Aberrant Crypt Foci in Colon Cancer Epidemiology

  • Sharad Khare
  • Kamran Chaudhary
  • Marc Bissonnette
  • Robert Carroll
Part of the Methods in Molecular Biology book series (MIMB, volume 472)


Colonic carcinogenesis is characterized by progressive accumulations of genetic and epigenetic derangements. These molecular events are accompanied by histological changes that progress from mild cryptal architectural abnormalities in small adenomas to eventual invasive cancers. The transition steps from normal colonic epithelium to small adenomas are little understood. In experimental models of colonic carcinogenesis aberrant crypt foci (ACF), collections of abnormal appearing colonic crypts, are the earliest detectable abnormality and precede adenomas. Whether in fact ACF are precursors of colon cancer, however, remains controversial. Recent advances in magnification chromoendoscopy now allow these lesions to be identified in vivo and their natural history ascertained.

While increasing lines of evidence suggest that dysplastic ACF harbor a malignant potential, there are few prospective studies to confirm causal relationships and supporting epidemiological studies are scarce. It would be very useful, for example, to clarify the relationship of ACF incidence to established risks for colon cancer, including age, smoking, sedentary lifestyle, and Western diets. In experimental animal models, carcinogens dose-dependently increase ACF, whereas most chemopreventive agents reduce ACF incidence or growth. In humans, however, few agents have been validated to be chemopreventive of colon cancer. It remains unproven, therefore, whether human ACF could be used as reliable surrogate markers of efficacy of chemopreventive agents. If these lesions could be used as reliable biomarkers of colon cancer risk and their reductions as predictors of effective chemopreventive agents, metrics to quantify ACF could greatly facilitate the study of colonic carcinogenesis and chemoprevention.

Key words:

Aberrant crypt foci colon cancer 


  1. 1.
    Jemal, A., Murray, T., Samuels, A., Gha-foor, A., Ward, E., and Thun, M. J. (2003) Cancer statistics 2003. CA Cancer J Clin. 53, 5–26.CrossRefPubMedGoogle Scholar
  2. 2.
    Fernandez, E., Gallus, S., La Vecchia, C., Talamini, R., Negri, E., and Franceschi, S. (2004) Family history and environmental risk factors for colon cancer. Cancer Epidemiol Biomarkers Prev. 13, 658–661.PubMedGoogle Scholar
  3. 3.
    Lieberman, D. A., Prindiville, S., Weiss, D. G., and Willett, W. (2003) Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals. JAMA 290, 2959–2967.CrossRefPubMedGoogle Scholar
  4. 4.
    Emmons, K. M., McBride, C. M., Puleo, E., Pollak, K. I., Clipp, E., Kuntz, K., Marcus, B. H., Napolitano, M., Onken, J., Far-raye, F., and Fletcher, R. (2005) Project PREVENT: a randomized trial to reduce multiple behavioral risk factors for colon cancer. Cancer Epidemiol Biomarkers Prev. 14, 1453–1459.CrossRefPubMedGoogle Scholar
  5. 5.
    Schatzkin, A. (2000) Intermediate markers as surrogate endpoints in cancer research. Hematol Oncol Clin North Am. 14, 887–905.CrossRefPubMedGoogle Scholar
  6. 6.
    Winawer, S. J., Zauber, A. G., Ho, M. N., O'Brien, M. J., Gottlieb, L. S., Sternberg, S. S., Waye, J. D., Schapiro, M., Bond, J. H., Panish, J. F., and et al. (1993) Prevention of colorectal cancer by colonoscopic polypec-tomy. The National Polyp Study Workgroup. N Engl J Med. 329, 1977–1981.CrossRefPubMedGoogle Scholar
  7. 7.
    Kinzler, K. W. and Vogelstein, B. (1996) Lessons from hereditary colorectal cancer. Cell 87, 159–170.CrossRefPubMedGoogle Scholar
  8. 8.
    Winawer, S. J. (2005) Screening of color-ectal cancer. Surg Oncol Clin N Am. 14, 699–722.CrossRefPubMedGoogle Scholar
  9. 9.
    Hurlstone, D. P., Fujii, T., and Lobo, A. J. (2002) Early detection of colorectal cancer using high-magnification chromoscopic colonoscopy. Br J Surg. 89, 272–282.CrossRefPubMedGoogle Scholar
  10. 10.
    Hurlstone, D. P., Karajeh, M., Sanders, D. S., Drew, S. K., and Cross, S. S. (2005) Rectal aberrant crypt foci identified using high-magnification-chromoscopic colonoscopy: biomarkers for flat and depressed neoplasia. Am J Gastroenterol. 100, 1283–1289.CrossRefPubMedGoogle Scholar
  11. 11.
    Ross, A. S. and Waxman, I. (2006) Flat and depressed neoplasms of the colon in Western populations. Am J Gastroenterol. 101, 172–180.CrossRefPubMedGoogle Scholar
  12. 12.
    Srivastava, S., Verma, M., and Henson, D. E. (2001) Biomarkers for early detection of colon cancer. Clin Cancer Res. 7, 1118–1126.PubMedGoogle Scholar
  13. 13.
    Takayama, T., Katsuki, S., Takahashi, Y., Ohi, M., Nojiri, S., Sakamaki, S., Kato, J., Kogawa, K., Miyake, H., and Niitsu, Y. (1998) Aberrant crypt foci of the colon as precursors of adenoma and cancer. N Engl J Med. 339, 1277–1284.CrossRefPubMedGoogle Scholar
  14. 14.
    Takayama, T., Ohi, M., Hayashi, T., Miya-nishi, K., Nobuoka, A., Nakajima, T., Satoh, T., Takimoto, R., Kato, J., Sakamaki, S., and Niitsu, Y. (2001) Analysis of K-ras, APC, and beta-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial ade-nomatous polyposis. Gastroenterology 121, 599–611.CrossRefPubMedGoogle Scholar
  15. 15.
    Bird, R. P. (1987) Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett. 37, 147–151.CrossRefPubMedGoogle Scholar
  16. 16.
    McLellan, E. A. and Bird, R. P. (1988) Aberrant crypts: potential preneoplas-tic lesions in the murine colon. Cancer Research 48, 6187–6192.PubMedGoogle Scholar
  17. 17.
    Corpet, D. E. and Tache, S. (2002) Most effective colon cancer chemopreventive agents in rats: a systematic review of aberrant crypt foci and tumor data, ranked by potency. Nutr Cancer 43, 1–21.CrossRefPubMedGoogle Scholar
  18. 18.
    Roncucci, L., Modica, S., Pedroni, M., Tamassia, M. G., Ghidoni, M., Losi, L., Fante, R., Di Gregorio, C., Manenti, A., Gafa, L., and Ponz de Leon, M. (1998) Aberrant crypt foci in patients with colorectal cancer. Br J Cancer 77, 2343–2348.PubMedGoogle Scholar
  19. 19.
    Yokota, T., Sugano, K., Kondo, H., Saito, D., Sugihara, K., Fukayama, N., Ohkura, H., Ochiai, A., and Yoshida, S. (1997) Detection of aberrant crypt foci by magnifying colonoscopy. Gastrointest Endosc. 46, 61–65.CrossRefPubMedGoogle Scholar
  20. 20.
    Hurlstone, D. P. and Cross, S. S. (2005) Role of aberrant crypt foci detected using high-magnification-chromoscopic colonos-copy in human colorectal carcinogenesis. J Gastroenterol Hepatol. 20, 173–181.CrossRefPubMedGoogle Scholar
  21. 21.
    Seike, K., Koda, K., Oda, K., Kosugi, C., Shimizu, K., Nishimura, M., Shioiri, M., Takano, S., Ishikura, H., and Miyazaki, M. (2006) Assessment of rectal aberrant crypt foci by standard chromoscopy and its predictive value for colonic advanced neoplasms. Am J Gastroenterol. 101, 1362–1369.CrossRefPubMedGoogle Scholar
  22. 22.
    Roncucci, L., Stamp, D., Medline, A., Cul-len, J. B., and Bruce, W. R. (1991) Identification and quantification of aberrant crypt foci and microadenomas in the human colon. Hum Pathol. 22, 287–294.CrossRefPubMedGoogle Scholar
  23. 23.
    Rao, A. V., Janezic, S. A., Friday, D., and Kendall, C. W. (1992) Dietary cholesterol enhances the induction and development of colonic preneoplastic lesions in C57BL/6J and BALB/cJ mice treated with azoxymeth-ane. Cancer Lett. 63, 249–257.CrossRefPubMedGoogle Scholar
  24. 24.
    Kendall, C. W., Koo, M., Sokoloff, E., and Rao, A. V. (1992) Effect of dietary oxidized cholesterol on azoxymethane-induced colonic preneoplasia in mice. Cancer Lett. 66, 241–248.CrossRefPubMedGoogle Scholar
  25. 25.
    Pretlow, T. P., Barrow, B. J., Ashton, W. S., O'Riordan, M. A., Pretlow, T. G., Jurcisek, J. A., and Stellato, T. A. (1991) Aberrant crypts: putative preneoplastic foci in human colonic mucosa. Cancer Res. 51, 1564–1567.PubMedGoogle Scholar
  26. 26.
    Roncucci, L., Pedroni, M., Fante, R., Di Gregorio, C., and Ponz de Leon, M. (1993) Cell kinetic evaluation of human colonic aberrant crypts. (Colorectal Cancer Study Group of the University of Modena and the Health Care District 16, Modena, Italy). Cancer Res. 53, 3726–3729.PubMedGoogle Scholar
  27. 27.
    Di Gregorio, C., Losi, L., Fante, R., Mod-ica, S., Ghidoni, M., Pedroni, M., Tamassia, M. G., Gafa, L., Ponz de Leon, M., and Roncucci, L. (1997) Histology of aberrant crypt foci in the human colon. Histopathology 30, 328–334.CrossRefPubMedGoogle Scholar
  28. 28.
    Shpitz, B., Bomstein, Y., Mekori, Y., Cohen, R., Kaufman, Z., Neufeld, D., Galkin, M., and Bernheim, J. (1998) Aberrant crypt foci in human colons: distribution and histomorphologic characteristics. Hum Pathol. 29, 469–475.CrossRefPubMedGoogle Scholar
  29. 29.
    Bouzourene, H., Chaubert, P., Seelentag, W., Bosman, F. T., and Saraga, E. (1999) Aberrant crypt foci in patients with neoplastic and nonneoplastic colonic disease. Hum Pathol. 30, 66–71CrossRefPubMedGoogle Scholar
  30. 30.
    Yamada, Y., Yoshimi, N., Hirose, Y., Kawabata, K., Matsunaga, K., Shimizu, M., Hara, A., and Mori, H. (2000) Frequent beta-catenin gene mutations and accumulations of the protein in the putative preneoplastic lesions lacking macroscopic aberrant crypt foci appearance, in rat colon carcinogenesis. Cancer Res. 60, 3323–3327.PubMedGoogle Scholar
  31. 31.
    Yamada, Y., Yoshimi, N., Hirose, Y., Mat-sunaga, K., Katayama, M., Sakata, K., Shimizu, M., Kuno, T., and Mori, H. (2001) Sequential analysis of morphological and biological properties of beta-catenin-accumulated crypts, provable premalignant lesions independent of aberrant crypt foci in rat colon carcinogenesis. Cancer Res. 61, 1874–1878.PubMedGoogle Scholar
  32. 32.
    Paulsen, J. E., Loberg, E. M., Olstorn, H. B., Knutsen, H., Steffensen, I. L., and Alexander, J. (2005) Flat dysplastic aberrant crypt foci are related to tumorigenesis in the colon of azoxymethane-treated rat. Cancer Res. 65, 121–129.PubMedGoogle Scholar
  33. 33.
    Caderni, G., Femia, A. P., Giannini, A., Favuzza, A., Luceri, C., Salvadori, M., and Dolara, P. (2003) Identification of mucin-depleted foci in the unsectioned colon of azoxymethane-treated rats: correlation with carcinogenesis. Cancer Res. 63, 2388–2392.PubMedGoogle Scholar
  34. 34.
    Vaccina, F., Scorcioni, F., Pedroni, M., Tamassia, M. G., De Leon, M. P., De Pol, A., Marzona, L., and Roncucci, L. (1998) Scanning electron microscopy of aberrant crypt foci in human colorectal mucosa. Anticancer Res. 18, 3451–3456.PubMedGoogle Scholar
  35. 35.
    Otori, K., Sugiyama, K., Hasebe, T., Fuku-shima, S., and Esumi, H. (1995) Emergence of adenomatous aberrant crypt foci (ACF) from hyperplastic ACF with concomitant increase in cell proliferation. Cancer Research 55, 4743–4746.PubMedGoogle Scholar
  36. 36.
    Ochiai, M., Watanabe, M., Nakanishi, M., Taguchi, A., Sugimura, T., and Nakagama, H. (2005) Differential staining of dysplas-tic aberrant crypt foci in the colon facilitates prediction of carcinogenic potentials of chemicals in rats. Cancer Lett. 220, 67–74.CrossRefPubMedGoogle Scholar
  37. 37.
    Losi, L., Roncucci, L., di Gregorio, C., de Leon, M. P., and Benhattar, J. (1996) K-ras and p53 mutations in human colorectal aberrant crypt foci. J Pathol. 178, 259–263.CrossRefPubMedGoogle Scholar
  38. 38.
    Otori, K., Konishi, M., Sugiyama, K., Hasebe, T., Shimoda, T., Kikuchi-Yanos-hita, R., Mukai, K., Fukushima, S., Miyaki, M., and Esumi, H. (1998) Infrequent somatic mutation of the adenomatous polyposis coli gene in aberrant crypt foci of human colon tissue. Cancer 83, 896–900.CrossRefPubMedGoogle Scholar
  39. 39.
    Greenspan, E. J., Cyr, J. L., Pleau, D. C., Levine, J., Rajan, T. V., Rosenberg, D. W., and Heinen, C. D. (2007) Microsat-ellite instability in aberrant crypt foci from patients without concurrent colon cancer. Carcinogenesis 28, 769–776.CrossRefPubMedGoogle Scholar
  40. 40.
    Cheng, L. and Lai, M. D. (2003) Aberrant crypt foci as microscopic precursors of colorectal cancer. World J Gastroenterol. 9, 2642–2649.PubMedGoogle Scholar
  41. 41.
    Pretlow, T. P. and Pretlow, T. G. (2005) Mutant KRAS in aberrant crypt foci (ACF): initiation of colorectal cancer? Biochim Bio-phys Acta 1756, 83–96.Google Scholar
  42. 42.
    Alrawi, S. J., Schiff, M., Carroll, R. E., Dayton, M., Gibbs, J. F., Kulavlat, M., Tan, D., Berman, K., Stoler, D. L., and Anderson, G. R. (2006) Aberrant crypt foci. Antican-cer Res. 26, 107–119.Google Scholar
  43. 43.
    Gupta, A. K., Pretlow, T. P., and Schoen, R. E. (2007) Aberrant crypt foci: what we know and what we need to know. Clin Gas-troenterol Hepatol. 5, 526–533.CrossRefGoogle Scholar
  44. 44.
    Luo, L., Shen, G. Q., Stiffler, K. A., Wang, Q. K., Pretlow, T. G., and Pretlow, T. P. (2006) Loss of heterozygosity in human aberrant crypt foci (ACF), a putative precursor of colon cancer. Carcinogenesis 27, 1153–1159.CrossRefPubMedGoogle Scholar
  45. 45.
    Augenlicht, L. H., Richards, C., Corner, G., and Pretlow, T. P. (1996) Evidence for genomic instability in human colonic aberrant crypt foci. Oncogene 12, 1767–1772PubMedGoogle Scholar
  46. 46.
    Heinen, C. D., Shivapurkar, N., Tang, Z., Groden, J., and Alabaster, O. (1996) Microsatellite instability in aberrant crypt foci from human colons. Cancer Res. 56, 5339–5341.PubMedGoogle Scholar
  47. 47.
    Gryfe, R., Kim, H., Hsieh, E. T., Aronson, M. D., Holowaty, E. J., Bull, S. B., Red-ston, M., and Gallinger, S. (2000) Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 342, 69–77.CrossRefPubMedGoogle Scholar
  48. 48.
    Polakis, P. (1999) The oncogenic activation of beta-catenin. Curr Opin Genet Dev. 9, 15–21.CrossRefPubMedGoogle Scholar
  49. 49.
    Giles, R. H., van Es, J. H., and Clevers, H. (2003) Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 1653, 1–24.PubMedGoogle Scholar
  50. 50.
    Powell, S. M., Zilz, N., Beazer-Barclay, Y., Bryan, T. M., Hamilton, S. R., Thibodeau, S. N., Vogelstein, B., and Kinzler, K. W. (1992) APC mutations occur early during colorectal tumorigenesis. Nature 359, 235–237.CrossRefPubMedGoogle Scholar
  51. 51.
    Iwamoto, M., Ahnen, D. J., Franklin, W. A., and Maltzman, T. H. (2000) Expression of beta-catenin and full-length APC protein in normal and neoplastic colonic tissues. Carcinogenesis 21, 1935–1940.CrossRefPubMedGoogle Scholar
  52. 52.
    Jen, J., Powell, S. M., Papadopoulos, N., Smith, K. J., Hamilton, S. R., Vogelstein, B., and Kinzler, K. W. (1994) Molecular determinants of dysplasia in colorectal lesions. :Cancer Res. 54, 5523–5526.PubMedGoogle Scholar
  53. 53.
    Smith, A. J., Stern, H. S., Penner, M., Hay, K., Mitri, A., Bapat, B. V., and Gallinger, S. (1994) Somatic APC and K-ras codon 12 mutations in aberrant crypt foci from human colons. Cancer Res. 54, 5527–5530.PubMedGoogle Scholar
  54. 54.
    Shivapurkar, N., Tang, Z., Ferreira, A., Nasim, S., Garett, C., and Alabaster, O. (1994) Sequential analysis of K-ras mutations in aberrant crypt foci and colonic tumors induced by azoxymethane in Fischer-344 rats on high-risk diet. Carcino-genesis 15, 775–778.CrossRefGoogle Scholar
  55. 55.
    Cohen, G., Mustafi, R., Chumsangsri, A., Little, N., Nathanson, J., Cerda, S., Jaga-deeswaran, S., Dougherty, U., Joseph, L., Hart, J., Yerian, L., Tretiakova, M., Yuan, W., Obara, P., Khare, S., Sinicrope, F. A., Fichera, A., Boss, G. R., Carroll, R., and Bissonnette, M. (2006) Epidermal growth factor receptor signaling is up-regulated in human colonic aberrant crypt foci. Cancer Res. 66, 5656–5664.CrossRefPubMedGoogle Scholar
  56. 56.
    Fichera, A., Little, N., Jagadeeswaran, S., Dougherty, U., Sehdev, A., Mustafi, R., Cerda, S., Yuan, W., Khare, S., Tretiakova, M., Gong, C., Tallerico, M., Cohen, G., Joseph, L., Hart, J., Turner, J. R., and Bis-sonnette, M. (2007) Epidermal growth factor receptor signaling is required for microadenoma formation in the mouse azoxymethane model of colonic carcino-genesis. Cancer Res. 67, 827–835.CrossRefPubMedGoogle Scholar
  57. 57.
    Adler, D. G., Gostout, C. J., Sorbi, D., Bur-gart, L. J., Wang, L., and Harmsen, W. S. (2002) Endoscopic identification and quantification of aberrant crypt foci in the human colon. Gastrointest Endosc. 56, 657–662.CrossRefPubMedGoogle Scholar
  58. 58.
    Yamashita, N., Minamoto, T., Ochiai, A., Onda, M., and Esumi, H. (1995) Frequent and characteristic K-ras activation in aberrant crypt foci of colon. Is there preference among K-ras mutants for malignant progression? Cancer 75, 1527–1533.CrossRefPubMedGoogle Scholar
  59. 59.
    Siu, I. M., Pretlow, T. G., Amini, S. B., and Pretlow, T. P. (1997) Identification of dys-plasia in human colonic aberrant crypt foci. Am J Pathol. 150, 1805–1813.PubMedGoogle Scholar
  60. 60.
    Siu, I. M., Robinson, D. R., Schwartz, S., Kung, H. J., Pretlow, T. G., Petersen, R. B., and Pretlow, T. P. (1999) The identification of monoclonality in human aberrant crypt foci. Cancer Res. 59, 63–66.PubMedGoogle Scholar
  61. 61.
    Gold, P., Shuster, J., and Freedman, S. O. (1978) Carcinoembryonic antigen (CEA) in clinical medicine: historical perspectives, pitfalls and projections. Cancer 42, 1399–1405.CrossRefPubMedGoogle Scholar
  62. 62.
    Pretlow, T. P., Roukhadze, E. V., O'Riordan, M. A., Chan, J. C., Amini, S. B., and Stel-lato, T. A. (1994) Carcinoembryonic antigen in human colonic aberrant crypt foci. Gastroenterology 107, 1719–1725.PubMedGoogle Scholar
  63. 63.
    Miyoshi, Y., Ando, H., Nagase, H., Nishisho, I., Horii, A., Miki, Y., Mori, T., Utsunomiya, J., Baba, S., Petersen, G., and et al. (1992) Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci USA 89, 4452–4456.CrossRefPubMedGoogle Scholar
  64. 64.
    Qi, J., Zhu, Y. Q., Luo, J., and Tao, W. H. (2006) Hypermethylation and expression regulation of secreted frizzled-related protein genes in colorectal tumor. World J Gastroenterol. 12, 7113–7117.PubMedGoogle Scholar
  65. 65.
    Samowitz, W. S., Powers, M. D., Spirio, L. N., Nollet, F., van Roy, F., and Slattery, M. L. (1999) b-catenin mutations are more frequent in small colorectal adenomas than in larger adenomas and invasive carcinomas. Cancer Res. 59, 1442–1444.PubMedGoogle Scholar
  66. 66.
    Howe, L. R., Subbaramaiah, K., Chung, W. J., Dannenberg, A. J., and Brown, A. M. (1999) Transcriptional activation of cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial cells. Cancer Res. 59, 1572–1577.PubMedGoogle Scholar
  67. 67.
    Bissonnette, M., Khare, S., von Lintig, F. C., Wali, R. K., Nguyen, L., Zhang, Y., Hart, J., Skarosi, S., Varki, N., Boss, G. R., and Brasitus, T. A. (2000) Mutational and nonmutational activation of p21ras in rat colonic azoxymethane-induced tumors: effects on mitogen-activated protein kinase, cyclooxygenase-2, and cyclin D1. Cancer Res. 60, 4602–4609.PubMedGoogle Scholar
  68. 68.
    Eisinger, A. L., Nadauld, L. D., Shelton, D. N., Peterson, P. W., Phelps, R. A., Chidester, S., Stafforini, D. M., Prescott, S. M., and Jones, D. A. (2006) The adenoma-tous polyposis coli tumor suppressor gene regulates expression of cyclooxygenase-2 by a mechanism that involves retinoic acid. J Biol Chem. 281, 20474–20482.CrossRefPubMedGoogle Scholar
  69. 69.
    Bjerknes, M., Cheng, H., Hay, K., and Gallinger, S. (1997) APC mutation and the crypt cycle in murine and human intestine. Am J Pathol. 150, 833–839.PubMedGoogle Scholar
  70. 70.
    Otori, K., Oda, Y., Sugiyama, K., Hasebe, T., Mukai, K., Fujii, T., Tajiri, H., Yoshida, S., Fukushima, S., and Esumi, H. (1997) High frequency of K-ras mutations in human colorectal hyperplastic polyps. Gut 40, 660–663.PubMedGoogle Scholar
  71. 71.
    Hill, M. J., Morson, B. C., and Bussey, H. J. (1978) Aetiology of adenoma—carcinoma sequence in large bowel. Lancet 1, 245–247.CrossRefPubMedGoogle Scholar
  72. 72.
    Day, D. W. and Morson, B. C. (1978) The adenoma-carcinoma sequence. Major Probl Pathol. 10, 58–71.PubMedGoogle Scholar
  73. 73.
    Granqvist, S. (1981) Distribution of polyps in the large bowel in relation to age. A colonoscopic study. Scand J Gastroenterol. 16, 1025–1031.CrossRefPubMedGoogle Scholar
  74. 74.
    Devesa, S. S. and Chow, W. H. (1993) Variation in colorectal cancer incidence in the United States by subsite of origin. Cancer 71, 3819–3826.CrossRefPubMedGoogle Scholar
  75. 75.
    Konstantakos, A. K., Siu, I. M., Pretlow, T. G., Stellato, T. A., and Pretlow, T. P. (1996) Human aberrant crypt foci with carcinoma in situ from a patient with sporadic colon cancer. Gastroenterology 111, 772–777.CrossRefPubMedGoogle Scholar
  76. 76.
    Boland, C. R., Sinicrope, F. A., Brenner, D. E., and Carethers, J. M. (2000) Colorectal cancer prevention and treatment. Gastroen-terology 118, 115–128.CrossRefGoogle Scholar
  77. 77.
    Stevens, R. G., Swede, H., Heinen, C. D., Jablonski, M., Grupka, M., Ross, B., Parente, M., Tirnauer, J. S., Giardina, C., Rajan, T. V., Rosenberg, D. W., and Levine, J. (2007) Aberrant crypt foci in patients with a positive family history of sporadic colorectal cancer. Cancer Lett. 248, 262–268.CrossRefPubMedGoogle Scholar
  78. 78.
    Rudolph, R. E., Dominitz, J. A., Lampe, J. W., Levy, L., Qu, P., Li, S. S., Lampe, P. D., Bronner, M. P., and Potter, J. D. (2005) Risk factors for colorectal cancer in relation to number and size of aberrant crypt foci in humans. Cancer Epidemiol Biomarkers Prev. 14, 605–608.CrossRefPubMedGoogle Scholar
  79. 79.
    Armitage, P. and Doll, R. (1954) The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer 8, 1–12.PubMedGoogle Scholar
  80. 80.
    Papanikolaou, A., Wang, Q. S., Papanikolaou, D., Whiteley, H. E., and Rosenberg, D. W. (2000) Sequential and morphological analyses of aberrant crypt foci formation in mice of differing susceptibility to azoxymethane-induced colon carcinogenesis. Carcinogenesis 21, 1567–1572.CrossRefPubMedGoogle Scholar
  81. 81.
    Nambiar, P. R., Nakanishi, M., Gupta, R., Cheung, E., Firouzi, A., Ma, X. J., Flynn, C., Dong, M., Guda, K., Levine, J., Raja, R., Achenie, L., and Rosenberg, D. W. (2004) Genetic signatures of high-and low-risk aberrant crypt foci in a mouse model of sporadic colon cancer. Cancer Res. 64, 6394–6401.CrossRefPubMedGoogle Scholar
  82. 82.
    Shpitz, B., Klein, E., Buklan, G., Neufeld, D., Nissan, A., Freund, H. R., Grankin, M., and Bernheim, J. (2003) Suppressive effect of aspirin on aberrant crypt foci in patients with colorectal cancer. Gut 52, 1598–1601.CrossRefPubMedGoogle Scholar
  83. 83.
    Moxon, D., Raza, M., Kenney, R., Ewing, R., Arozullah, A., Mason, J. B., and Carroll, R. E. (2005) Relationship of aging and tobacco use with the development of aberrant crypt foci in a predominantly African-American population. Clin Gastroenterol Hepatol. 3, 271–278.CrossRefPubMedGoogle Scholar
  84. 84.
    Slaughter, D. P., Southwick, H. W., and Smejkal, W. (1953) Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6, 963–968.CrossRefPubMedGoogle Scholar
  85. 85.
    Benner, S. E., Hong, W. K., Lippman, S. M., Lee, J. S., and Hittelman, W. M. (1992) Intermediate biomarkers in upper aerod-igestive tract and lung chemoprevention trials. J Cell Biochem Suppl. 16G, 33–38.CrossRefPubMedGoogle Scholar
  86. 86.
    Wattenberg, L. W. (1985) Chemopreven-tion of cancer. Cancer Res. 45, 1–8.CrossRefPubMedGoogle Scholar
  87. 87.
    Sandler, R. S., Halabi, S., Baron, J. A., Budinger, S., Paskett, E., Keresztes, R., Petrelli, N., Pipas, J. M., Karp, D. D., Loprinzi, C. L., Steinbach, G., and Schilsky, R. (2003) A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med. 348, 883–890.CrossRefPubMedGoogle Scholar
  88. 88.
    Baron, J. A., Cole, B. F., Sandler, R. S., Haile, R. W., Ahnen, D., Bresalier, R., McKeown-Eyssen, G., Summers, R. W., Rothstein, R., Burke, C. A., Snover, D. C., Church, T. R., Allen, J. I., Beach, M., Beck, G. J., Bond, J. H., Byers, T., Greenberg, E. R., Mandel, J. S., Marcon, N., Mott, L. A., Pearson, L., Saibil, F., and van Stolk, R. U. (2003) A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 348, 891–899.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Sharad Khare
    • 1
  • Kamran Chaudhary
    • 2
  • Marc Bissonnette
    • 3
  • Robert Carroll
    • 2
  1. 1.Department of MedicineLoyola UniversityMaywoodUSA
  2. 2.Department of MedicineUniversity of IllinoisChicagoUSA
  3. 3.Department of MedicineUniversity of ChicagoChicagoUSA

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