Skip to main content

Advertisement

SpringerLink
Log in

Investigating FGFR2 gene as a blood-based epigenetic biomarker in gastric cancer

  • Brief Report
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

Gastric adenocarcinoma is a prevalent form of cancer that often remains undetected in its early stages due to the lack of specific symptoms. This delayed diagnosis leads to poor clinical outcomes, underscoring the need for an effective and non-invasive method for early detection. Recent advances in cancer epigenetics have led to the identification of biomarkers that have the potential to revolutionize the early detection and monitoring of this disease. One such promising biomarker is the methylation of the FGFR2 promoter. This study aims to measure the methylation levels of a specific CpG site in the FGFR2 promoter gene in DNA extracted from blood leukocytes from patients with intestinal metaplasia, gastric cancer, and healthy control.

Material and methods

The CpG site of the FGFR2 gene promoter was identified in its control region. Methylation alteration of the selected FGFR2 CpG site was determined through the (methylation-sensitive restriction enzyme) MSRE-qPCR. Genomic DNA was extracted from one hundred twenty-five participants.

Results

The normal group had mean methylation levels of 93.23 ± 4.929%, while the IM group had a level of 69.85 ± 27.15%. In GC patients, the levels varied, with 25.96 ± 18.98% in the intestinal type and 28.30 ± 16.07% in the diffuse type. The methylation levels in the IM and GC patients were significantly lower than those in the normal control group. However, no significant difference was observed between the methylation status of the intestinal type of GC and the diffuse type. The Receiver operating characteristic (ROC) curve analysis showed that FGFR2 CpG methylation levels in GC patients compared to normal controls had a high sensitivity of 100% and specificity of 100%, with a cut-off of < 74.25%; when GC patients were compared to IM patients, the sensitivity was 85%, and the specificity was 80%, with a cut-off < 44.45%.

Conclusions

The potential of the FGFR2 methylation status as a non-invasive biomarker lies in its ability to be detected in blood leukocytes, which makes it a promising tool for the early detection of intestinal metaplasia and gastric cancer. This could significantly improve the detection and management of these gastric conditions.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The data generated and/or analyzed during the current study are not publicly available but are available from the corresponding author who organized the study.

References

  1. Thrift AP, Wenker TN, El-Serag HB (2023) Global burden of gastric cancer: epidemiological trends, risk factors, screening and prevention. Nat Rev Clin Oncol 20(5):338–349. https://doi.org/10.1038/s41571-023-00747-0

    Article  PubMed  Google Scholar 

  2. Smyth EC et al (2020) Gastric cancer. Lancet 396(10251):635–648. https://doi.org/10.1016/s0140-6736(20)31288-5

    Article  CAS  PubMed  Google Scholar 

  3. Sotelo S et al (2022) Prevalence of gastric preneoplastic lesions in first-degree relatives of patients with gastric cancer: a cross-sectional study. J Gastrointest Cancer. https://doi.org/10.1007/s12029-022-00827-x

    Article  PubMed  Google Scholar 

  4. Shao L et al (2018) Risk of gastric cancer among patients with gastric intestinal metaplasia. Int J Cancer 143(7):1671–1677. https://doi.org/10.1002/ijc.31571

    Article  CAS  PubMed  Google Scholar 

  5. Herrero R, Parsonnet J, Greenberg ER (2014) Prevention of gastric cancer. JAMA 312(12):1197–1198. https://doi.org/10.1001/jama.2014.10498

    Article  CAS  PubMed  Google Scholar 

  6. Blagosklonny MV (2005) Molecular theory of cancer. Cancer Biol Ther 4(6):621–627. https://doi.org/10.4161/cbt.4.6.1818

    Article  CAS  PubMed  Google Scholar 

  7. Kanwal R, Gupta S (2012) Epigenetic modifications in cancer. Clin Genet 81(4):303–311. https://doi.org/10.1111/j.1399-0004.2011.01809.x

    Article  CAS  PubMed  Google Scholar 

  8. Zhang Y et al (2018) The signature of liver cancer in immune cells DNA methylation. Clin Epigenetics 10:8. https://doi.org/10.1186/s13148-017-0436-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mehdi A et al (2020) DNA methylation signatures of prostate cancer in peripheral T-cells. BMC Cancer 20(1):588. https://doi.org/10.1186/s12885-020-07078-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Parashar S et al (2018) DNA methylation signatures of breast cancer in peripheral T-cells. BMC Cancer 18(1):574. https://doi.org/10.1186/s12885-018-4482-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shivapurkar N, Gazdar AF (2010) DNA methylation based biomarkers in non-invasive cancer screening. Curr Mol Med 10(2):123–132. https://doi.org/10.2174/156652410790963303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Heyn H et al (2013) DNA methylation profiling in breast cancer discordant identical twins identifies DOK7 as novel epigenetic biomarker. Carcinogenesis 34(1):102–108. https://doi.org/10.1093/carcin/bgs321

    Article  CAS  PubMed  Google Scholar 

  13. Ritchie ME et al (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43(7):e47–e47

    Article  PubMed  PubMed Central  Google Scholar 

  14. Li Y, Ge D, Lu C (2019) The SMART App: an interactive web application for comprehensive DNA methylation analysis and visualization. Epigenetics Chromatin 12(1):71. https://doi.org/10.1186/s13072-019-0316-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li T et al (2017) TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res 77(21):e108–e110. https://doi.org/10.1158/0008-5472.Can-17-0307

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  16. Oakes CC et al (2006) Evaluation of a quantitative DNA methylation analysis technique using methylation-sensitive/dependent restriction enzymes and real-time PCR. Epigenetics 1(3):146–152. https://doi.org/10.4161/epi.1.3.3392

    Article  PubMed  Google Scholar 

  17. Yang C et al (2022) Comprehensive analysis of the prognostic value and immune infiltration of FGFR family members in gastric cancer. Front Oncol. https://doi.org/10.3389/fonc.2022.936952

    Article  PubMed  PubMed Central  Google Scholar 

  18. Li P et al (2019) FGFR2 promotes expression of PD-L1 in colorectal cancer via the JAK/STAT3 signaling pathway. J Immunol 202(10):3065–3075. https://doi.org/10.4049/jimmunol.1801199

    Article  CAS  PubMed  Google Scholar 

  19. Li L et al (2018) FGF2 and FGFR2 in patients with idiopathic pulmonary fibrosis and lung cancer. Oncol Lett 16(2):2490–2494. https://doi.org/10.3892/ol.2018.8903

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kim HS et al (2019) Pathological and prognostic impacts of FGFR2 overexpression in gastric cancer: a meta-analysis. J Cancer 10(1):20–27. https://doi.org/10.7150/jca.28204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Huang T et al (2017) FGF7/FGFR2 signal promotes invasion and migration in human gastric cancer through upregulation of thrombospondin-1. Int J Oncol 50(5):1501–1512. https://doi.org/10.3892/ijo.2017.3927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Huang T et al (2018) FGFR2 promotes gastric cancer progression by inhibiting the expression of thrombospondin4 via PI3K-Akt-Mtor pathway. Cell Physiol Biochem 50(4):1332–1345. https://doi.org/10.1159/000494590

    Article  CAS  PubMed  Google Scholar 

  23. Zhang Y et al (2017) Association between FGFR2 (rs2981582, rs2420946 and rs2981578) polymorphism and breast cancer susceptibility: a meta-analysis. Oncotarget 8(2):3454–3470. https://doi.org/10.18632/oncotarget.13839

    Article  PubMed  Google Scholar 

  24. De Luca A et al (2020) FGFR fusions in cancer: from diagnostic approaches to therapeutic intervention. Int J Mol Sci 21(18):6856. https://doi.org/10.3390/ijms21186856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tahara T et al (2013) Examination of whole blood DNA methylation as a potential risk marker for gastric cancer. Cancer Prev Res 6(10):1093. https://doi.org/10.1158/1940-6207.CAPR-13-0034

    Article  CAS  Google Scholar 

  26. Boonsongserm P et al (2019) Tumor-induced DNA methylation in the white blood cells of patients with colorectal cancer. Oncol Lett 18(3):3039–3048. https://doi.org/10.3892/ol.2019.10638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nojima M et al (2018) Correlation between global methylation level of peripheral blood leukocytes and serum C reactive protein level modified by MTHFR polymorphism: a cross-sectional study. BMC Cancer 18(1):184. https://doi.org/10.1186/s12885-018-4089-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Palakurthi S et al (2019) The combined effect of FGFR inhibition and PD-1 blockade promotes tumor-intrinsic induction of antitumor immunity. Cancer Immunol Res 7(9):1457–1471. https://doi.org/10.1158/2326-6066.Cir-18-0595

    Article  CAS  PubMed  Google Scholar 

  29. Ohue Y, Nishikawa H (2019) Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target? Cancer Sci 110(7):2080–2089. https://doi.org/10.1111/cas.14069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Graham DY, Rugge M, Genta RM (2019) Diagnosis: gastric intestinal metaplasia—what to do next? Curr Opin Gastroenterol 35(6):535–543. https://doi.org/10.1097/mog.0000000000000576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nell RJ et al (2020) Quantification of DNA methylation independent of sodium bisulfite conversion using methylation-sensitive restriction enzymes and digital PCR. Hum Mutat 41(12):2205–2216. https://doi.org/10.1002/humu.24111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful for the support of grant number 667 from the National Institute of Genetic Engineering and Biotechnology (NIGEB). Our work would not have been possible without their generous funding.

Funding

The study was funded by grant 667 from the National Institute of Genetic Engineering and Biotechnology (NIGEB).

Author information

Authors and Affiliations

  1. Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), 17 Km Tehran–Karaj Highway, Pajoohesh Blvd, Tehran, Iran

    Seyed Ahmad Aleyasin, Arash Moradi, Naeimeh Abolhasani & Mahvash Abdollahi

Authors
  1. Seyed Ahmad Aleyasin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arash Moradi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naeimeh Abolhasani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mahvash Abdollahi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SAA developed the concepts and methodology for the experimental study, and AM developed the concepts and methodology for the computational-based study. NA and MA carried out the sampling and experimental laboratory work. SAA was responsible for data acquisition, analysis, and interpretation of experimental studies, and AM conducted comprehensive bioinformatic studies and analysis. AM and SAA collaborated on manuscript writing and revisions. SAA provided administrative, technical/material support, provided raw experimental data, and supervised the study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Seyed Ahmad Aleyasin.

Ethics declarations

Competing interest

All authors read the manuscript, and no competing interests were declared.

Ethics approval

The study underwent a rigorous ethical review process by the Ethical Committee of the National Institute of Genetic Engineering and Biotechnology (NIGEB) before its approval (Ethical code #: IR.NIGEB.EC1398.12.3.A). The research team followed all relevant guidelines and regulations to ensure all participants’ safety and well-being. Participants were fully informed of the research’s purpose and procedures and provided an informed consent form before participating. The consent form detailed the use of their clinical samples and personal data throughout the study, which was to be conducted under their physician’s supervision. The research team prepared the informed consent form with the utmost care, and all participants willingly signed it before participating. Participants were free to withdraw their consent at any point during the study. Throughout the study, the research team upheld the highest ethical standards and strictly adhered to all relevant regulations to ensure the privacy and confidentiality of all participants’ data.

Consent for publication

Not applicable.

Additional information

Publisher's Note

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

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aleyasin, S.A., Moradi, A., Abolhasani, N. et al. Investigating FGFR2 gene as a blood-based epigenetic biomarker in gastric cancer. Mol Biol Rep 51, 253 (2024). https://doi.org/10.1007/s11033-023-09082-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11033-023-09082-0

Keywords

Search

Navigation