Advertisement

International Journal of Colorectal Disease

, Volume 23, Issue 1, pp 15–19 | Cite as

SFRP2 methylation in fecal DNA—a marker for colorectal polyps

  • Michael Oberwalder
  • Marion Zitt
  • Cornelia Wöntner
  • Heidi Fiegl
  • Georg Goebel
  • Matthias Zitt
  • Olivia Köhle
  • Gilbert Mühlmann
  • Dietmar Öfner
  • Raimund Margreiter
  • Hannes M. MüllerEmail author
Original Article

Abstract

Introduction

DNA methylation of secreted frizzled-related proteins (SFRPs) can be detected in colorectal cancer (CRC) tissue, in tissue of adenomas, and in aberrant crypt foci, whereas in normal colorectal mucosa tissue, SFRP genes are unmethylated. Recently, our study group was able to demonstrate SFRP2 methylation as the most sensitive single DNA-based marker in stool for identification of CRC. The purpose of this study was to clarify whether SFRP2 methylation in fecal DNA can be found in stool of individuals with hyperplastic and adenomatous colorectal polyps.

Materials and methods

Patients who were diagnosed with colorectal polyps or showed negative colonoscopy were included in this study. DNA from stool samples was isolated. SFRP2 methylation was assessed by means of MethyLight.

Results

Stool samples from 68 individuals were checked for DNA content; 23% of the samples (6 of 26) from healthy controls, 46% of the samples (6 of 13) from patients with hyperplastic polyps, and 45% of the samples (13 of 29) from patients with adenomas were positive for human DNA. SFRP2 methylation in stool samples was found in none of the healthy controls, in 33% (2 of 6) patients with hyperplastic polyps, and in 46% (6 of 13) patients with adenomas. Statistical analysis revealed that the frequency of SFRP2 methylation increased significantly (P = 0.028) from healthy controls to patients with hyperplastic polyps and to patients with adenomas.

Conclusions

In the current study, we report for the first time that SFRP2 methylation in fecal DNA increases significantly from healthy controls to patients with hyperplastic polyps and to patients with adenomas. SFRP2 methylation may serve as a marker for molecular stool-based adenoma and CRC screening.

Keywords

DNA methylation SFRP2 Colorectal polyps MethyLight Fecal DNA Stool 

Notes

Acknowledgements

Supported by a grant from “Jubiläumsfonds der Österreichischen Nationalbank” (Project number 10929), from “Tiroler Wissenschaftsfonds”, and from “Österreichische Krebshilfe-Krebsgesellschaft Tirol”. Michael Oberwalder and Marion Zitt contributed equally to this work.

References

  1. 1.
    Jass JR, Whitehall VL, Young J, Leggett BA (2002) Emerging concepts in colorectal neoplasia. Gastroenterology 123:862–876PubMedCrossRefGoogle Scholar
  2. 2.
    Kozuka S, Nogaki M, Ozeki T, Masumori S (1975) Premalignancy of the mucosal polyp in the large intestine: II. Estimation of the periods required for malignant transformation of mucosal polyps. Dis Colon Rectum 18:494–500PubMedCrossRefGoogle Scholar
  3. 3.
    Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767PubMedCrossRefGoogle Scholar
  4. 4.
    Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170PubMedCrossRefGoogle Scholar
  5. 5.
    Morson BC (1974) Evolution of cancer of the colon and rectum. Cancer 34(Suppl 3):845–849PubMedCrossRefGoogle Scholar
  6. 6.
    O’Brien MJ, Winawer SJ, Zauber AG, Gottlieb LS, Sternberg SS, Diaz B, Dickersin GR, Ewing S, Geller S, Kasimian D et al (1990) The National Polyp Study. Patient and polyp characteristics associated with high-grade dysplasia in colorectal adenomas. Gastroenterology 98:371–379PubMedGoogle Scholar
  7. 7.
    Zitt M, Zitt M, Müller HM (2007) DNA methylation in colorectal cancer–impact on screening and therapy monitoring modalities? Dis Markers 23(1–2):51–71PubMedGoogle Scholar
  8. 8.
    Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428PubMedCrossRefGoogle Scholar
  9. 9.
    Laird PW (2003) Early detection: The power and the promise of DNA methylation markers. Nat Rev Cancer 3:253–266PubMedCrossRefGoogle Scholar
  10. 10.
    Widschwendter M, Jones PA (2002) DNA methylation and breast carcinogenesis. Oncogene 21:5462–5482PubMedCrossRefGoogle Scholar
  11. 11.
    Jubb AM, Bell SM, Quirke P (2001) Methylation and colorectal cancer. J Pathol 195:111–134PubMedCrossRefGoogle Scholar
  12. 12.
    Caldwell GM, Jones C, Gensberg K, Jan S, Hardy RG, Byrd P, Chughtai S, Wallis Y, Matthews GM, Morton DG (2004) The Wnt antagonist sFRP1 in colorectal tumorigenesis. Cancer Res 64:883–888PubMedCrossRefGoogle Scholar
  13. 13.
    Qi J, Zhu YQ, Luo J, Tao WH (2006) Hypermethylation and expression regulation of secreted frizzled-related protein genes in colorectal tumor. World J Gastroenterol 12:7113–7117PubMedGoogle Scholar
  14. 14.
    Suzuki H, Gabrielson E, Chen W, Ambazhagan R, van Engeland M, Weijenberg MP, Herman JG, Baylin SB (2002) A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 31:141–149PubMedCrossRefGoogle Scholar
  15. 15.
    Müller HM, Oberwalder M, Fiegl H, Morandell M, Goebel G, Zitt M, Mühlthaler M, Öfner D, Margreiter R, Widschwendter M (2004) Methylation changes in faecal DNA: a marker for colorectal cancer screening? Lancet 363:1283–1285PubMedCrossRefGoogle Scholar
  16. 16.
    Petko Z, Ghiassi M, Shuber A, Gorham J, Smalley W, Washington MK, Schultenover S, Gautham S, Markowitz SD, Grady WM (2005) Aberrantly methylated CDKN2A, MGMT, and MLH1 in colon polyps and in fecal DNA from patients with colorectal polyps. Clin Cancer Res 11:1203–1209PubMedGoogle Scholar
  17. 17.
    Weisenberger DJ, Campan M, Long TI, Kim M, Woods C, Fiala E, Melanie Ehrlich M, Laird PW (2005) Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res 33(21):6823–6836PubMedCrossRefGoogle Scholar
  18. 18.
    Eads CA, Danenberg KD, Kawakami K, Saltz LB, Blake C, Shibata D, Danenberg PV, Laird PW (2000) MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 28:E32PubMedCrossRefGoogle Scholar
  19. 19.
    Müller HM, Widschwendter A, Fiegl H, Ivarson L, Goebel G, Perkmann E, Marth C, Widschwendter M (2003) DNA methylation in serum of breast cancer patients: an independent prognostic marker. Cancer Res 63:7641–7645PubMedGoogle Scholar
  20. 20.
    Vijan S, Inadomi J, Hayward RA, Hofer TP, Fendrick AM (2004) Projections of demand and capacity for colonoscopy related to increasing rates of colorectal cancer screening in the United States. Aliment Pharmacol Ther 20:507–515PubMedCrossRefGoogle Scholar
  21. 21.
    Imperiale TF, Ransohoff DF, Itzkowitz SH, Turnbull BA, Ross ME (2004) Fecal DNA versus fecal occult blood for colorectal-cancer screening in an average-risk population. N Engl J Med 351:2704–2714PubMedCrossRefGoogle Scholar
  22. 22.
    Pignone M, Rich M, Teutsch SM, Berg AO, Lohr KN (2002) Screening for colorectal cancer in adults at average risk: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 137:132–141PubMedGoogle Scholar
  23. 23.
    Ahlquist DA, Shuber AP (2002) Stool screening for colorectal cancer: evolution from occult blood to molecular markers. Clin Chim Acta 315:157–168PubMedCrossRefGoogle Scholar
  24. 24.
    Davies RJ, Miller R, Coleman N (2005) Colorectal cancer screening: prospects for molecular stool analysis. Nat Rev Cancer 5:199–209PubMedCrossRefGoogle Scholar
  25. 25.
    Loktionov A, O’Neill IK, Silvester KR, Cummings JH, Middleton SJ, Miller R (1998) Quantitation of DNA from exfoliated colonocytes isolated from human stool surface as a novel noninvasive screening test for colorectal cancer. Clin Cancer Res 4:337–342PubMedGoogle Scholar
  26. 26.
    Boynton KA, Summerhayes IC, Ahlquist DA, Shuber AP (2003) DNA integrity as a potential marker for stool-based detection of colorectal cancer. Clin Chem 49:1058–1065PubMedCrossRefGoogle Scholar
  27. 27.
    Ahuja N, Li Q, Mohan AL, Baylin SB, Issa JP (1998) Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res 58:5489–5494PubMedGoogle Scholar
  28. 28.
    Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB (1994) Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 7:536–540PubMedCrossRefGoogle Scholar
  29. 29.
    Nakagawa H, Nuovo GJ, Zervos EE, Martin EW Jr, Salovaara R, Aaltonen LA, de la Chapelle A (2001) Age-related hypermethylation of the 5′ region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development. Cancer Res 61:6991–6995PubMedGoogle Scholar
  30. 30.
    Yoo CB, Jones PA (2006) Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 5:37–50PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Michael Oberwalder
    • 1
  • Marion Zitt
    • 1
    • 2
  • Cornelia Wöntner
    • 1
  • Heidi Fiegl
    • 2
  • Georg Goebel
    • 3
  • Matthias Zitt
    • 1
  • Olivia Köhle
    • 1
  • Gilbert Mühlmann
    • 1
  • Dietmar Öfner
    • 1
  • Raimund Margreiter
    • 1
    • 2
  • Hannes M. Müller
    • 1
    Email author
  1. 1.Department of General and Transplant SurgeryInnsbruck Medical UniversityInnsbruckAustria
  2. 2.Tyrolean Cancer Research InstituteInnsbruckAustria
  3. 3.Department of Medical Statistics, Informatics and Health EconomicsInnsbruck Medical UniversityInnsbruckAustria

Personalised recommendations