Journal Mobile Options
Table of Contents
Vol. 30, Suppl. 2, 2012
Issue release date: November 2012
Dig Dis 2012;30(suppl 2):16–26

Noninvasive Screening Tests for Colorectal Cancer

Imperiale T.F.
Indiana University School of Medicine, Regenstrief Institute, Inc. and Richard L. Roudebush VA Medical Center, Indianapolis, Ind., USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Background: Identifying an accurate, reliable, affordable, and acceptable noninvasive screening test for colorectal cancer (CRC) would greatly facilitate population screening. Methods: Published literature from 2000 through February 2012 on noninvasive CRC screening tests was identified, reviewed, and summarized. Results: The highest quality evidence for noninvasive screening exists for guaiac-based fecal occult blood tests (gFOBTs), for which the CRC-specific incidence and mortality reductions are modest. Fecal immunochemical tests (FITs) offer better sensitivity and comparable specificity. Cross-sectional studies comparing gFOBTs and FITs suggest that FITs provide higher detection of advanced neoplasia. Modeling studies favor FITs over gFOBTs with respect to effectiveness and cost-effectiveness. A myriad of studies report the performance of fecal-based and blood-based genetic and protein-based biomarkers; the studies differ in patient population assembled, marker selection, and assay methods. Several markers and panels of markers are promising, although nearly all studies focus on new markers and/or assay methods on small sets of referred patients rather than validating markers using optimal assays in a screening setting. Conclusion: In the absence of long-term randomized trials, adoption of the noninvasive tests will require cross-sectional data on test characteristics obtained from the screening setting, where CRC prevalence is low and the full spectrum of colorectal findings exists, along with estimates of cumulative risks, benefits, and cost-effectiveness. Test adoption will ultimately depend on test characteristics, availability, affordability, and user appeal. There is no noninvasive substitute for the currently recommended screening tests. FITs should replace gFOBTs wherever gFOBTs are used for screening.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Gutierrez-Ibarluzea I, Asua J, Latorre K: Policies of screening for colorectal cancer in European countries. Int J Technol Assess Health Care 2008;24:270–276.
  2. Arditi C, et al: Appropriateness of colonoscopy in Europe (EPAGE II). Screening for colorectal cancer. Endoscopy 2009;41:200–208.
  3. Levin B, et al: 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. Gastroenterology 2008;134:1570–1595.
  4. Levin B, et al: 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 2008;58:130–160.
  5. Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008;149:627–637.
  6. Rex DK, et al: American College of Gastroenterology guidelines for colorectal cancer screening 2009 (corrected). Am J Gastroenterol 2009;104:739–750.
  7. Kahi CJ, et al: Effect of screening colonoscopy on colorectal cancer incidence and mortality. Clin Gastroenterol Hepatol 2009;7:770–775, quiz 711.
  8. Winawer SJ, et al: Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993;329:1977–1981.
  9. Zauber AG, et al: Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 2012;366:687–696.
  10. Frazier AL, et al: Cost-effectiveness of screening for colorectal cancer in the general population. JAMA 2000;284:1954–1961.
  11. Heitman SJ, et al: Colorectal cancer screening for average-risk North Americans: an economic evaluation. PLoS Med 2010;7:e1000370.
  12. Lansdorp-Vogelaar I, et al: Effect of rising chemotherapy costs on the cost savings of colorectal cancer screening. J Natl Cancer Inst 2009;101:1412–1422.
  13. Parekh M, Fendrick AM, Ladabaum U: As tests evolve and costs of cancer care rise: reappraising stool-based screening for colorectal neoplasia. Aliment Pharmacol Ther 2008;27:697–712.
  14. van Rossum LG, et al: Colorectal cancer screening comparing no screening, immunochemical and guaiac fecal occult blood tests: a cost-effectiveness analysis. Int J Cancer 2010;128:1908–1917.

    External Resources

  15. Zauber AG, et al: Evaluating test strategies for colorectal cancer screening: a decision analysis for the U.S. Preventive Services Task Force. Ann Intern Med 2008;149:659–669.
  16. Seeff LC, et al: Is there endoscopic capacity to provide colorectal cancer screening to the unscreened population in the United States? Gastroenterology 2004;127:1661–1669.
  17. Seeff LC, et al: How many endoscopies are performed for colorectal cancer screening? Results from CDC’s survey of endoscopic capacity. Gastroenterology 2004;127:1670–1677.
  18. Cancer screening – United States, 2010. MMWR Morb Mortal Wkly Rep 2012;61:41–45.
  19. Chiang TH, et al: Performance of the immunochemical fecal occult blood test in predicting lesions in the lower gastrointestinal tract. CMAJ 2011;183:1474–1481.
  20. Hardcastle JD, et al: Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996;348:1472–1477.
  21. Kronborg O, et al: Randomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet 1996;348:1467–1471.
  22. Faivre J, et al: Reduction in colorectal cancer mortality by fecal occult blood screening in a French controlled study. Gastroenterology 2004;126:1674–1680.
  23. Lindholm E, Brevinge H, Haglind E: Survival benefit in a randomized clinical trial of faecal occult blood screening for colorectal cancer. Br J Surg 2008;95:1029–1036.
  24. Mandel JS, et al: Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993;328:1365–1371.
  25. Mandel JS, et al: The effect of fecal occult-blood screening on the incidence of colorectal cancer. N Engl J Med 2000;343:1603–1607.
  26. Hewitson P, et al: Cochrane Systematic Review of colorectal cancer screening using the fecal occult blood test (hemoccult): an update. Am J Gastroenterol 2008;102:1541–1549.

    External Resources

  27. Kewenter J, et al: Results of screening, rescreening, and follow-up in a prospective randomized study for detection of colorectal cancer by fecal occult blood testing. Results for 68,308 subjects. Scand J Gastroenterol 1994;29:468–473.
  28. Guittet L, et al: Comparison of a guaiac based and an immunochemical faecal occult blood test in screening for colorectal cancer in a general average risk population. Gut 2007;56:210–214.
  29. Levi Z, et al: A quantitative immunochemical fecal occult blood test for colorectal neoplasia. Ann Intern Med 2007;146:244–255.
  30. Morikawa T, et al: A comparison of the immunochemical fecal occult blood test and total colonoscopy in the asymptomatic population. Gastroenterology 2005;129:422–428.
  31. van Rossum LG, et al: Random comparison of guaiac and immunochemical fecal occult blood tests for colorectal cancer in a screening population. Gastroenterology 2008;135:82–90.
  32. Hol L, et al: Screening for colorectal cancer: randomised trial comparing guaiac-based and immunochemical faecal occult blood testing and flexible sigmoidoscopy. Gut 2010;59:62–68.
  33. Oort FA, et al: Colonoscopy-controlled intra-individual comparisons to screen relevant neoplasia: faecal immunochemical test vs. guaiac-based faecal occult blood test. Aliment Pharmacol Ther 2009;31:432–439.
  34. Hundt S, Haug U, Brenner H: Comparative evaluation of immunochemical fecal occult blood tests for colorectal adenoma detection. Ann Intern Med 2009;150:162–169.
  35. Ahlquist DA, et al: Stool DNA and occult blood testing for screen detection of colorectal neoplasia. Ann Intern Med 2008;149:441–450, W81.
  36. Ahlquist DA, et al: Colorectal cancer screening by detection of altered human DNA in stool: feasibility of a multitarget assay panel. Gastroenterology 2000;119:1219–1227.
  37. Boynton KA, et al: DNA integrity as a potential marker for stool-based detection of colorectal cancer. Clin Chem 2003;49:1058–1065.
  38. Calistri D, et al: Fecal multiple molecular tests to detect colorectal cancer in stool. Clin Gastroenterol Hepatol 2003;1:377–383.
  39. Calistri D, et al: Detection of colorectal cancer by a quantitative fluorescence determination of DNA amplification in stool. Neoplasia 2004;6:536–540.
  40. Calistri D, et al: Quantitative fluorescence determination of long-fragment DNA in stool as a marker for the early detection of colorectal cancer. Cell Oncol 2009;31:11–17.
  41. Chen WD, et al: Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J Natl Cancer Inst 2005;97:1124–1132.
  42. Huang Z, Li L, Wang J: Hypermethylation of SFRP2 as a potential marker for stool-based detection of colorectal cancer and precancerous lesions. Dig Dis Sci 2007;52:2287–2291.
  43. Imperiale TF, et al: Fecal DNA versus fecal occult blood for colorectal-cancer screening in an average-risk population. N Engl J Med 2004;351:2704–2714.
  44. Itzkowitz SH, et al: Improved fecal DNA test for colorectal cancer screening. Clin Gastroenterol Hepatol 2007;5:111–117.
  45. Lenhard K, et al: Analysis of promoter methylation in stool: a novel method for the detection of colorectal cancer. Clin Gastroenterol Hepatol 2005;3:142–149.
  46. Müller HM, et al: Methylation changes in faecal DNA: a marker for colorectal cancer screening? Lancet 2004;363:1283–1285.
  47. Tagore KS, et al: Sensitivity and specificity of a stool DNA multitarget assay panel for the detection of advanced colorectal neoplasia. Clin Colorectal Cancer 2003;3:47–53.
  48. Traverso G, et al: Detection of APC mutations in fecal DNA from patients with colorectal tumors. N Engl J Med 2002;346:311–320.
  49. Whitney D, et al: Enhanced retrieval of DNA from human fecal samples results in improved performance of colorectal cancer screening test. J Mol Diagn 2004;6:386–395.
  50. Baek YH, et al: Stool methylation-specific polymerase chain reaction assay for the detection of colorectal neoplasia in Korean patients. Dis Colon Rectum 2009;52:1452–1459, discussion 1459–1463.
  51. Glockner SC, et al: Methylation of TFPI2 in stool DNA: a potential novel biomarker for the detection of colorectal cancer. Cancer Res 2009;69:4691–4699.
  52. Hellebrekers DM, et al: GATA4 and GATA5 are potential tumor suppressors and biomarkers in colorectal cancer. Clin Cancer Res 2009;15:3990–3997.
  53. Huang ZH, et al: Detection of aberrant methylation in fecal DNA as a molecular screening tool for colorectal cancer and precancerous lesions. World J Gastroenterol 2007;13:950–954.
  54. Itzkowitz S, et al: A simplified, noninvasive stool DNA test for colorectal cancer detection. Am J Gastroenterol 2008;103:2862–2870.
  55. Kim MS, et al: Promoter DNA methylation of oncostatin m receptor-beta as a novel diagnostic and therapeutic marker in colon cancer. PLoS One 2009;4:e6555.
  56. Leung WK, et al: Detection of epigenetic changes in fecal DNA as a molecular screening test for colorectal cancer: a feasibility study. Clin Chem 2004;50:2179–2182.
  57. Leung WK, et al: Detection of hypermethylated DNA or cyclooxygenase-2 messenger RNA in fecal samples of patients with colorectal cancer or polyps. Am J Gastroenterol 2007;102:1070–1076.
  58. Li M, et al: Sensitive digital quantification of DNA methylation in clinical samples. Nat Biotechnol 2009;27:858–863.
  59. Melotte V, et al: N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer. J Natl Cancer Inst 2009;101:916–927.
  60. Nagasaka T, et al: Analysis of fecal DNA methylation to detect gastrointestinal neoplasia. J Natl Cancer Inst 2009;101:1244–1258.
  61. Oberwalder M, et al: SFRP2 methylation in fecal DNA a marker for colorectal polyps. Int J Colorectal Dis 2008;23:15–19.
  62. Petko Z, et al: Aberrantly methylated CDKN2A, MGMT, and MLH1 in colon polyps and in fecal DNA from patients with colorectal polyps. Clin Cancer Res 2005;11:1203–1209.
  63. Wang DR, Tang D: Hypermethylated SFRP2 gene in fecal DNA is a high potential biomarker for colorectal cancer noninvasive screening. World J Gastroenterol 2008;14:524–531.
  64. Abbaszadegan MR, et al: Stool-based DNA testing, a new noninvasive method for colorectal cancer screening, the first report from Iran. World J Gastroenterol 2007;13:1528–1533.
  65. Kutzner N, et al: Non-invasive detection of colorectal tumours by the combined application of molecular diagnosis and the faecal occult blood test. Cancer Lett 2005;229:33–41.
  66. Matsushita H, et al: A new method for isolating colonocytes from naturally evacuated feces and its clinical application to colorectal cancer diagnosis. Gastroenterology 2005;129:1918–1927.
  67. Onouchi S, et al: New method for colorectal cancer diagnosis based on SSCP analysis of DNA from exfoliated colonocytes in naturally evacuated feces. Anticancer Res 2008;28:145–150.
  68. Puig P, et al: A highly sensitive method for K-ras mutation detection is useful in diagnosis of gastrointestinal cancer. Int J Cancer 2000;85:73–77.
  69. Traverso G, et al: Detection of proximal colorectal cancers through analysis of faecal DNA. Lancet 2002;359:403–404.
  70. Wan J, et al: Detection of K-ras gene mutation in fecal samples from elderly large intestinal cancer patients and its diagnostic significance. World J Gastroenterol 2004;10:743–746.
  71. Brand RE, Ross ME, Shuber AP: Reproducibility of a multitarget stool-based DNA assay for colorectal cancer detection. Am J Gastroenterol 2004;99:1338–1341.
  72. Syngal S, et al: Detection of stool DNA mutations before and after treatment of colorectal neoplasia. Cancer 2006;106:277–283.
  73. Ahlquist DA, et al: Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology 2012;142:248–256, quiz e25–e26.
  74. Ahmed FE, et al: Transcriptomic molecular markers for screening human colon cancer in stool and tissue. Cancer Genomics Proteomics 2007;4:1–20.
  75. Chien CC, et al: Correlation of K-ras codon 12 mutations in human feces and ages of patients with colorectal cancer (CRC). Transl Res 2007;149:96–102.
  76. Kanaoka S, et al: Potential usefulness of detecting cyclooxygenase 2 messenger RNA in feces for colorectal cancer screening. Gastroenterology 2004;127:422–427.
  77. Koga Y, et al: Detection of colorectal cancer cells from feces using quantitative real-time RT-PCR for colorectal cancer diagnosis. Cancer Sci 2008;99:1977–1983.
  78. Takai T, et al: Fecal cyclooxygenase 2 plus matrix metalloproteinase 7 mRNA assays as a marker for colorectal cancer screening. Cancer Epidemiol Biomarkers Prev 2009;18:1888–1893.
  79. Bosch LJ, et al: Molecular tests for colorectal cancer screening. Clin Colorectal Cancer 2011;10:8–23.
  80. Ahlquist DA: Molecular detection of colorectal neoplasia. Gastroenterology 2010;138:2127–2139.
  81. Hundt S, Haug U, Brenner H: Blood markers for early detection of colorectal cancer: a systematic review. Cancer Epidemiol Biomarkers Prev 2007;16:1935–1953.
  82. Link A, et al: Fecal microRNAs as novel biomarkers for colon cancer screening. Cancer Epidemiol Biomarkers Prev 2010;19:1766–1774.
  83. Newton KF, Newman W, Hill J: Review of biomarkers in colorectal cancer. Colorectal Dis 2010;14:3–17.

    External Resources

  84. Wu WK, et al: MicroRNA in colorectal cancer: from benchtop to bedside. Carcinogenesis 2010;32:247–253.
  85. Diehl F, et al: Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci USA 2005;102:16368–16373.
  86. Diehl F, et al: Analysis of mutations in DNA isolated from plasma and stool of colorectal cancer patients. Gastroenterology 2008;135:489–498.
  87. Grutzmann R, et al: Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay. PLoS One 2008;3:e3759.
  88. Lee BB, et al: Aberrant methylation of APC, MGMT, RASSF2A, and Wif-1 genes in plasma as a biomarker for early detection of colorectal cancer. Clin Cancer Res 2009;15:6185–6191.
  89. deVos T, et al: Circulating methylated SEPT9 DNA in plasma is a biomarker for colorectal cancer. Clin Chem 2009;55:1337–1346.
  90. Lofton-Day C, et al: DNA methylation biomarkers for blood-based colorectal cancer screening. Clin Chem 2008;54:414–423.
  91. Tanzer M, et al: Performance of epigenetic markers SEPT9 and ALX4 in plasma for detection of colorectal precancerous lesions. PLoS One 2010;5:e9061.
  92. Warren JD, et al: Septin 9 methylated DNA is a sensitive and specific blood test for colorectal cancer. BMC Med 2011;9:133.
  93. Church TR, et al: Prospective clinical validation of an assay for methylated SEPT9 DNA in human plasma as a colorectal cancer screening tool in average risk men and women ≥50 years. Gastroenterology 2010;139:e18.
  94. Ladabaum U, et al: Screening for colorectal cancer with a blood test: projected effectiveness and cost-effectiveness of a novel plasma methylated Septin-9 DNA (mSEPT9) assay. Digestive Disease Week, Chicago, 2011.
  95. Huang Z, et al: Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int J Cancer 2010;127:118–126.
  96. Khair G, Monson JR, Greenman J: Epithelial molecular markers in the peripheral blood of patients with colorectal cancer. Dis Colon Rectum 2007;50:1188–1203.
  97. Dong SM, et al: Detecting colorectal cancer in stool with the use of multiple genetic targets. J Natl Cancer Inst 2001;93:858–865.
  98. Schiedeck TH, et al: Diagnosis and monitoring of colorectal cancer by L6 blood serum polymerase chain reaction is superior to carcinoembryonic antigen-enzyme-linked immunosorbent assay. Dis Colon Rectum 2003;46:818–825.
  99. Lledo SM, et al: Real time quantification in plasma of human telomerase reverse transcriptase (hTERT) mRNA in patients with colorectal cancer. Colorectal Dis 2004;6:236–242.
  100. Thomson DM, et al: The radioimmunoassay of circulating carcinoembryonic antigen of the human digestive system. Proc Natl Acad Sci USA 1969;64:161–167.
  101. Habermann JK, et al: Increased serum levels of complement C3a anaphylatoxin indicate the presence of colorectal tumors. Gastroenterology 2006;131:1020–1029, quiz 1284.
  102. Hurst NG, et al: Elevated serum matrix metalloproteinase 9 (MMP-9) concentration predicts the presence of colorectal neoplasia in symptomatic patients. Br J Cancer 2007;97:971–977.
  103. Karl J, et al: Improved diagnosis of colorectal cancer using a combination of fecal occult blood and novel fecal protein markers. Clin Gastroenterol Hepatol 2008;6:1122–1128.
  104. Kim HJ, et al: Identification of S100A8 and S100A9 as serological markers for colorectal cancer. J Proteome Res 2009;8:1368–1379.
  105. Leman ES, et al: Initial analyses of colon cancer-specific antigen (CCSA)-3 and CCSA-4 as colorectal cancer-associated serum markers. Cancer Res 2007;67:5600–5605.
  106. Liu XP, et al: A serum proteomic pattern for the detection of colorectal adenocarcinoma using surface enhanced laser desorption and ionization mass spectrometry. Cancer Invest 2006;24:747–753.
  107. Zou H, et al: High detection rates of colorectal neoplasia by stool DNA testing with a novel digital melt curve assay. Gastroenterology 2009;136:459–470.
  108. Dressman D, et al: Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations. Proc Natl Acad Sci USA 2003;100:8817–8822.
  109. Ahlquist DA, et al: The stool DNA test is more accurate than the plasma septin 9 test in detecting colorectal neoplasia. Clin Gastroenterol Hepatol 2012;10:272–277.e1.
  110. Ransohoff DF: Bias as a threat to the validity of cancer molecular-marker research. Nat Rev Cancer 2005;5:142–149.
  111. Ransohoff DF, Gourlay ML: Sources of bias in specimens for research about molecular markers for cancer. J Clin Oncol 2009;28:698–704.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50