Evaluating the clinical performance of SDC2/NDRG4 methylation for colorectal cancer detection
Abstract
Purpose: The performance and clinical accuracy of combined SDC2/NDRG4 methylation were evaluated in diagnosing colorectal cancer (CRC) and advanced adenoma. Methods: A total of 2333 participants were enrolled to assess the sensitivity and specificity of biomarkers in diagnosing CRC in a multicenter clinical trial through feces DNA methylation tests. Results:SDC2/NDRG4 methylation showed excellent performance for CRC detection in biomarker research and the real world. Its sensitivity for detecting CRC, early CRC and advanced adenoma were 92.06%, 91.45% and 62.61%, respectively. Its specificity was 94.29%, with a total coincidence rate of 88.28%. When interference samples were included, the specificity was still good (82.61%). Therefore, the SDC2/NDRG4 methylation test showed excellent performance in detecting CRC and advanced adenoma under clinical application.
Plain language summary
Colorectal cancer (CRC) is one of the most malignant tumors of the digestive system and second only to breast cancer and lung cancer in terms of global incidence. Early CRCs are challenging to determine given their atypical nature. In contrast, late CRC symptoms are affected by the type, location and range of the lesion and complications. Therefore, CRC patients are generally diagnosed late, present with a high degree of malignancy, and have poor prognosis and 5-year survival rates. The current study therefore evaluated whether SDC2 and NDRG4 methylation could be used for diagnosis CRCs at an early stage and whether it has the potential to detect asymptomatic patients with adenomas. The findings presented herein will certainly help support the early diagnosis of CRC and precancerous lesions in clinical practice.
Tweetable abstract
SDC2/NDRG4 methylation showed excellent performance for CRC detection in a real-world setting. Its sensitivity for detecting CRC, early CRC and advanced adenoma were 92.06%, 91.45% and 62.61%, respectively. Its specificity was 94.29%, with a total coincidence rate of 88.28%.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Colorectal cancer. Lancet 394(10207), 1467–1480 (2019).
- 2. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71(3), 209–249 (2021). •• Provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Colorectal cancer (CRC) is also the second leading cause of cancer-related deaths worldwide, with an estimated 1.93 million new cases having been diagnosed in 2020.
- 3. . Application of artificial intelligence in diagnosis and treatment of colorectal cancer: a novel prospect. Front. Med. (Lausanne) 10, 1128084 (2023).
- 4. . Early-onset colorectal cancer. Surg. Oncol. Clin. N. Am. 31(2), 143–155 (2022).
- 5. . Colorectal cancer development and advances in screening. Clin. Interv. Aging 11, 967–976 (2016).
- 6. . DNA methylation-based diagnostic, prognostic, and predictive biomarkers in colorectal cancer. Biochim. Biophys. Acta Rev. Cancer 1877(3), 188722 (2022).
- 7. A comprehensive framework for early-onset colorectal cancer research. Lancet Oncol. 23(3), e116–e128 (2022).
- 8. . Promising epigenetic biomarkers for the early detection of colorectal cancer: a systematic review. Cancers (Basel) 13(19), (2021).
- 9. DNA methylation biomarkers in stool for early screening of colorectal cancer. J. Cancer 10(21), 5264–5271 (2019).
- 10. Syndecan-2 is a novel target of insulin-like growth factor binding protein-3 and is over-expressed in fibrosis. PLOS ONE 7(8), e43049 (2012).
- 11. . Syndecan-2 cytoplasmic domain regulates colon cancer cell migration via interaction with syntenin-1. Biochem. Biophys. Res. Commun. 409(1), 148–153 (2011).
- 12. . New insights into syndecan-2 expression and tumourigenic activity in colon carcinoma cells. J. Mol. Histol. 35(3), 319–326 (2004).
- 13. Clinical validation of a multitarget fecal immunochemical test for colorectal cancer screening: a diagnostic test accuracy study. Ann. Intern. Med. 174(9), 1224–1231 (2021).
- 14. Early detection of colorectal cancer based on presence of methylated syndecan-2 (SDC2) in stool DNA. Clin. Epigenetics 11(1), 51 (2019). •• The results of this study validated the capability of stool DNA-based-SDC2 methylation tests by LTE-qMSP for early detection of CRC patients with high specificity. Stool DNA-based meSDC2 LTE-qMSP showed an overall sensitivity of 90.2% with AUC of 0.902 in detecting CRC (0–IV) not associated with tumor stage, location, sex or age (p > 0.05), with a specificity of 90.2%.
- 15. SDC2 and TFPI2 methylation in stool samples as an integrated biomarker for early detection of colorectal cancer. Cancer Manag. Res. 13, 3601–3617 (2021).
- 16. Feasibility of quantifying SDC2 methylation in stool DNA for early detection of colorectal cancer. Clin. Epigenetics 9, 126 (2017). •• Taken together, the manuscript result indicates that a stool DNA-based SDC2 methylation test by LTE-qMSP is a potentially noninvasive diagnostic tool for the early detection of CRC. The overall sensitivity was 90.0% for detecting CRC and 33.3% for detecting small polyps, with a specificity of 90.9%.
- 17. . Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart. Genomics 73(1), 86–97 (2001).
- 18. Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish. Dev. Biol. 317(2), 486–496 (2008).
- 19. N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer. J. Natl Cancer Inst. 101(13), 916–927 (2009).
- 20. NDRG4, a novel candidate tumor suppressor, is a predictor of overall survival of colorectal cancer patients. Oncotarget 6(10), 7584–7596 (2015).
- 21. High-throughput primer design by scoring in piecewise logistic model for multiple polymerase chain reaction variants. Sci. Rep. 12(1), 21136 (2022).
- 22. Risk of incident and fatal colorectal cancer after young-onset adenoma diagnosis: a national cohort study. Am. J. Gastroenterol.
doi: 10.14309/ajg.0000000000002296 (2023). - 23. Colorectal cancer screening methods and molecular markers for early detection. Technol. Cancer Res. Treat. 19, 1533033820980426 (2020). •• Illustrates novel routine screening and diagnostic methods (e.g., endoscopy and CT colonoscopy, SEPT9 methylation assay, fecal test) and found reliable molecular markers for the early diagnosis of CRC.
- 24. . Early-onset colorectal cancer: A review of current knowledge. World J. Gastroenterol. 29(8), 1289–1303 (2023).
- 25. Characteristics of early-onset vs late-onset colorectal cancer: a review. JAMA Surg. 156(9), 865–874 (2021).
- 26. Colorectal Cancer Screening (PDQ(R)): Health Professional Version. In: PDQ Cancer Information Summaries. MD, USA (2002).
- 27. . Emerging tests for noninvasive colorectal cancer screening. Clin. Gastroenterol. Hepatol. 21(3), 604–616 (2023). • Reviewed current screening modalities and discussed the principles behind the most promising emerging CRC screening tests and the data supporting their potential to be used in clinical practice.
- 28. . Colorectal cancer screening in a changing world. Gastroenterol. Clin. North Am. 51(3), 577–591 (2022).
- 29. Opportunistic colonoscopy in healthy individuals: a non-trivial risk of adenoma. PLOS ONE 18(4), e0283575 (2023).
- 30. . Biochemical markers in colorectal cancer: diagnostic and therapeutic implications. Gastroenterol. Clin. North Am. 17(4), 931–940 (1988).
- 31. . Preoperative evaluation of colorectal cancer using CT colonography, MRI, and PET/CT. World J. Gastroenterol. 20(45), 16964–16975 (2014).
- 32. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. N. Engl. J. Med. 349(23), 2191–2200 (2003).
- 33. . Multitarget stool DNA testing for colorectal-cancer screening. N. Engl. J. Med. 371(2), 187–188 (2014).
- 34. . Stool testing for colorectal cancer screening. Gastroenterology 149(5), 1286–1293 (2015).
- 35. . Fecal biomarkers: Non-invasive diagnosis of colorectal cancer. Front. Oncol. 12, 971930 (2022).
- 36. . Colorectal cancer diagnosis: the obstacles we face in determining a non-invasive test and current advances in biomarker detection. Cancers (Basel) 14(8), (2022).
- 37. Multitarget stool DNA testing for colorectal-cancer screening. N. Engl. J. Med. 370(14), 1287–1297 (2014).
- 38. DNA methylation analysis of SFRP2, GATA4/5, NDRG4 and VIM for the detection of colorectal cancer in fecal DNA. Oncol. Lett. 8(4), 1751–1756 (2014). • Showed that methylation of the SFRP2, GATA4/5, NDRG4 and VIM promoters in fecal DNA is associated with the presence of colorectal tumors. Therefore, the detection of aberrantly methylated DNA in fecal samples may present a promising, noninvasive screening method for CRC.
- 39. Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology 142(2), 248–256; quiz e225-246 (2012).
- 40. Robust performance of a novel stool DNA test of methylated SDC2 for colorectal cancer detection: a multicenter clinical study. Clin. Epigenetics 12(1), 162 (2020). • Describes a noninvasive sDNA test using methylated SDC2 as the exclusive biomarker is a clinically viable and accurate CRC detection method.
- 41. Evaluating the clinical performance of a dual-target stool DNA test for colorectal cancer detection. J. Mol. Diagn. 24(2), 131–143 (2022). • The iColocomf test showed robust performance for the early detection of colorectal cancer and potential monitoring ability in clinical practice.
- 42. Detection of TFPI2 methylation in the serum of gastric cancer patients. Anticancer Res. 31(11), 3835–3838 (2011).
- 43. A novel stool methylation test for the non-invasive screening of gastric and colorectal cancer. Front. Oncol. 12, 860701 (2022).
- 44. A liquid biopsy-based approach for monitoring treatment response in post-operative colorectal cancer patients. Int. J. Mol. Sci. 23(7), 3774 (2022).
- 45. Efficient detection and post-surgical monitoring of colon cancer with a multi-marker DNA methylation liquid biopsy. Proc. Natl Acad. Sci. USA 118(5), e2017421118 (2021).