Table Info

Table 2.

Clinicopathologic characteristics of patients with positive cfDNA plasma test results by methylation status of SDC2 and SEPT9 markers

Variable	All	Combined test positive (n = 78)	*No. of mSDC2* positive (n = 69)**	*No. of mSEPT9* positive (n = 30)**
Age (years)
≤ 49	108	19 (24.4%)	18 (26.1%)	9 (30.0%)
50–59	60	20 (25.6%)	16 (23.2%)	7 (23.3%)
60–69	60	25 (32.1%)	23 (33.3%)	7 (23.3%)
≥ 70	25	14 (17.9%)	12 (17.4%)	7 (23.3%)
Gender
Male	83	28 (35.9%)	25 (36.2%)	13 (43.3%)
Female	170	50 (64.1%)	44 (63.8%)	17 (56.7%)
Location
Proximal colon	70	33 (47.1%)	28 (45.2%)	18 (66.7%)
Distal colon	68	37 (52.9%)	34 (54.8%)	9 (33.3%)
CRC stage
I + II	8	8	8	6
III + IV	10	10	9	6
Histological classification
Advanced adenoma	14	11	9	5
Serrated lesions	17	10	10	4
Non-advanced adenoma	57	19	17	4
Hyperplastic polyps	19	8	5	3

Supplementary materials

The supplementary figure for this article is available at: https://www.explorationpub.com/uploads/Article/file/1001322_sup_1.pdf. The supplementary table for this article is available at: https://www.explorationpub.com/uploads/Article/file/1001322_sup_2.xlsx.

Declarations

Author contributions

V Borobova: Formal analysis, Investigation, Software, Visualization, Writing—original draft. AA: Data curation, Resources. DS: Data curation, Methodology. V Baklaushev: Resourses. DI: Resources, Investigation. EV: Investigation, Data curation. AV: Methodology. NO: Data curation. PL: Methodology, Project administration, Supervision, Writing—review & editing. SK: Conceptualization, Validation. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This study was approved by the ethics committee of the Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, Federal Medical and Biological Agency of Russia, Moscow (Protocol No. 5_2024, 04.06.2024). Biopsy material was obtained in compliance with the legislation of the Russian Federation, and written informed consent was provided by all the patients.

Consent to participate

Informed consent to participate in the study was obtained from all participants.

Consent to publication

Informed consent to publication was obtained from relevant participants.

Availability of data and materials

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding

Not applicable.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63. [DOI] [PubMed]

Knudsen AB, Trentham-Dietz A, Kim JJ, Mandelblatt JS, Meza R, Zauber AG, et al. Estimated US Cancer Deaths Prevented With Increased Use of Lung, Colorectal, Breast, and Cervical Cancer Screening. JAMA Netw Open. 2023;6:e2344698. [DOI] [PubMed] [PMC]

Zauber AG. The Impact of Screening on Colorectal Cancer Mortality and Incidence: Has It Really Made a Difference? Dig Dis Sci. 2015;60:681–91. [DOI] [PubMed] [PMC]

González-López N, Quintero E, Gimeno-Garcia AZ, Bujanda L, Banales J, Cubiella J, et al.; Oncology Group of Asociación Española de Gastroenterología. Screening uptake of colonoscopy versus fecal immunochemical testing in first-degree relatives of patients with non-syndromic colorectal cancer: A multicenter, open-label, parallel-group, randomized trial (ParCoFit study). PLoS Med. 2023;20:e1004298. [DOI] [PubMed] [PMC]

Muthukrishnan M, Arnold LD, James AS. Patients’ self-reported barriers to colon cancer screening in federally qualified health center settings. Prev Med Rep. 2019;15:100896. [DOI] [PubMed] [PMC]

Elsafi SH, Alqahtani NI, Zakary NY, Al Zahrani EM. The sensitivity, specificity, predictive values, and likelihood ratios of fecal occult blood test for the detection of colorectal cancer in hospital settings. Clin Exp Gastroenterol. 2015;8:279–84. [DOI] [PubMed] [PMC]

Niedermaier T, Balavarca Y, Brenner H. Stage-Specific Sensitivity of Fecal Immunochemical Tests for Detecting Colorectal Cancer: Systematic Review and Meta-Analysis. Am J Gastroenterol. 2020;115:56–69. [DOI] [PubMed] [PMC]

Hasegawa R, Yashima K, Ikebuchi Y, Sasaki S, Yoshida A, Kawaguchi K, et al. Characteristics of Advanced Colorectal Cancer Detected by Fecal Immunochemical Test Screening in Participants with a Negative Result the Previous Year. Yonago Acta Med. 2020;63:63–9. [DOI] [PubMed] [PMC]

Haug U, Knudsen AB, Brenner H, Kuntz KM. Is fecal occult blood testing more sensitive for left- versus right-sided colorectal neoplasia? A systematic literature review. Expert Rev Mol Diagn. 2011;11:605–16. [DOI] [PubMed]

10.

Imperiale TF, Gruber RN, Stump TE, Emmett TW, Monahan PO. Performance Characteristics of Fecal Immunochemical Tests for Colorectal Cancer and Advanced Adenomatous Polyps: A Systematic Review and Meta-analysis. Ann Intern Med. 2019;170:319–29. [DOI] [PubMed]

11.

Song LL, Li YM. Current noninvasive tests for colorectal cancer screening: An overview of colorectal cancer screening tests. World J Gastrointest Oncol. 2016;8:793–800. [DOI] [PubMed] [PMC]

12.

Adler A, Geiger S, Keil A, Bias H, Schatz P, deVos T, et al. Improving compliance to colorectal cancer screening using blood and stool based tests in patients refusing screening colonoscopy in Germany. BMC Gastroenterol. 2014;14:183. [DOI] [PubMed] [PMC]

13.

Daura-Oller E, Cabre M, Montero MA, Paternain JL, Romeu A. Specific gene hypomethylation and cancer: New insights into coding region feature trends. Bioinformation. 2009;3:340–3. [DOI] [PubMed] [PMC]

14.

Church TR, Wandell M, Lofton-Day C, Mongin SJ, Burger M, Payne SR, et al.; PRESEPT Clinical Study Steering Committee; Investigators and Study Team. Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut. 2014;63:317–25. [DOI] [PubMed] [PMC]

15.

Sun J, Zheng MY, Li YW, Zhang SW. Structure and function of Septin 9 and its role in human malignant tumors. World J Gastrointest Oncol. 2020;12:619–31. [DOI] [PubMed] [PMC]

16.

Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, et al. Multitarget Stool DNA Testing for Colorectal-Cancer Screening. N Engl J Med. 2014;370:1287–97. [DOI] [PubMed]

17.

Imperiale TF, Porter K, Zella J, Gagrat ZD, Olson MC, Statz S, et al.; BLUE-C Study Investigators. Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening. N Engl J Med. 2024;390:984–93. [DOI] [PubMed]

18.

Chung DC, Gray DM 2nd, Singh H, Issaka RB, Raymond VM, Eagle C, et al. A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening. N Engl J Med. 2024;390:973–83. [DOI] [PubMed]

19.

Jensen SØ, Øgaard N, Ørntoft MW, Rasmussen MH, Bramsen JB, Kristensen H, et al. Novel DNA methylation biomarkers show high sensitivity and specificity for blood-based detection of colorectal cancer-a clinical biomarker discovery and validation study. Clin Epigenetics. 2019;11:158. [DOI] [PubMed] [PMC]

20.

Inadomi JM. Cost-Effectiveness of Blood-Based Biomarkers for Colorectal Cancer Screening—An Ounce of Prevention Is Worth a Pound of Cure. JAMA Netw Open. 2023;6:e2343346. [DOI] [PubMed]

21.

Müller D, Győrffy B. DNA methylation-based diagnostic, prognostic, and predictive biomarkers in colorectal cancer. Biochim Biophys Acta Rev Cancer. 2022;1877:188722. [DOI] [PubMed]

22.

Barták BK, Kalmár A, Péterfia B, Patai ÁV, Galamb O, Valcz G, et al. Colorectal adenoma and cancer detection based on altered methylation pattern of SFRP1, SFRP2, SDC2, and PRIMA1 in plasma samples. Epigenetics. 2017;12:751–63. [DOI] [PubMed] [PMC]

23.

Tänzer M, Balluff B, Distler J, Hale K, Leodolter A, Röcken C, et al. Performance of Epigenetic Markers SEPT9 and ALX4 in Plasma for Detection of Colorectal Precancerous Lesions. PLoS One. 2010;5:e9061. [DOI] [PubMed] [PMC]

24.

He Q, Chen HY, Bai EQ, Luo YX, Fu RJ, He YS, et al. Development of a multiplex MethyLight assay for the detection of multigene methylation in human colorectal cancer. Cancer Genet Cytogenet. 2010;202:1–10. [PubMed]

25.

Lofton-Day C, Model F, Devos T, Tetzner R, Distler J, Schuster M, et al. DNA Methylation Biomarkers for Blood-Based Colorectal Cancer Screening. Clin Chem. 2008;54:414–23. [DOI] [PubMed]

26.

Oh T, Kim N, Moon Y, Kim MS, Hoehn BD, Park CH, et al. Genome-Wide Identification and Validation of a Novel Methylation Biomarker, SDC2, for Blood-Based Detection of Colorectal Cancer. J Mol Diagn. 2013;15:498–507. [DOI] [PubMed]

27.

Essner JJ, Chen E, Ekker SC. Syndecan-2. Int J Biochem Cell Biol. 2006;38:152–6. [DOI] [PubMed]

28.

Mytilinaiou M, Nikitovic D, Berdiaki A, Kostouras A, Papoutsidakis A, Tsatsakis AM, et al. Emerging roles of syndecan 2 in epithelial and mesenchymal cancer progression. IUBMB Life. 2017;69:824–33. [DOI] [PubMed]

29.

Hua R, Yu J, Yan X, Ni Q, Zhi X, Li X, et al. Syndecan-2 in colorectal cancer plays oncogenic role via epithelial-mesenchymal transition and MAPK pathway. Biomedicine & Pharmacotherapy. 2020;121:109630. [DOI] [PubMed]

30.

Li Y, Li B, Jiang R, Liao L, Zheng C, Yuan J, et al. A novel screening method of DNA methylation biomarkers helps to improve the detection of colorectal cancer and precancerous lesions. Cancer Med. 2023;12:20626–38. [DOI] [PubMed] [PMC]

31.

Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70:145–64. [DOI] [PubMed]

32.

deVos T, Tetzner R, Model F, Weiss G, Schuster M, Distler J, et al. Circulating Methylated SEPT9 DNA in Plasma Is a Biomarker for Colorectal Cancer. Clin Chem. 2009;55:1337–46. [DOI] [PubMed]

33.

Potter NT, Hurban P, White MN, Whitlock KD, Lofton-Day CE, Tetzner R, et al. Validation of a Real-Time PCR–Based Qualitative Assay for the Detection of Methylated SEPT9 DNA in Human Plasma. Clin Chem. 2014;60:1183–91. [DOI] [PubMed]

34.

Tóth K, Sipos F, Kalmár A, Patai AV, Wichmann B, Stoehr R, et al. Detection of Methylated SEPT9 in Plasma Is a Reliable Screening Method for Both Left- and Right-Sided Colon Cancers. PLoS One. 2012;7:e46000. [DOI] [PubMed] [PMC]

35.

Ørntoft MW, Nielsen HJ, Ørntoft TF, Andersen CL; Danish Study Group on Early Detection of Colorectal Cancer. Performance of the colorectal cancer screening marker Sept9 is influenced by age, diabetes and arthritis: a nested case-control study. BMC Cancer. 2015;15:819. [DOI] [PubMed] [PMC]

36.

Wu D, Zhou G, Jin P, Zhu J, Li S, Wu Q, et al. Detection of Colorectal Cancer Using a Simplified SEPT9 Gene Methylation Assay Is a Reliable Method for Opportunistic Screening. J Mol Diagn. 2016;18:535–45. [DOI] [PubMed]

37.

Song L, Jia J, Yu H, Peng X, Xiao W, Gong Y, 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. 2017;143:1093–101. [DOI] [PubMed]

38.

Liu Y, Zhao G, Miao J, Li H, Ma Y, Liu X, et al. Performance Comparison Between Plasma and Stool Methylated SEPT9 Tests for Detecting Colorectal Cancer. Front Genet. 2020;11:324. [DOI] [PubMed] [PMC]

39.

Wang J, Liu S, Wang H, Zheng L, Zhou C, Li G, et al. Robust performance of a novel stool DNA test of methylated SDC2 for colorectal cancer detection: a multicenter clinical study. Clin Epigenetics. 2020;12:162. [DOI] [PubMed] [PMC]

40.

Cao X, Meng P, Liu Y, Li X, Shi X, Sun X, et al. Adenoma location, size, and morphology are risk factors for FOBT false-negative results in inpatients with advanced colorectal adenoma. Sci Rep. 2024;14:831. [DOI] [PubMed] [PMC]

41.

Ladabaum U, Church TR, Feng Z, Ransohoff DF, Schoen RE. Counting Advanced Precancerous Lesions as True Positives When Determining Colorectal Cancer Screening Test Specificity. J Natl Cancer Inst. 2022;114:1040–3. [DOI] [PubMed] [PMC]

42.

Zhao G, Liu X, Liu Y, Li H, Ma Y, Li S, et al. Aberrant DNA Methylation of SEPT9 and SDC2 in Stool Specimens as an Integrated Biomarker for Colorectal Cancer Early Detection. Front Genet. 2020;11:643. [DOI] [PubMed] [PMC]

43.

Han YD, Oh TJ, Chung TH, Jang HW, Kim YN, An S, et al. Early detection of colorectal cancer based on presence of methylated syndecan-2 (SDC2) in stool DNA. Clin Epigenetics. 2019;11:51. [DOI] [PubMed] [PMC]

44.

Zhao G, Ma Y, Li H, Li S, Zhu Y, Liu X, et al. A novel plasma based early colorectal cancer screening assay base on methylated SDC2 and SFRP2. Clin Chim Acta. 2020;503:84–89. [DOI] [PubMed]

45.

Han X, Wang J, Sun Y. Circulating Tumor DNA as Biomarkers for Cancer Detection. Genomics Proteomics Bioinformatics. 2017;15:59–72. [DOI] [PubMed] [PMC]

46.

Yamane L, Scapulatempo-Neto C, Reis RM, Guimarães DP. Serrated pathway in colorectal carcinogenesis. World J Gastroenterol. 2014;20:2634–40. [DOI] [PubMed] [PMC]

47.

Oono Y, Fu K, Nakamura H, Iriguchi Y, Yamamura A, Tomino Y, et al. Progression of a Sessile Serrated Adenoma to an Early Invasive Cancer Within 8 Months. Dig Dis Sci. 2009;54:906–9. [DOI] [PubMed]

48.

García-Solano J, Pérez-Guillermo M, Conesa-Zamora P, Acosta-Ortega J, Trujillo-Santos J, Cerezuela-Fuentes P, et al. Clinicopathologic study of 85 colorectal serrated adenocarcinomas: further insights into the full recognition of a new subset of colorectal carcinoma. Hum Pathol. 2010;41:1359–68. [DOI] [PubMed]

49.

Johnson DA, Barclay RL, Mergener K, Weiss G, König T, Beck J, et al. Plasma Septin9 versus Fecal Immunochemical Testing for Colorectal Cancer Screening: A Prospective Multicenter Study. PLoS One. 2014;9:e98238. [DOI] [PubMed] [PMC]

50.

Jin P, Kang Q, Wang X, Yang L, Yu Y, Li N, et al. Performance of a second-generation methylated SEPT9 test in detecting colorectal neoplasm. J Gastroenterol Hepatol. 2015;30:830–3. [DOI] [PubMed]

51.

Fu B, Yan P, Zhang S, Lu Y, Pan L, Tang W, et al. Cell-Free Circulating Methylated SEPT9 for Noninvasive Diagnosis and Monitoring of Colorectal Cancer. Dis Markers. 2018;2018:6437104. [DOI] [PubMed] [PMC]