DOI QR코드

DOI QR Code

Sensitive and Noninvasive Detection of Aberrant SFRP2 and MGMT-B Methylation in Iranian Patients with Colon Polyps

  • Naini, M Alizade (Department of Internal Medicine, School of Medicine, Shiraz University of Medical Sciences) ;
  • Mokarram, P (Gastroenterohepatology Research Center, Nemazi Hospital, School of Medicine, Shiraz University of Medical Sciences) ;
  • Kavousipour, S (Biotechnology, School of Advanced Medical Science and Technologies, Shiraz University of Medical Sciences) ;
  • Zare, N (Department of Biochemistry, Science and Research Branch, Islamic Azad University) ;
  • Atapour, A (Biotechnology, School of Advanced Medical Science and Technologies, Shiraz University of Medical Sciences) ;
  • Zarin, M Hassan (Department of Internal Medicine, School of Medicine, Shiraz University of Medical Sciences) ;
  • Mehrabani, G (School of Medicine, Shiraz University of Medical Sciences) ;
  • Borji, M (Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences)
  • Published : 2016.06.01

Abstract

Background: The pathogenesis of sporadic colorectal cancer (CRC) is influenced by the patient genetic background and environmental factors. Based on prior understanding, these are classified in two major pathways of genetic instability. Microsatellite instability (MSI) and CPG island methylator phenotype (CIMP) are categorized as features of the hypermethylated prototype, and chromosomal instability (CIN) is known to be indicative of the non-hypermethylated category. Secreted frizzled related protein 2 (SFRP2), APC1A in WNT signaling pathway and the DNA repair gene, O6-methylguanine-DNA methyltransferase (MGMT), are frequently hypermethylated in colorectal cancer. Detection of methylated DNA as a biomarker by easy and inexpensive methods might improve the quality of life of patients with CRC via early detection of cancer or a precancerous condition. Aim: To evaluate the rate of SFRP2 and MGMT hypermethylation in both polyp tissue and serum of patients in south Iran as compared with matched control normal population corresponding samples. Materials and Methods: Methylation-specific PCR was used to detect hypermethylation in DNA extracted from 48 polypoid tissue samples and 25 healthy individuals. Results: Of total polyp samples, 89.5% had at least one promoter gene hypermethylation. The most frequent methylated locus was SFRP2 followed by MGMT-B (81.2 and 66.6 percent respectively). Serologic detection of hypermethylation was 95% sensitive as compared with polyp tissue. No hypermethylation was detected in normal tissue and serum and its detection in patients with polyps, especially of serrated type, was specific. Conclusions: Serologic investigation for detection of MGMT-B, SFRP2 hypermethylation could facilitate prioritization of high risk patients for colonoscopic polyp detection and excision.

Keywords

Colorectal cancer;polyp;MGMT;SFRP2;APC;methylation;serum diagnosis

Acknowledgement

Supported by : Shiraz University of Medical Sciences

References

  1. Bishehsari F, Mahdavinia M, Vacca M, et al (2014). Epidemiological transition of colorectal cancer in developing countries: Environmental factors, molecular pathways, and opportunities for prevention. World J Gastroenterol, 20, 6055-72. https://doi.org/10.3748/wjg.v20.i20.6055
  2. Carethers JM, Jung BH (2015). Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer. Gastroenterol, 149, 1177- 90.e3. https://doi.org/10.1053/j.gastro.2015.06.047
  3. Chang E, Park DI, Kim YJ, et al (2010). Detection of colorectal neoplasm using promoter methylation of ITGA4, SFRP2, and p16 in stool samples: a preliminary report in Korean patients. Hepatogastroenterol, 57, 720-7.
  4. Coppede F, Lopomo A, Spisni R, et al (2014). Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer. World J Gastroenterol, 20, 943-56. https://doi.org/10.3748/wjg.v20.i4.943
  5. De Maio G, Rengucci C, Zoli W, et al (2014). Circulating and stool nucleic acid analysis for colorectal cancer diagnosis. World J Gastroenterol, 20, 957-67. https://doi.org/10.3748/wjg.v20.i4.957
  6. Esteller M, Hamilton SR, Burger PC, et al (1999). Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res, 59, 793-7.
  7. Feldman M, Friedman LS (2010). Sleisenger and Fordtran's Gastrointestinal and Liver Disease. In Eds Saunders elsevier. Philadelphia.
  8. Fisher JA, Fikry C, Troxel AB (2006). Cutting cost and increasing access to colorectal cancer screening: another approach to following the guidelines. Cancer Epidemiol Biomarkers Prev, 15, 108-13. https://doi.org/10.1158/1055-9965.EPI-05-0198
  9. Hagrass HA, Pasha HF, Shaheen MA, et al (2014). Methylation status and protein expression of RASSF1A in breast cancer patients. Mol Biol Rep, 41, 57-65. https://doi.org/10.1007/s11033-013-2837-3
  10. Halford S, Rowan A, Sawyer E, et al (2005). O(6)-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C>A:T transitions. Gut, 54, 797-802. https://doi.org/10.1136/gut.2004.059535
  11. Hassanzade J, Molavi EVH, Farahmand M, et al (2011). Incidence and mortality rate of common gastrointestinal cancers in south of Iran, a population based study. Iran J Cancer Prev, 4, 163-9.
  12. Heitzer E, Ulz P, Geigl JB (2015). Circulating tumor DNA as a liquid biopsy for cancer. Clin Chem, 61, 112-23. https://doi.org/10.1373/clinchem.2014.222679
  13. Herbst A, Rahmig K, Stieber P, et al (2011). Methylation of NEUROG1 in serum is a sensitive marker for the detection of early colorectal cancer. Am J Gastroenterol, 106, 1110-8. https://doi.org/10.1038/ajg.2011.6
  14. Herman JG, Baylin SB (2003). Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med, 349, 2042-54. https://doi.org/10.1056/NEJMra023075
  15. Hibi K, Goto T, Mizukami H, et al (2009). MGMT gene is aberrantly methylated from the early stages of colorectal cancers. Hepatogastroenterol, 56, 1642-4.
  16. Huang ZH, Li LH, Yang F, et al (2007). Detection of aberrant methylation in fecal DNA as a molecular screening tool for colorectal cancer and precancerous lesions. World J Gastroenterol, 13, 950-4. https://doi.org/10.3748/wjg.v13.i6.950
  17. Kim MS, Lee J, Sidransky D (2010). DNA methylation markers in colorectal cancer. Cancer Metastasis Rev, 29, 181-206. https://doi.org/10.1007/s10555-010-9207-6
  18. Kycler W, Szarzynska B, Lozinski C, et al (2012). Analysis of O6-methylguanine-DNA methyltransferase methylation status in sporadic colon polyps. Rep Pract Oncol Radiother, 17, 13-8. https://doi.org/10.1016/j.rpor.2011.11.002
  19. Lee BB, Lee EJ, Jung EH, et al (2009). Aberrant methylation of APC, MGMT, RASSF2A, and Wif-1 genes in plasma as a biomarker for early detection of colorectal cancer. Clin Cancer Res, 15, 6185-91. https://doi.org/10.1158/1078-0432.CCR-09-0111
  20. Leggett BA, Hewett DG (2015). Colorectal cancer screening. Intern Med J, 45, 6-15.
  21. Levin B, Lieberman DA, McFarland B, et al (2008). Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin, 58, 130-60. https://doi.org/10.3322/CA.2007.0018
  22. Lo Nigro C, Wang H, McHugh A, et al (2013). Methylated tissue factor pathway inhibitor 2 (TFPI2) DNA in serum is a biomarker of metastatic melanoma. J Invest Dermatol, 133, 1278-85. https://doi.org/10.1038/jid.2012.493
  23. Lofton-Day C, Model F, Devos T, et al (2008). DNA methylation biomarkers for blood-based colorectal cancer screening. Clin Chem, 54, 414-23. https://doi.org/10.1373/clinchem.2007.095992
  24. Lu H, Huang S, Zhang X, et al (2014). DNA methylation analysis of SFRP2, GATA4/5, NDRG4 and VIM for the detection of colorectal cancer in fecal DNA. Oncol Lett, 8, 1751-6. https://doi.org/10.3892/ol.2014.2413
  25. Mokarram P, Kavousipour S, Sarabi MM, et al (2015). MGMT-B gene promoter hypermethylation in patients with inflammatory bowel disease - a novel finding. Asian Pac J Cancer Prev, 16, 1945-52. https://doi.org/10.7314/APJCP.2015.16.5.1945
  26. Mokarram P, Naghibalhossaini F, Saberi Firoozi M, et al (2008). Methylenetetrahydrofolate reductase C677T genotype affects promoter methylation of tumor-specific genes in sporadic colorectal cancer through an interaction with folate/ vitamin B12 status. World J Gastroenterol, 14, 3662-71. https://doi.org/10.3748/wjg.14.3662
  27. Mokarram P, Zamani M, Kavousipour S, et al (2013). Different patterns of DNA methylation of the two distinct O6- methylguanine-DNA methyltransferase (O6-MGMT) promoter regions in colorectal cancer. Mol Biol Rep, 40, 3851-7. https://doi.org/10.1007/s11033-012-2465-3
  28. Muller HM, Oberwalder M, Fiegl H, et al (2004). Methylation changes in faecal DNA: a marker for colorectal cancer screening? Lancet, 363, 1283-5. https://doi.org/10.1016/S0140-6736(04)16002-9
  29. Murakami T, Mitomi H, Saito T, et al (2015). Distinct WNT/ beta-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum. Mod Pathol, 28, 146-58. https://doi.org/10.1038/modpathol.2014.41
  30. Naghibalhossaini F, Zamani M, Mokarram P, et al (2012). Epigenetic and genetic analysis of WNT signaling pathway in sporadic colorectal cancer patients from Iran. Mol Biol Rep, 39, 6171-8. https://doi.org/10.1007/s11033-011-1434-6
  31. Oberwalder M, Zitt M, Wontner C, et al (2008). SFRP2 methylation in fecal DNA--a marker for colorectal polyps. Int J Colorectal Dis, 23, 15-9.
  32. Oh T, Kim N, Moon Y, et al (2013). Genome-wide identification and validation of a novel methylation biomarker, SDC2, for blood-based detection of colorectal cancer. J Mol Diagn, 15, 498-507. https://doi.org/10.1016/j.jmoldx.2013.03.004
  33. Okugawa Y, Grady WM, Goel A (2015). Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers. Gastroenterol, 149, 1204-25. https://doi.org/10.1053/j.gastro.2015.07.011
  34. Psofaki V, Kalogera C, Tzambouras N, et al (2010). Promoter methylation status of hMLH1, MGMT, and CDKN2A/p16 in colorectal adenomas. World J Gastroenterol, 16, 3553-60. https://doi.org/10.3748/wjg.v16.i28.3553
  35. Salehi R, Mohammadi M, Emami MH, et al (2012). Methylation pattern of SFRP1 promoter in stool sample is a potential marker for early detection of colorectal cancer. Adv Biomed Res, 1, 87. https://doi.org/10.4103/2277-9175.105169
  36. Segditsas S, Sieber OM, Rowan A, et al (2008). Promoter hypermethylation leads to decreased APC mRNA expression in familial polyposis and sporadic colorectal tumours, but does not substitute for truncating mutations. Exp Mol Pathol, 85, 201-6. https://doi.org/10.1016/j.yexmp.2008.09.006
  37. Segditsas S, Tomlinson I (2006). Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene, 25, 7531-7. https://doi.org/10.1038/sj.onc.1210059
  38. Shah R, Jones E, Vidart V, et al (2014). Biomarkers for early detection of colorectal cancer and polyps: systematic review. Cancer Epidemiol Biomarkers Prev, 23, 1712-28. https://doi.org/10.1158/1055-9965.EPI-14-0412
  39. Shen L, Kondo Y, Rosner GL, et al (2005). MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst, 97, 1330-8. https://doi.org/10.1093/jnci/dji275
  40. Silva AL, Dawson SN, Arends MJ, et al (2014). Boosting Wnt activity during colorectal cancer progression through selective hypermethylation of Wnt signaling antagonists. BMC Cancer, 14, 891. https://doi.org/10.1186/1471-2407-14-891
  41. Stoffel EM, Boland CR (2015). Genetics and Genetic Testing in Hereditary Colorectal Cancer. Gastroenterol, 149, 1191-203. https://doi.org/10.1053/j.gastro.2015.07.021
  42. Stracci F, Zorzi M, Grazzini G (2014). Colorectal Cancer Screening: Tests, Strategies, and Perspectives. Frontiers Public Health, 2, 210.
  43. Summers T, Langan RC, Nissan A, et al (2013). Serum-based DNA methylation biomarkers in colorectal cancer: potential for screening and early detection. J Cancer, 4, 210-6. https://doi.org/10.7150/jca.5839
  44. Takane K, Midorikawa Y, Yagi K, et al (2014). Aberrant promoter methylation of PPP1R3C and EFHD1 in plasma of colorectal cancer patients. Cancer Med, 3, 1235-45. https://doi.org/10.1002/cam4.273
  45. Takeda M, Nagasaka T, Dong-Sheng S, et al (2011). Expansion of CpG methylation in the SFRP2 promoter region during colorectal tumorigenesis. Acta Med Okayama, 65, 169-77.
  46. Tang D, Liu J, Wang DR, et al (2011). Diagnostic and prognostic value of the methylation status of secreted frizzled-related protein 2 in colorectal cancer. Clin Invest Med, 34, 88-95. https://doi.org/10.25011/cim.v34i1.15105
  47. Tanzer M, Balluff B, Distler J, et al (2010). Performance of epigenetic markers SEPT9 and ALX4 in plasma for detection of colorectal precancerous lesions. PLoS One, 5, 9061. https://doi.org/10.1371/journal.pone.0009061
  48. van Bemmel D, Lenz P, Liao LM, et al (2012). Correlation of LINE-1 methylation levels in patient-matched buffy coat, serum, buccal cell, and bladder tumor tissue DNA samples. Cancer Epidemiol Biomarkers Prev, 21, 1143-8. https://doi.org/10.1158/1055-9965.EPI-11-1030
  49. Voorham QJ, Janssen J, Tijssen M, et al (2013). Promoter methylation of Wnt-antagonists in polypoid and nonpolypoid colorectal adenomas. BMC Cancer, 13, 603. https://doi.org/10.1186/1471-2407-13-603
  50. Wang D-R, Tang D (2008). Hypermethylated SFRP2 gene in fecal DNA is a high potential biomarker for colorectal cancer noninvasive screening. World J Gastroenterol, 14, 524-31. https://doi.org/10.3748/wjg.14.524
  51. Wang X, Kuang YY, Hu XT (2014). Advances in epigenetic biomarker research in colorectal cancer. World J Gastroenterol, 20, 4276-87. https://doi.org/10.3748/wjg.v20.i15.4276
  52. Wang Z, Jiang W, Wang Y, et al (2015). promoter methylation in serum and cerebrospinal fluid as a tumor-specific biomarker of glioma. Biomed Rep, 3, 543-8. https://doi.org/10.3892/br.2015.462
  53. Whitehall VL, Walsh MD, Young J, et al (2001). Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability. Cancer Res, 61, 827-30.
  54. Yi JM, Dhir M, Guzzetta AA, et al (2012). DNA methylation biomarker candidates for early detection of colon cancer. Tumour Biol, 33, 363-72. https://doi.org/10.1007/s13277-011-0302-2
  55. Ying Y, Tao Q (2009). Epigenetic disruption of the WNT/betacatenin signaling pathway in human cancers. Epigenetics, 4, 307-12. https://doi.org/10.4161/epi.4.5.9371
  56. Zhang W, Bauer M, Croner RS, et al (2007). DNA stool test for colorectal cancer: hypermethylation of the secreted frizzledrelated protein-1 gene. Dis Colon Rectum, 50, 1618-26. https://doi.org/10.1007/s10350-007-0286-6
  57. Zhang X, Song YF, Lu HN, et al (2015). Combined detection of plasma GATA5 and SFRP2 methylation is a valid noninvasive biomarker for colorectal cancer and adenomas. World J Gastroenterol, 21, 2629-37. https://doi.org/10.3748/wjg.v21.i9.2629
  58. Zou H, Harrington JJ, Shire AM, et al (2007). Highly methylated genes in colorectal neoplasia: implications for screening. Cancer Epidemiol Biomarkers Prev, 16, 2686-96. https://doi.org/10.1158/1055-9965.EPI-07-0518

Cited by

  1. Epigenetic biomarkers in colorectal cancer: premises and prospects pp.1366-5804, 2016, https://doi.org/10.1080/1354750X.2016.1252961