubMed  Google Scholar 

  43. Carvalho IN, Reis AH, Cabello PH, Vargas FR (2013) Polymorphisms of CDKN1A gene and risk of retinoblastoma. Carcinogenesis 34(12):2774–2777. https://doi.org/10.1093/carcin/bgt308

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Can Ates for the advice on the statistical analysis method.

Funding

This work was supported by grants from the Research Foundation of Van Yüzüncü Yıl University (BAP) (TYL-2017–6480).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zehra Kaya.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study has been approved by the ethics committee of SBU Van Education and Research Hospital (2017/7).

Consent to participate

Informed consent was obtained from all study participants.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kaya, Z., Karan, B.M. & Almalı, N. CDKN1A (p21 gene) polymorphisms correlates with age in esophageal cancer. Mol Biol Rep 49, 249–258 (2022). https://doi.org/10.1007/s11033-021-06865-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-06865-1

Keywords

Navigation