Tumor Biology

, Volume 35, Issue 7, pp 6195–6206 | Cite as

Focus on genetic and epigenetic events of colorectal cancer pathogenesis: implications for molecular diagnosis

  • Federica Zoratto
  • Luigi Rossi
  • Monica Verrico
  • Anselmo Papa
  • Enrico Basso
  • Angelo Zullo
  • Luigi Tomao
  • Adriana Romiti
  • Giuseppe Lo Russo
  • Silverio Tomao


Originally, colorectal cancer (CRC) tumorigenesis was understood as a multistep process that involved accumulation of tumor suppressor genes and oncogenes mutations, such as APC, TP53 and KRAS. However, this assumption proposed a relatively limited repertoire of genetic alterations. In the last decade, there have been major advances in knowledge of multiple molecular pathways involved in CRC pathogenesis, particularly regarding cytogenetic and epigenetic events. Microsatellite instability, chromosomal instability and CpG island methylator phenotype are the most analyzed cytogenetic changes, while DNA methylation, modifications in histone proteins and microRNAs (miRNAs) were analyzed in the field of epigenetic alterations. Therefore, CRC development results from interactions at many levels between genetic and epigenetic amendments. Furthermore, hereditary cancer syndrome and individual or environmental risk factors should not be ignored. The difficulties in this setting are addressed to understand the molecular basis of individual susceptibility to CRC and to determine the roles of genetic and epigenetic alterations, in order to yield more effective prevention strategies in CRC patients and directing their treatment. This review summarizes the most investigated biomolecular pathways involved in CRC pathogenesis, their role as biomarkers for early CRC diagnosis and their possible use to stratify susceptible patients into appropriate screening or surveillance programs.


Colorectal cancer pathogenesis Genetic events Epigenetic events Biomolecular markers 


Conflicts of interest



  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics 2012. CA Cancer J Clin. 2012;62(1):10–29.PubMedGoogle Scholar
  2. 2.
    Sengupta N, Gill KA, MacFie TS, Lai CS, Suraweera N, McDonald S, et al. Management of colorectal cancer: a role for genetics in prevention and treatment? Pathol Res Pract. 2008;204(7):469–77.PubMedGoogle Scholar
  3. 3.
    Migliore L, Migheli F, Spisni R, Coppedè F. Genetics, cytogenetics and epigenetics of colorectal cancer. J Biomed Biotechnol. 2011;2011:792362.PubMedCentralPubMedGoogle Scholar
  4. 4.
    Kinzler KW, Vogelstein B. Cancer susceptibility genes. Gatekeepers and caretakers. Nature. 1997;386(6627):761–3.PubMedGoogle Scholar
  5. 5.
    Karen E. Kim; Early detection and prevention of colorectal cancer. Slack Incorporated 2009.Google Scholar
  6. 6.
    Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. Oncologist. 2010;15(7):699–731.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Kahng LS. Genetic aspects of non-polypoid colorectal neoplasms. Gastrointest Endosc Clin N Am. 2010;20(3):573–8.PubMedGoogle Scholar
  8. 8.
    Pancione M, Remo A, Colantuoni V. Genetic and epigenetic events generate multiple pathways in colorectal cancer progression. Pathol Res Int. 2012;2012:509348.Google Scholar
  9. 9.
    Worthley DL, Leggett BA. Colorectal cancer: molecular features and clinical opportunities. Clin Biochem Rev. 2010;31(2):31–8.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Costedio M, Church J. Pathways of carcinogenesis are reflected in patterns of polyp pathology in patients screened for colorectal cancer. Dis Colon Rectum. 2011;54(10):1224–8.PubMedGoogle Scholar
  11. 11.
    Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011;6:479–507.PubMedGoogle Scholar
  12. 12.
    Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–67.PubMedGoogle Scholar
  13. 13.
    Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010;138(6):2059–72.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Huang D, Du X. Crosstalk between tumor cells and microenvironment via Wnt pathway in colorectal cancer dissemination. World J Gastroenterol. 2008;14(12):1823–7.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Booth RA. Minimally invasive biomarkers for detection and staging of colorectal cancer. Cancer Lett. 2007;249(1):87–96.PubMedGoogle Scholar
  16. 16.
    De Roock W, Biesmans B, De Schutter J, Tejpar S. Clinical biomarkers in oncology: focus on colorectal cancer. Mol Diag Ther. 2009;13(2):103–14.Google Scholar
  17. 17.
    Lievre A, Blons H, Laurent-Puig P. Oncogenic mutations as predictive factors in colorectal cancer. Oncogene. 2010;29(21):3033–43.PubMedGoogle Scholar
  18. 18.
    Douillard YJ, Oliner KS, Siena S, et al. N Engl J Med. 2013;369(11):1023–34.PubMedGoogle Scholar
  19. 19.
    Vogelstein B, Fearon ER, Hamilta SR, et al. N Engl J Med. 1988;319:525–32.PubMedGoogle Scholar
  20. 20.
    Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. Oncologist. 2010;15(7):699–731.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Jen J, Kim H, Piantadosi S, et al. N Engl J Med. 1994;331:213–21.PubMedGoogle Scholar
  22. 22.
    Kanthan R, Senger AL, Kanthan C. Molecular events in primary and metastatic colorectal carcinoma: a review. Pathol Res Int. 2012;2012:597497.Google Scholar
  23. 23.
    Markowitz SD, Bertagnolli MM. Molecular basis of colorectal cancer. N Engl J Med. 2009;361(25):2404–60.Google Scholar
  24. 24.
    Cahill DP, Lengauer C, Yu J, et al. Nature. 1998;392(6673):300–3.PubMedGoogle Scholar
  25. 25.
    Ogino S, Goel A. Molecular classification and correlates in colorectal cancer. J Mol Diagn. 2008;10(1):13–27.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007;50(1):113–30.PubMedGoogle Scholar
  27. 27.
    Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2009;31(1):27–36.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Esteller M. Molecular origins of cancer: epigenetics in cancer. N Engl J Med. 2008;358(11):1148–096.PubMedGoogle Scholar
  29. 29.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.PubMedGoogle Scholar
  30. 30.
    Grady WM, Carethers JM. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology. 2008;135(4):1079–99.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138(6):2073–87.PubMedCentralPubMedGoogle Scholar
  32. 32.
    Iacopetta B, Grieu F, Amanuel B. Microsatellite instability in colorectal cancer. Asia-Pac J Clin Oncol. 2010;6(4):260–9.PubMedGoogle Scholar
  33. 33.
    De la Chapelle A, Hampel H. Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol. 2010;28(20):3380–7.PubMedCentralPubMedGoogle Scholar
  34. 34.
    De la Chapelle A. Microsatellite instability. N Engl J Med. 2003;349(3):209–2010.PubMedGoogle Scholar
  35. 35.
    Goel A, Nagasaka T, Arnold CN, Inoue T, Hamilton C, Niedzwiecki D, et al. The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology. 2007;132(1):127–38.PubMedGoogle Scholar
  36. 36.
    Yim KL. Microsatellite instability in metastatic colorectal cancer: a review of pathology, response to chemotherapy and clinical outcome. Med Oncol. 2012;29(3):1796–801.PubMedGoogle Scholar
  37. 37.
    Grady WM, Carethers JM. Genomic and epigenetic instability in colorectal cancer. Gastroenterology. 2008;135(4):1079–99.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Yamauchi M, Lochhead P, Morikawa T, Huttenhower C, Chan AT, Giovannucci E, et al. Colorectal cancer: a tale of two sides, or a continuum? Gut. 2012;61(6):794–7.PubMedCentralPubMedGoogle Scholar
  39. 39.
    Garzon R, Calin GA, Croce CM. MicroRNAs in cancer. Annu Rev Med. 2009;60:167–79.PubMedGoogle Scholar
  40. 40.
    Slaby O, Svoboda M, Michalek J, Vyzula R. MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Mol Cancer. 2009;8:102.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Goel A, Boland CR. Recent insights into the pathogenesis of colorectal cancer. Curr Opin Gastroenterol. 2010;26(1):47–52.PubMedCentralPubMedGoogle Scholar
  42. 42.
    de Krijger I, Mekenkamp LJM, Punt CJA, Nagtegaal ID. MicroRNAs in colorectal cancer metastasis. J Pathol. 2011;224:438–47.PubMedGoogle Scholar
  43. 43.
    Yang L, Belaguli N, Berger DH. MicroRNA and colorectal cancer. World J Surg. 2009;33(4):638–46.PubMedGoogle Scholar
  44. 44.
    Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28(10):1057–68.PubMedGoogle Scholar
  45. 45.
    Wong JJL, Hawkins NJ, Ward RL. Colorectal cancer: a model for epigenetic tumorigenesis. Gut. 2007;56(1):140–8.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Venkatachalam R, Ligtenberg MJ, Hoogerbrugge N, de Bruijn DR, Kuiper RP. Geurts van Kessel, A. The epigenetics of (hereditary) colorectal cancer. Cancer Genet Cytogenet. 2010;203(1):1–6.PubMedGoogle Scholar
  47. 47.
    Kim YS, Deng G. Epigenetic changes (aberrant DNA methylation) in colorectal neoplasia. Gut Liver. 2007;1(1):1–11.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Ogino S, Hazra A, Tranah GJ, Kirkner GJ, Kawasaki T, Nosho K, et al. MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer. Carcinogenesis. 2007;28(9):1985–90.PubMedGoogle Scholar
  49. 49.
    Raptis S, Mrkonjic M, Green RC, Pethe VV, Monga N, Chan YM, et al. MLH1-93G > A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer. J Natl Cancer Inst. 2007;99(6):463–74.PubMedGoogle Scholar
  50. 50.
    Samowitz WS, Curtin K, Wolff RK, Albertsen H, Sweeney C, Caan BJ, et al. The MLH1-93 G > A promoter polymorphism and genetic and epigenetic alterations in colon cancer. Genes Chromosome Cancer. 2008;47(10):835–44.Google Scholar
  51. 51.
    Burgess DJ. Gene expression: colorectal cancer classification. Nat Rev Cancer. 2013;13(6):380–1.PubMedGoogle Scholar
  52. 52.
    Sadanandam A, Lyssiotis CA, Homicsko H, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013;19(5):619–25.PubMedCentralPubMedGoogle Scholar
  53. 53.
    De Sosa E, Melo F, Wang X, Jansen M, et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med. 2013;19(5):614–8.Google Scholar
  54. 54.
    Ogino S, Stampfer M. Lifestyle factors and microsatellite instability in colorectal cancer: the evolving field of molecular pathological epidemiology. J Natl Cancer Inst. 2010;102(6):365–7.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Ogino S, Chan AT, Fuchs S, Giovannucci E. Molecular Pathologic epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field. Gut. 2011;60(3):397–411.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Ogino S, Kawasaki T, Kirkner GJ, Loda M, Fuchs CS. CpG island methylator phenotype-low (CIMP-Low) in colorectal cancer: possible associations with male sex and KRAS mutations. J Mol Diagn. 2006;8(5):582–8.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Hinoue T, Weisenberger JD, Lange CPE, Shen H, Byun HM, van den Berg D, et al. Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res. 2012;22(2):271–82.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Shen L, Toyota M, Kondo Y, Lin E, Zhang L, Guo Y, et al. Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci U S A. 2007;104(47):18654–9.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Issa JP. Methylation and prognosis: of molecular clocks and hypermethylator phenotypes. Clin Cancer Res. 2003;9(8):2879–81.PubMedGoogle Scholar
  60. 60.
    Shen L, Catalano PJ, Benson AB, O’Dwyer P, Hamilton SR, Issa JP. Association between DNA methylation and shortened survival in patients with advanced colorectal cancer treated with 5-fluorouracil based chemotherapy. Clin Cancer Res. 2007;13(20):6093–8.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Minoo P, Baker K, Goswami R, Chong G, Foulkes WD, Ruszkiewicz AR, et al. Extensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis. Gut. 2006;55(10):1467–74.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Chirieac LR, Shen L, Catalano PJ, Issa JP, Hamilton SR. Phenotype of microsatellite-stable colorectal carcinomas with CpG island methylation. Am J Surg Pathol. 2005;29:429–36.PubMedGoogle Scholar
  63. 63.
    Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol. 2011;42:1–10.PubMedGoogle Scholar
  64. 64.
    Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010;138:2044–58.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Gonzalez CA, Riboli E. Diet and cancer prevention: contributions from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Eur J Cancer. 2010;46:2555–62.PubMedGoogle Scholar
  66. 66.
    Hiraoka S, Kato J, Fujiki S, Kaji E, Morikami T, Nawa T, et al. The presence of large serrated polyps increases risk for colorectal cancer. Gastroenterology. 2010;139:1503–10.PubMedGoogle Scholar
  67. 67.
    Hoffmeister M, Schmitz S, Karmrodt E, Stegmaier C, Haug U, Arndt V, et al. Male sex and smoking have a larger impact on the prevalence of colorectal neoplasia than family history of colorectal cancer. Clin Gastroenterol Hepatol. 2010;8:870–6.PubMedGoogle Scholar
  68. 68.
    Huang L, Wang X, Gong W, Huang Y, Jiang B. The comparison of the clinical manifestations and risk factors of colorectal cancer and adenomas: results from a colonoscopy-based study in southern Chinese. Int J Color Dis. 2010;25:1343–51.Google Scholar
  69. 69.
    Larsson SC, Wolk A. Meat consumption and risk of colorectal cancer: a meta-analysis of prospective studies. Int J Cancer. 2006;119:2657–64.PubMedGoogle Scholar
  70. 70.
    Bretthauer M. Evidence for colorectal cancer screening. Best Pract Res Clin Gastroenterol. 2010;24:417–25.PubMedGoogle Scholar
  71. 71.
    Schernhammer ES, Giovannucci E, Kawasaki T, Rosner R, Fuchs CS, Ogino S. Dietary folate, alcohol, and B vitamins in relation to line-1 hypomethylation in colon cancer. Gut. 2010;59:794–9.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Dahm CC, Keogh RH, Spencer EA, Greenwood DC, Key TJ, Fentiman IS, et al. Dietary fiber and colorectal cancer risk: a nested case-control study using food diaries. J Natl Cancer Inst. 2010;102:614–26.PubMedGoogle Scholar
  73. 73.
    Hildebrand JS, Jacobs EJ, Campbell PT, McCullough ML, Teras LR, Thun MJ, et al. Colorectal cancer incidence and postmenopausal hormone use by type, recency, and duration in cancer prevention study II. Cancer Epidemiol Biomarkers Prev. 2009;18:2835–41.PubMedGoogle Scholar
  74. 74.
    Kim DH, Smith-Warner SA, Spiegelman D, Yaun SS, Colditz GA, Freudenheim JL, et al. Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer. Cancer Causes Control. 2010;21:1919–30.PubMedCentralPubMedGoogle Scholar
  75. 75.
    Burt RW, Leppert MF, Slattery ML, Samowitz WS, Spirio LN, Kerber RA, et al. Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology. 2004;127:44–51.Google Scholar
  76. 76.
    Slattery ML, Curtin K, Sweeney C, Levin TR, Potter J, Wolff RK, et al. Diet and lifestyle factor associations with CpG island methylator phenotype and BRAF mutations in colon cancer. Int J Cancer. 2007;120(3):656–63.PubMedGoogle Scholar
  77. 77.
    Satia JA, Keku T, Galanko JA, Martin C, Doctolero RT, Tajima A, et al. Diet, lifestyle, and genomic instability in the North Carolina Colon Cancer Study. Cancer Epidemiol Biomarkers Prev. 2005;14:429–36.PubMedGoogle Scholar
  78. 78.
    Campbell PT, Jacobs ET, Ulrich CM, Figueiredo JC, Poynter JN, McLaughlin JR, et al. Case-control study of overweight, obesity, and colorectal cancer risk, overall and by tumor microsatellite instability status. J Natl Cancer Inst. 2010;17:391–400.Google Scholar
  79. 79.
    Kuchiba A, Morikawa T, Yamauchi M, Imamura Y, Liao X, Chan AT, et al. Body mass index and risk of colorectal cancer according to fatty acid synthase expression in the nurses’ health study. J Natl Cancer Inst. 2012;104:415–20.PubMedCentralPubMedGoogle Scholar
  80. 80.
    Morikawa T, Kuchiba A, Lochhead P, Nishihara R, Yamauchi M, Imamura Y, et al. Prospective analysis of body mass index, physical activity, and colorectal cancer risk associated with b-catenin (CTNNB1) status. Cancer Res. 2013;73(5):1600–10.PubMedCentralPubMedGoogle Scholar
  81. 81.
    Samowitz WS, Albertsen H, Sweeney C, Herrick J, Caan BJ, Anderson KE, et al. Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. J Natl Cancer Inst. 2006;98(23):1731–8.PubMedGoogle Scholar
  82. 82.
    Limsui D, Vierkant RA, Tillmans LS, Wang AH, Weisenberger DJ, Laird PW, et al. Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. J Natl Cancer Inst. 2010;21(102):1012–22.Google Scholar
  83. 83.
    Nishihara R, Morikawa T, Kuchiba A, Lochhead P, Yamauchi M, Liao X, et al. A prospective study of duration of smoking cessation and colorectal cancer risk by epigenetics-related tumor classification. Am J Epidemiol. 2013;1(178):84–100.Google Scholar
  84. 84.
    Nishihara R, Lochhead P, Kuchiba A, Jung S, Yamauchi M, Liao X, et al. Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA. 2013;309(24):2563–71.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med. 2007;356(21):2131–42.PubMedGoogle Scholar
  86. 86.
    Rizzo A, Pallone F, Monteleone G, Fantini MC. Intestinal inflammation and colorectal cancer: a double-edged sword? World J Gastroenterol. 2011;17:3092–100.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Erreni M, Mantovani A, Allavena P. Tumor-associated macrophages (tam) and inflammation in colorectal cancer. Cancer Microenviron. 2011;4:141–54.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Mueller MM, Fusenig NE. Friends or foes—Bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004;4:839–49.PubMedGoogle Scholar
  89. 89.
    Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–35.PubMedCentralPubMedGoogle Scholar
  90. 90.
    Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med. 1990;323:1228–33.PubMedGoogle Scholar
  91. 91.
    Curtin K, Slattery ML, Ulrich CM, Bigler J, Levin TR, Wolff RK, et al. Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet. Carcinogenesis. 2007;28(8):1672–9.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Keku T, Millikan R, Worley K, Winkel S, Eaton A, Biscoco L, et al. 5,10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites. Cancer Epidemiol Biomarkers Prev. 2002;11(12):1611–21.PubMedGoogle Scholar
  93. 93.
    Levine AJ, Siegmund KD, Ervin CM, Diep A, Lee ER, Frankl HD, et al. The methylenetetrahydrofolate reductase 677C → T polymorphism and distal colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev. 2000;9(7):657–63.PubMedGoogle Scholar
  94. 94.
    Yamaji T, Iwasaki M, Sasazuki S, Sakamoto H, Yoshida T, Tsugane S. Methionine synthase A2756G polymorphism interacts with alcohol and folate intake to influence the risk of colorectal adenoma. Cancer Epidemiol Biomarkers Prev. 2009;18(1):267–74.PubMedGoogle Scholar
  95. 95.
    Iacopetta B, Heyworth J, Girschik J, Grieu F, Clayforth C, Fritschi L. The MTHFR C677T and ΔDNMT3B C-149 T polymorphisms confer different risks for right- and left-sided colorectal cancer. Int J Cancer. 2009;125(1):84–90.PubMedGoogle Scholar
  96. 96.
    Mokarram P, Kumar K, Brim H, Naghibaldhossaini F, Saberi-froozi M, Nouraie M, et al. Distinct high-profile methylated genes in colorectal cancer. PLoS One. 2009;4(9):e7012.PubMedCentralPubMedGoogle Scholar
  97. 97.
    Zeisel SH. Gene response elements, genetic polymorphisms and epigenetics influence the human dietary requirement for choline. IUBMB Life. 2007;59(6):380–7.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Van Engeland M, Weijenberg MP, Roemen GMJM, Brink M, De Bruine AP, Goldbohm RA, et al. Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer. Cancer Res. 2003;63(12):3133–7.PubMedGoogle Scholar
  99. 99.
    Hamid A, Kiran M, Rana S, Kaur J. Low folate transport across intestinal basolateral surface is associated with down-regulation of reduced folate carrier in in vivo model of folate malabsorption. IUBMB Life. 2009;61(3):236–43.PubMedGoogle Scholar
  100. 100.
    Paun BC, Kukuruga D, Jin Z, Mori Y, Cheng Y, Duncan M, et al. Relation between normal rectal methylation, smoking status, and the presence or absence of colorectal adenomas. Cancer. 2010;116(19):4495–501.PubMedCentralPubMedGoogle Scholar
  101. 101.
    Slattery ML, Curtin K, Sweeney C, Levin TR, Potter J, Wolff RK, et al. Diet and lifestyle factor associations with CpG island methylator phenotype and BRAF mutations in colon cancer. Int J Cancer. 2007;120(3):656–63.PubMedGoogle Scholar
  102. 102.
    Hughes LAE, van den Brandt PA, de Bruïne AP, Wouters KA, Hulsmans S, Spiertz A, et al. Early life exposure to famine and colorectal cancer risk: a role for epigenetic mechanisms. PLoS One. 2009;4(11):e7951.PubMedCentralPubMedGoogle Scholar
  103. 103.
    Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet. 2009;76(1):1–18.PubMedCentralPubMedGoogle Scholar
  104. 104.
    Plaschke J, Engel C, Kruger S, Holinski-Feder E, Pagenstecher C, Mangold E, et al. Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic msh6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J Clin Oncol. 2004;22:4486–94.PubMedGoogle Scholar
  105. 105.
    Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.PubMedCentralPubMedGoogle Scholar
  106. 106.
    Järvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomäki P, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology. 2000;118:829–34.PubMedGoogle Scholar
  107. 107.
    Burn J. Aspirin prevents cancer in Lynch syndrome. Eur J Cancer. 2009;7:320–1.Google Scholar
  108. 108.
    Schmeler KM, Lynch HT, Chen LM, Munsell MF, Soliman PT, Clark MB, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med. 2006;354:261–9.PubMedGoogle Scholar
  109. 109.
    Juhn E, Khachemoune A. Gardner syndrome: skin manifestations, differential diagnosis and management. Am J Clin Dermatol. 2010;11(2):117–22.PubMedGoogle Scholar
  110. 110.
    Nieuwenhuis MH, Vasen HF. Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol. 2007;61:153–61.PubMedGoogle Scholar
  111. 111.
    McGarrity TJ, Amos C. Peutz–Jeghers syndrome: clinicopathology and molecular alterations. Cell Mol Life Sci. 2006;63(18):2135–44.PubMedGoogle Scholar
  112. 112.
    Calva D, Howe JR. Hamartomatous polyposis syndromes. Surg Clin N Am. 2008;88(4):779–817.PubMedCentralPubMedGoogle Scholar
  113. 113.
    Kaemmerer E, Klaus C, Jeon MK, Gassler N. Molecular classification of colorectal carcinomas: the genotype to phenotype relation. World J Gastroenterol. 2013;19(45):8163–7.PubMedCentralPubMedGoogle Scholar
  114. 114.
    Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology. 2010;138:2088–100.PubMedGoogle Scholar
  115. 115.
    East JE, Saunders BP, Jass JR. Sporadic and syndromic hyperplastic polyps and serrated adenomas of the colon: classification, molecular genetics, natural history, and clinical management. Gastroenterol Clin N Am. 2008;37:25–46.Google Scholar
  116. 116.
    Fanali C, Lucchetti D, Farina M, Corbi M, Cufino V, Cittadini A, et al. Cancer stem cells in colorectal cancer from pathogenesis to therapy: controversies and perspectives. World J Gastroenterol. 2014;20(4):923–42.PubMedCentralPubMedGoogle Scholar
  117. 117.
    Winawer S, Fletcher R, Rex D, Bond J, Burt R, Ferrucci J, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale-update based on new evidence. Gastroenterology. 2003;124(2):544–60.PubMedGoogle Scholar
  118. 118.
    Osborn NK, Ahlquist DA. Stool screening for colorectal cancer: molecular approaches. Gastroenterology. 2005;128(1):192–206.PubMedGoogle Scholar
  119. 119.
    Hardcastle JD, Thomas WM, Chamberlain J, Pye G, Sheffield J, James PD, et al. Randomised, controlled trial of faecal occult blood screening for colorectal cancer: results for first 107,349 subjects. Lancet. 1989;1(8648):1160–4.PubMedGoogle Scholar
  120. 120.
    Brenner DE, Rennert G. Fecal DNA biomarkers for the detection of colorectal neoplasia: attractive, but is it feasible? J Natl Cancer Inst. 2005;97(15):1107–9.PubMedGoogle Scholar
  121. 121.
    Creeden J, Junker F, Vogel-Ziebolz S, Rex D. Serum tests for colorectal cancer screening. Mol Diagn Ther. 2011;15(3):129–41.PubMedGoogle Scholar
  122. 122.
    Kim MS, Lee J, Sidransky D. DNA methylation markers in colorectal cancer. Cancer Metastasis Rev. 2010;29(1):181–206.PubMedGoogle Scholar
  123. 123.
    Wong JJL, Hawkins NJ, Ward RL, Hitchins MP. Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer. Mod Pathol. 2011;24(3):396–411.PubMedGoogle Scholar
  124. 124.
    Dong SM, Traverso G, Johnson C, et al. Detecting colorectal cancer in stool with the use of multiple genetic targets. J Natl Cancer Inst. 2001;93:851–65.Google Scholar
  125. 125.
    Alquist DA, Skoletsky JE, Boynton KA, et al. Colorectal cancer screening]by detection of altered human DNA in stool; feasibility of a mutitarget assay panel. Gastroenterology. 2000;119:1219–27.Google Scholar
  126. 126.
    Calistri D, Rengucci C, Bocchini R, et al. Fecal multiple molecular tests to detect colorectal cancer in stool. Clin Gastroenterol Hepatol. 2003;1:377–83.PubMedGoogle Scholar
  127. 127.
    Roperch JP, Incitti R, Forbin F, et al. Aberrant methylation of NPY, PENK, and WIF1 as a promising marker for blood-based diagnosis of colorectal cancer. BMC Cancer. 2013;13:566.PubMedCentralPubMedGoogle Scholar
  128. 128.
    Madhavan D, Cuk K, Burwinkel B, Yang R. Cancer diagnosis and prognosis decoded by blood-based circulating microRNA signatures. Front Genet. 2013;4:116.PubMedCentralPubMedGoogle Scholar
  129. 129.
    Toiyama Y, Takahashi M, Hur K, et al. Serum miR-21 as a diagnostic and prognostic biomarker in colorectal cancer. J Natl Cancer Inst. 2013;105(12):849–59.PubMedCentralPubMedGoogle Scholar
  130. 130.
    Kim MS, Lee J, Sidransky D. DNA methylation markers in colorectal cancer. Cancer Metastasis Rev. 2010;29(1):181–206.PubMedGoogle Scholar
  131. 131.
    Grady WM, Carethers JM. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology. 2008;135(4):1079–99.PubMedCentralPubMedGoogle Scholar
  132. 132.
    Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007;50(1):113–30.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Federica Zoratto
    • 1
  • Luigi Rossi
    • 2
  • Monica Verrico
    • 2
  • Anselmo Papa
    • 2
  • Enrico Basso
    • 3
  • Angelo Zullo
    • 4
  • Luigi Tomao
    • 5
  • Adriana Romiti
    • 6
  • Giuseppe Lo Russo
    • 2
  • Silverio Tomao
    • 2
  1. 1.Oncology Unit 2Azienda Ospedaliera–Universitaria PisanaPisaItaly
  2. 2.Oncology Unit, ICOT, Department of Medico-Surgical Sciences and Biotechnologies“Sapienza” UniversityLatinaItaly
  3. 3.Oncology UnitPotenzaItaly
  4. 4.Gastroenterology DivisionRomeItaly
  5. 5.Biostatistics and Scientific DirectionRegina Elena National Cancer InstituteRomeItaly
  6. 6.Oncology Unit“Sapienza” UniversityRomeItaly

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