Molecular Pathogenesis of Colorectal Cancer
Authors:
J. Král 1,2; J. Slyšková 2; P. Vodička 2; J. Špičák 1
Authors‘ workplace:
Klinika hepatogastroenterologie, Transplantcentrum, IKEM, Praha
1; Oddělení molekulární biologie nádorů, Ústav experimentální medicíny, AV ČR, v. v. i., Praha
2
Published in:
Klin Onkol 2016; 29(6): 419-427
Category:
Review
doi:
https://doi.org/10.14735/amko2016419
Overview
Background:
Colorectal cancer (CRC) remains a major health burden with an incidence of 1.3 million new cases worldwide and a mortality of almost 8.5%. It is the 2nd most common cancer in women (1st breast carcinoma) and 3rd most common in men (1st lung carcinoma, 2nd prostate carcinoma). CRC alongside breast, lung, prostate and stomach cancer is in the top five most common cancers in men and women worldwide. There are still more than 50% of CRC patients diagnosed with advanced disease (stage III and IV) in the Czech Republic. Genetically, CRC is a very heterogeneous disease with many factors playing key roles in pathogenesis. There are two types of CRC, hereditary with an incidence of between 5% and 10% with APC (FAP, aFAP) or MMR (HNPCC) genes affected, and sporadic colorectal cancer with an incidence of 90–95% with a lot of mutations in variable genes that accumulate during pathogenesis (APC, KRAS, MMR, microRNA, CIMP etc.). Knowledge of the molecular pathogenesis of CRC (hereditary, sporadic) is crucial for treatment, assessment of risk, prognosis, and patient follow-up.
Conclusion:
This article summarizes the molecular pathogenesis of sporadic and hereditary CRC.
Keywords:
colorectal cancer – pathogenesis – hereditary – sporadic – risk factors
This work was supported by grant of Grant Agency of the Czech Republic No. 15-08239S.
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Submitted:
3. 5. 2016
Accepted:
2. 6. 2016
Sources
1. Ferlay J, Soerjomataram I, Ervik M et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11; 2013 [online]. Available from: http://globocan.iarc.fr/Pages/references.aspx.
2. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61 (5): 759–767.
3. Vogelstein B, Papadopoulos N, Velculescu VE et al. Cancer genome landscapes. Science 2013; 339 (6127): 1546–1558. doi: 10.1126/science.1235122.
4. Gala MK, Mizukami Y, Le LP et al. Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas. Gastroenterology 2014; 146 (2): 520–529.
5. Bettington M, Walker N, Clouston A et al. The serrated pathway to colorectal carcinoma: current concepts and challenges. Histopathology 2013; 62 (3): 367–386. doi: 10.1111/his.12055.
6. Bogaert J, Prenen H. Molecular genetics of colorectal cancer. Ann Gastroenterol 2014; 27 (1): 9–14.
7. Rustgi AK. The genetics of hereditary colon cancer. Genes Dev 2007; 21 (20): 2525–2538.
8. Varesco L. Familial adenomatous polyposis: genetics and epidemiology. Tech Coloproctol 2004; 8 (Suppl 2): 305–308.
9. Pezzi A, Roncucci L, Benatti P et al. Relative role of APC and MUTYH mutations in the pathogenesis of familial adenomatous polyposis. Scand J Gastroenterol 2009; 44 (9): 1092–1100. doi: 10.1080/00365520903100481.
10. Kartheuser A, West S, Walon C et al. The genetic background of familial adenomatous polyposis. Linkage analysis, the APC gene identification and mutation screening. Acta Gastroenterol Belg 1995; 58 (5–6): 433–451.
11. Chew MH, Tan WS, Liu Y et al. Genomics of hereditary colorectal cancer: lessons learnt from 25 years of the Singapore polyposis registry. Ann Acad Med Singapore 2015; 44 (8): 290–296.
12. Vaja R, McNicol L, Sisley I. Anaesthesia for patients with liver disease. Contin Educ Anaesth Crit Care Pain 2010; 10 (1): 15–19. doi: 10.1093/bjaceaccp/mkp040.
13. Al-Sohaily S, Biankin A, Leong R et al. Molecular pathways in colorectal cancer. J Gastroenterol Hepatol 2012; 27 (9): 1423–1431. doi: 10.1111/j.1440-1746.2012.07 200.x.
14. Armaghany T, Wilson JD, Chu Q et al. Genetic alterations in colorectal cancer. Gastrointest Cancer Res 2012; 5 (1): 19–27.
15. Strimpakos AS, Syrigos KN, Saif MW. Pharmacogenetics and biomarkers in colorectal cancer. Pharmacogenomics J 2009; 9 (3): 147–160. doi: 10.1038/tpj.2009.8.
16. Trautmann K, Terdiman JP, French AJ et al. Chromosomal instability in microsatellite-unstable and stable colon cancer. Clin Cancer Res 2006; 12 (21): 6379–6385.
17. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 2009; 361 (25): 2449–2460. doi: 10.1056/NEJMra0804588.
18. Farkas SA, Vymetalkova V, Vodickova L et al. DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/beta-catenin signaling pathway genes. Epigenomics 2014; 6 (2): 179–191. doi: 10.2217/epi.14.7.
19. Noffsinger AE. Serrated polyps and colorectal cancer: new pathway to malignancy. Annu Rev Pathol 2009; 4 (1): 343–364. doi: 10.1146/annurev.pathol.4.110807.092317.
20. 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 North Am 2008; 37 (1): 25–46. doi: 10.1016/j.gtc.2007.12.014.
21. Minoo P. Toward a molecular classification of colorectal cancer: the role of MGMT. Front Oncol 2013; 3: 266. doi: 10.3389/fonc.2013.00266.
22. Shen L, Kondo Y, Rosner GL et al. MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst 2005; 97 (18): 1330–1338.
23. Bodmer WF, Bailey CJ, Bodmer J et al. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 1987; 328 (6131): 614–616.
24. Kwong LN, Dove WF. APC and its modifiers in colon cancer. Adv Exp Med Biol 2009; 656: 85–106.
25. Berger AH, Knudson AG, Pandolfi PP. A continuum model for tumour suppression. Nature 2011; 476 (7359): 163–169. doi: 10.1038/nature10275.
26. Fearnhead NS, Wilding JL, Bodmer WF. Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumorigenesis. Br Med Bull 2002; 64: 27–43.
27. Benchabane H, Ahmed Y. The adenomatous polyposis coli tumor suppressor and Wnt signaling in the regulation of apoptosis. Adv Exp Med Biol 2009; 656: 75–84.
28. Walther A, Johnstone E, Swanton C et al. Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer 2009; 9 (7): 489–499. doi: 10.1038/nrc2645.
29. Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 2001; 1 (1): 55–67.
30. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 2000; 408 (6810): 307–310.
31. Naccarati A, Polakova V, Pardini B et al. Mutations and polymorphisms in TP53 gene – an overview on the role in colorectal cancer. Mutagenesis 2012; 27 (2): 211–218.
32. Royds JA, Iacopetta B. p53 and disease: when the guardian angel fails. Cell Death Differ 2006; 13 (6): 1017–1026.
33. Soussi T, Kato S, Levy PP et al. Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations. Hum Mutat 2005; 25 (1): 6–17.
34. Iacopetta B, Russo A, Bazan V et al. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study. Ann Oncol 2006; 17 (5): 842–847.
35. Lamy A, Blanchard F, Le Pessot F et al. Metastatic colorectal cancer KRAS genotyping in routine practice: results and pitfalls. Mod Pathol 2011; 24 (8): 1090–1100. doi: 10.1038/modpathol.2011.60.
36. Samuels Y, Waldman T. Oncogenic mutations of PIK3CA in human cancers. Curr Top Microbiol Immunol 2010; 347: 21–41. doi: 10.1007/82_2010_68.
37. Karakas B, Bachman KE, Park BH. Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 2006; 94 (4): 455–459.
38. Demes M, Scheil-Bertram S, Bartsch H et al. Signature of microsatellite instability, KRAS and BRAF gene mutations in German patients with locally advanced rectal adenocarcinoma before and after neoadjuvant 5-FU radiochemotherapy. J Gastrointest Oncol 2013; 4 (2): 182–192. doi: 10.3978/j.issn.2078-6891.2013.012.
39. Davies H, Bignell GR, Cox C et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417 (6892): 949–954.
40. Rosty C, Young JP, Walsh MD et al. Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features. Mod Pathol 2013; 26 (6): 825–834. doi: 10.1038/modpathol.2012.240.
41. Sartore-Bianchi A, Martini M, Molinari F et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 2009; 69 (5): 1851–1857. doi: 10.1158/0008-5472.CAN-08-2466.
42. Yin Y, Shen WH. PTEN: a new guardian of the genome. Oncogene 2008; 27 (41): 5443–5453. doi: 10.1038/onc.2008.241.
43. Knudson AG Jr. Hereditary cancer, oncogenes, and antioncogenes. Cancer Res 1985; 45 (4): 1437–1443.
44. Mehlen P, Fearon ER. Role of the dependence receptor DCC in colorectal cancer pathogenesis. J Clin Oncol 2004; 22 (16): 3420–3428.
45. Arakawa H. Netrin-1 and its receptors in tumorigenesis. Nat Rev Cancer 2004; 4 (12): 978–987.
46. Castets M, Broutier L, Molin Y et al. DCC constrains tumour progression via its dependence receptor activity. Nature 2012; 482 (7386): 534–537. doi: 10.1038/nature10708.
47. Mazelin L, Bernet A, Bonod-Bidaud C et al. Netrin-1 controls colorectal tumorigenesis by regulating apoptosis. Nature 2004; 431 (7004): 80–84.
48. Duman-Scheel M. Deleted in colorectal cancer (DCC) pathfinding: axon guidance gene finally turned tumor suppressor. Curr Drug Targets 2012; 13 (11): 1445–1453.
49. Ten Dijke P, Goumans MJ, Itoh F et al. Regulation of cell proliferation by Smad proteins. J Cell Physiol 2002; 191 (1): 1–16.
50. Zhang B, Halder SK, Kashikar ND et al. Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology 2010; 138 (3): 969–980. doi: 10.1053/j.gastro.2009.11.004.
51. Chin LJ, Slack FJ. A truth serum for cancer – microRNAs have major potential as cancer biomarkers. Cell Res 2008; 18 (10): 983–984. doi: 10.1038/cr.2008.290.
52. Bonfrate L, Altomare DF, Di Lena M et al. MicroRNA in colorectal cancer: new perspectives for diagnosis, prognosis and treatment. J Gastrointestin Liver Dis 2013; 22 (3): 311–320.
53. Wouters MD, van Gent DC, Hoeijmakers JH et al. Micro- RNAs, the DNA damage response and cancer. Mutat Res 2011; 717 (1–2): 54–66. doi: 10.1016/j.mrfmmm.2011.03.012.
54. Aslam MI, Patel M, Singh B et al. MicroRNA manipulation in colorectal cancer cells: from laboratory to clinical application. J Transl Med 2012; 10: 128. doi: 10.1186/1479-5876-10-128.
55. Garzon R, Calin GA, Croce CM. MicroRNAs in cancer. Annu Rev Med 2009; 60 (1): 167–179. doi: 10.1146/annurev.med.59.053006.104707.
56. Kusenda B, Mraz M, Maer J et al. MicroRNA biogenesis, functionality and cancer relevance. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2006; 150 (2): 205–215.
57. Raisch J, Darfeuille-Michaud A, Nguyen HT. Role of microRNAs in the immune system, inflammation and cancer. World J Gastroenterol 2013; 19 (20): 2985–2996. doi: 10.3748/wjg.v19.i20.2985.
58. Hrašovec S, Glavač D. MicroRNAs as novel biomarkers in colorectal cancer. Front Genet 2012; 3: 180. doi: 10.3389/fgene.2012.00180.
59. Slaby O, Svoboda M, Michalek J et al. MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Mol Cancer 2009; 8 (1): 102. doi: 10.1186/1476-4598-8-102.
60. Svoboda M, Slyskova J, Schneiderova M et al. HOTAIR long non-coding RNA is a negative prognostic factor not only in primary tumors, but also in the blood of colorectal cancer patients. Carcinogenesis 2014; 35 (7): 1510–1515. doi: 10.1093/carcin/bgu055.
61. Jacob S, Praz F. DNA mismatch repair defects: role in colorectal carcinogenesis. Biochimie 2002; 84 (1): 27–47.
62. Stigliano V, Assisi D, Cosimelli M et al. Survival of hereditary non-polyposis colorectal cancer patients compared with sporadic colorectal cancer patients. J Exp Clin Cancer Res 2008; 27 (1): 39. doi: 10.1186/1756-9966- 27-39.
63. Sandouk F, Al Jerf F, Al-Halabi MH. Precancerous lesions in colorectal cancer. Gastroenterol Res Pract 2013; 2013: 457901. doi: 10.1155/2013/457901.
64. Papadopoulos N, Lindblom A. Molecular basis of HNPCC: mutations of MMR genes. Hum Mutat 1997; 10 (2): 89–99.
65. Devaud N, Gallinger S. Chemotherapy of MMR-deficient colorectal cancer. Fam Cancer 2013; 12 (2): 301–306. doi: 10.1007/s10689-013-9633-z.
66. Tomlinson IP, Webb E, Carvajal-Carmona L et al. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet 2008; 40 (5): 623–630. doi: 10.1038/ng.111.
67. Houlston RS, members of COGENT. COGENT (COlorectal cancer GENeTics) revisited. Mutagenesis 2012; 27 (2): 143–151. doi: 10.1093/mutage/ger059.
68. Tsoi KK, Pau CY, Wu WK et al Cigarette smoking and the risk of colorectal cancer: a meta-analysis of prospective cohort studies. Clin Gastroenterol Hepatol 2009; 7 (6): 682–688. doi: 10.1016/j.cgh.2009.02.016.
69. Chan DS, Lau R, Aune D et al. Red and processed meat and colorectal cancer incidence: meta-analysis of prospective studies. PLoS One 2011; 6 (6): e20456. doi: 10.1371/journal.pone.0020456.
70. Park Y, Hunter DJ, Spiegelman D et al. Dietary fiber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies. JAMA 2005; 294 (22): 2849–2857.
71. Flossmann E, Rothwell PM. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 2007; 369 (9573): 1603–1613.
72. Pöschl G, Seitz HK. Alcohol and cancer. Alcohol Alcohol 2004; 39 (3): 155–165.
73. Fedirko V, Tramacere I, Bagnardi V et al. Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies. Ann Oncol 2011; 22 (9): 1958–1972. doi: 10.1093/annonc/mdq653.
74. Yang YX, Hennessy S, Lewis JD. Type 2 diabetes mellitus and the risk of colorectal cancer. Clin Gastroenterol Hepatol 2005; 3 (6): 587–594.
75. Berster JM, Göke B. Type 2 diabetes mellitus as risk factor for colorectal cancer. Arch Physiol Biochem 2008; 114 (1): 84–98. doi: 10.1080/13813450802008455.
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