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Research Article

A combination of methylation and protein markers is capable of detecting gastric cancer detection by combined markers

    Jianbiao Xu

    Department of General Surgery II, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, 650032, PR China

    ,
    Jianlin Song

    Department of General Surgery II, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, 650032, PR China

    ,
    Tongmin Wang

    Department of General Surgery II, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, 650032, PR China

    ,
    Wenchuan Zhu

    Department of General Surgery II, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, 650032, PR China

    ,
    Liangyu Zuo

    Department of General Surgery II, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, 650032, PR China

    ,
    Jinzhi Wu

    Department of General Surgery II, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, 650032, PR China

    ,
    Jianhui Guo

    **Author for correspondence: Tel.: +86 138 8816 6669;

    E-mail Address: jiguo@ufl.edu

    Department of General Surgery II, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, 650032, PR China

    &
    Xiaochun Yang

    *Author for correspondence: Tel.: +86 158 0882 5607;

    E-mail Address: blackstone502@163.com

    Department of Ophthalmology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, 650032, PR China

    Published Online:https://doi.org/10.2217/epi-2021-0080

    Aim: This study aimed to validate a combination of mSEPT9, mRNF180 and CA724 for gastric cancer (GC) detection. Patients & methods: The performance of mSEPT9, mRNF180 and CA724 was examined in a prospective cohort study with 518 participants (151 with GC, 56 with atrophic gastritis, 87 with other gastrointestinal diseases and 224 with no evidence of disease). Results:mSEPT9, mRNF180 or CA724 alone detected 48.3, 37.1 and 43.1% of GC, respectively. The combination of mSEPT9 and mRNF180 detected 60.3% of GC, and the combination of all three markers detected 68.6% of GC. The detection sensitivity of mSEPT9 and mRNF180 was significantly higher for gastric body and in elder subjects. mSEPT9 was correlated with poorer GC survival. Conclusion: The combination of mSEPT9, mRNF180 and CA724 was adequately sensitive for GC detection. The blood mSEPT9 was predictive for GC prognosis.

    Lay abstract

    Gastric cancer is the most common cancer type in the digestive system. In this study we developed an effective and convenient blood-based test to detect gastric cancer. This test combined a conventional protein test with a newly invented methylation test. We aimed to validate the test and examine its performance using a prospective cohort study. The study showed that the test has promising potential for noninvasive early detection of gastric cancer. We found that single protein or methylation markers detected a proportion of gastric cancer cases, while a combination of these markers exhibited maximal detection capability. Therefore we concluded that the combined test provided adequate efficacy and should be used as a strategy for future gastric cancer detection.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Chen W, Zheng R, Baade PD et al. Cancer statistics in China, 2015. CA Cancer J. Clin. 66(2), 115–132 (2016).
    • 2. Ychou M, Duffour J, Kramar A, Gourgou S, Grenier J. Clinical significance and prognostic value of CA724 compared with CEA and CA19-9 in patients with gastric cancer. Dis. Markers 16(3-4), 105–110 (2000).
    • 3. Emoto S, Ishigami H, Yamashita H, Yamaguchi H, Kaisaki S, Kitayama J. Clinical significance of CA125 and CA724 in gastric cancer with peritoneal dissemination. Gastric Cancer 15(2), 154–161 (2012).
    • 4. Chen XZ, Zhang WH, Yang K et al. Quantitative comparisons of summary receiver operating characteristics (sROC) curves among conventional serological tumor biomarkers for predicting gastric cancer in Chinese population. Tumour Biol. 35(9), 9015–9022 (2014).
    • 5. Jing JX, Wang Y, Xu XQ et al. Tumor markers for diagnosis, monitoring of recurrence and prognosis in patients with upper gastrointestinal tract cancer. Asian. Pac. J. Cancer Prev. 15(23), 10267–10272 (2014).
    • 6. Liang Y, Wang W, Fang C et al. Clinical significance and diagnostic value of serum CEA, CA19-9 and CA724 in patients with gastric cancer. Oncotarget 7(31), 49565–49573 (2016).
    • 7. Chen HM, Fang JY. Epigenetic biomarkers for the early detection of gastrointestinal cancer. Gastrointest. Tumors 1(4), 201–208 (2014).
    • 8. Sonohara F, Inokawa Y, Hayashi M, Kodera Y, Nomoto S. Epigenetic modulation associated with carcinogenesis and prognosis of human gastric cancer. Oncol. Lett. 13(5), 3363–3368 (2017).
    • 9. Song L, Li Y. Progress on the clinical application of the SEPT9 gene methylation assay in the past 5 years. Biomark. Med. 11(6), 415–418 (2017).
    • 10. Song L, Jia J, Peng X, Xiao W, Li Y. The performance of the SEPT9 gene methylation assay and a comparison with other CRC screening tests: a meta-analysis. Sci. Rep. 7(1), 3032 (2017).
    • 11. Song L, Li Y. SEPT9: a specific circulating biomarker for colorectal cancer. Adv. Clin. Chem. 72, 171–204 (2015).
    • 12. Li Y, Song L, Gong Y, He B. Detection of colorectal cancer by DNA methylation biomarker SEPT9 past, present and future. Biomark. Med. 8(5), 755–769 (2014).
    • 13. Cheung KF, Lam CN, Wu K et al. Characterization of the gene structure, functional significance, and clinical application of RNF180, a novel gene in gastric cancer. Cancer 118(4), 947–959 (2012).
    • 14. Xie XM, Deng JY, Hou YC et al. Evaluating the clinical feasibility: the direct bisulfite genomic sequencing for examination of methylated status of E3 ubiquitin ligase RNF180 DNA promoter to predict the survival of gastric cancer. Cancer Biomark. 15(3), 259–265 (2015).
    • 15. Deng J, Liang H, Ying G et al. Methylation of CpG sites in RNF180 DNA promoter prediction poor survival of gastric cancer. Oncotarget 5(10), 3173–3183 (2014).
    • 16. Zhang X, Zhang X, Sun B et al. Detection of aberrant promoter methylation of RNF180, DAPK1 and SFRP2 in plasma DNA of patients with gastric cancer. Oncol. Lett. 8(4), 1745–1750 (2014).
    • 17. Han F, Sun LP, Liu S et al. Promoter methylation of RNF180 is associated with H. pylori infection and serves as a marker for gastric cancer and atrophic gastritis. Oncotarget 7(17), 24800–24809 (2016).
    • 18. Deng J, Guo J, Guo X et al. Mediation of the malignant biological characteristics of gastric cancer cells by the methylated CpG islands in RNF180 DNA promoter. Oncotarget 7(28), 43461–43474 (2016).
    • 19. Lofton-Day C, Model F, Devos T et al. DNA methylation biomarkers for blood-based colorectal cancer screening. Clin. Chem. 54(2), 414–423 (2008).
    • 20. Dietrich D, Jung M, Puetzer S et al. Diagnostic and prognostic value of SHOX2 and SEPT9 DNA methylation and cytology in benign, paramalignant and malignant pleural effusions. PLoS ONE 8(12), e84225 (2013).
    • 21. Powrózek T, Krawczyk P, Kucharczyk T, Milanowski J. Septin 9 promoter region methylation in free circulating DNA-potential role in noninvasive diagnosis of lung cancer preliminary report. Med. Oncol. 31(4), 917 (2014).
    • 22. Paska AV, Hudler P. Aberrant methylation patterns in cancer a clinical view. Biochem. Med. (Zagreb) 25(2), 161–176 (2015).
    • 23. Matsui S, Kagara N, Mishima C et al. Methylation of the SEPT9_v2 promoter as a novel marker for the detection of circulating tumor DNA in breast cancer patients. Oncol. Rep. 36(4), 2225–2235 (2016).
    • 24. Verdier-Pinard P, Salaun D et al. Septin 9_i2 is downregulated in tumors, impairs cancer cell migration and alters subnuclear actin filaments. Sci. Rep. 7, 44976 (2017).
    • 25. Wu Y, Bu F, Yu H et al. Methylation of septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis. Toxicol. Appl. Pharmacol. 315, 35–49 (2017).
    • 26. Kuo IY, Chang JM, Jiang SS et al. Prognostic CpG methylation biomarkers identified by methylation array in esophageal squamous cell carcinoma patients. Int. J. Med. Sci. 11(8), 779–787 (2014).
    • 27. Cao CQ, Chang L, Wu Q. Circulating methylated septin 9 and ring finger protein 180 for noninvasive diagnosis of early gastric cancer. Transl. Cancer Res. 9(11), 7012–7021 (2020).
    • 28. Warren JD, Xiong W, Bunker AM et al. Septin 9 methylated DNA is a sensitive and specific blood test for colorectal cancer. BMC Med. 9, 133 (2011).
    • 29. Tóth K, Sipos F, Kalmár A et al. Detection of methylated SEPT9 in plasma is a reliable screening method for both left- and right-sided colon cancers. PLoS ONE 7(9), e46000 (2012).
    • 30. Church TR, Wandell M, Lofton-Day C et al. Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut 63(2), 317–325 (2014). •• First report of mSEPT9 assay performance in the screening of the average-risk population.
    • 31. Jin P, Kang Q, Wang X et al. Performance of a second-generation methylated SEPT9 test in detecting colorectal neoplasm. J. Gastroenterol. Hepatol. 30(5), 830–833 (2015). • First validation of mSEPT9 assay in Chinese population.
    • 32. Wu D, Zhou G, Jin P et al. Detection of colorectal cancer using a simplified SEPT9 gene methylation assay is a reliable method for opportunistic screening. J. Mol. Diagn. 18(4), 535–545 (2016). • First validation of mSEPT9 assay in opportunistic screening.
    • 33. Song L, Jia J, Yu H et al. The performance of the mSEPT9 assay is influenced by algorithm, cancer stage and age, but not sex and cancer location. J. Cancer Res. Clin. Oncol. 143(6), 1093–1101 (2017).
    • 34. Song L, Peng X, Li Y et al. The SEPT9 gene methylation assay is capable of detecting colorectal adenoma in opportunistic screening. Epigenomics 9(5), 599–610 (2017). • First validation of mSEPT9 assay in detecting colorectal adenoma.
    • 35. Schmidt B, Liebenberg V, Dietrich D et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer based on bronchial aspirates. BMC Cancer 10, 600 (2010).
    • 36. Schneider KU, Dietrich D, Fleischhacker M et al. Correlation of SHOX2 gene amplification and DNA methylation in lung cancer tumors. BMC Cancer 11, 102 (2011).
    • 37. Kneip C, Schmidt B, Seegebarth A et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer in plasma. J. Thorac. Oncol. 6(10), 1632–1638 (2011).
    • 38. Dietrich D, Kneip C, Raji O et al. Performance evaluation of the DNA methylation biomarker SHOX2 for the aid in diagnosis of lung cancer based on the analysis of bronchial aspirates. Int. J. Oncol. 40(3), 825–832 (2012).
    • 39. Schmidt B, Beyer J, Dietrich D, Bork I, Liebenberg V, Fleischhacker M. Quantification of cell-free mSHOX2 plasma DNA for therapy monitoring in advanced stage non-small cell (NSCLC) and small-cell lung cancer (SCLC) patients. PLoS ONE 10(2), e0118195 (2015).
    • 40. Klutstein M, Nejman D, Greenfield R, Cedar H. DNA methylation in cancer and aging. Cancer Res. 76(12), 3446–3450 (2016).
    • 41. Song L, Chen Y, Gong Y et al. Opportunistic screening and survival prediction of digestive cancers by the combination of blood mSEPT9 with protein markers. Ther. Adv. Med. Oncol. 16(12), 1758835920962966 (2020). •• First study comprehensively investigating the combination of mSEPT9 with protein markers in detecting four digestive cancers.
    • 42. Chen XZ, Zhang WK, Yang K et al. Correlation between serum CA724 and gastric cancer: multiple analyses based on Chinese population. Mol. Biol. Rep. 39(9), 9031–9039 (2012).
    • 43. Tham C, Chew M, Soong R et al. Postoperative serum methylation levels of TAC1 and SEPT9 are independent predictors of recurrence and survival of patients with colorectal cancer. Cancer 120(20), 3131–3141 (2014).
    • 44. Lee HS, Hwang SM, Kim TS et al. Circulating methylated septin 9 nucleic acid in the plasma of patients with gastrointestinal cancer in the stomach and colon. Transl. Oncol. 6(3), 290–296 (2013).
    • 45. Schröck A, Leisse A, de Vos L et al. Free-circulating methylated DNA in blood for diagnosis, staging, prognosis, and monitoring of head and neck squamous cell carcinoma patients an observational prospective cohort study. Clin. Chem. 63(7), 1288–1296 (2017).
    • 46. de Vos L, Gevensleben H, Schröck A et al. Comparison of quantification algorithms for circulating cell-free DNA methylation biomarkers in blood plasma from cancer patients. Clin. Epigenetics 9, 125 (2017).