Intest Res.  2014 Jul;12(3):184-193. 10.5217/ir.2014.12.3.184.

Clinical Application of Genetics in Management of Colorectal Cancer

• Kim ER
• Kim YH

• KMID: 2174377
• DOI: http://doi.org/10.5217/ir.2014.12.3.184

Abstract

The extensive study of genetic alterations in colorectal cancer (CRC) has led to molecular diagnostics playing an increasingly important role in CRC diagnosis and treatment. Currently, it is believed that CRC is a consequence of the accumulation of both genetic and epigenetic genomic alterations. It is known that there are at least 3 major pathways that lead to colorectal carcinogenesis: (1) the chromosomal instability pathway, (2) the microsatellite instability pathway, and (3) the cytosine-phospho-guanine island methylator phenotype pathway. With recent advances in CRC genetics, the identification of specific molecular alterations responsible for CRC pathogenesis has directly influences clinical care. Patients at high risk for developing CRC can be identified by genetic testing for specific molecular alterations, and the use of molecular biomarkers for predictive and prognostic purposes is also increasing. This is clearly supported by the recent advances in genetic testing for CRC whereby specific molecular alterations are identified for the purpose of guiding treatment with targeting therapies such as anti-endothelial growth factor receptor monoclonal antibodies.

Keyword

Colorectal neoplasms; Chromosomal instability; Microsatellite instability; Epigenetic instability; Biological markers

MeSH Terms

Antibodies, Monoclonal
Biomarkers
Carcinogenesis
Chromosomal Instability
Colorectal Neoplasms*
Diagnosis
Epigenomics
Genetic Testing
Genetics*
Humans
Microsatellite Instability
Pathology, Molecular
Phenotype
Antibodies, Monoclonal

Reference

1. Jung KW, Won YJ, Kong HJ, Oh CM, Lee DH, Lee JS. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2011. Cancer Res Treat. 2014; 46:109–123. PMID: 24851102.

2. Coppede F. Epigenetic biomarkers of colorectal cancer: Focus on DNA methylation. Cancer Lett. 2014; 342:238–247. PMID: 22202641.

3. Coppede F, Lopomo A, Spisni R, Migliore L. Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer. World J Gastroenterol. 2014; 20:943–956. PMID: 24574767.

4. Marisa L, de Reynies A, Duval A, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013; 10:e1001453. PMID: 23700391.

5. Tsang AH, Cheng KH, Wong AS, et al. Current and future molecular diagnostics in colorectal cancer and colorectal adenoma. World J Gastroenterol. 2014; 20:3847–3857. PMID: 24744577.

6. Bogaert J, Prenen H. Molecular genetics of colorectal cancer. Ann Gastroenterol. 2014; 27:9–14. PMID: 24714764.

7. Pancione M, Remo A, Colantuoni V. Genetic and epigenetic events generate multiple pathways in colorectal cancer progression. Patholog Res Int. 2012; 2012:509348. PMID: 22888469.

8. Michor F, Iwasa Y, Lengauer C, Nowak MA. Dynamics of colorectal cancer. Semin Cancer Biol. 2005; 15:484–493. PMID: 16055342.

9. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998; 396:643–649. PMID: 9872311.

10. Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010; 138:2059–2072. PMID: 20420946.

11. Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C. The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer. 2003; 3:695–701. PMID: 12951588.

12. Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011; 6:479–507. PMID: 21090969.

13. Al-Sohaily S, Biankin A, Leong R, Kohonen-Corish M, Warusavitarne J. Molecular pathways in colorectal cancer. J Gastroenterol Hepatol. 2012; 27:1423–1431. PMID: 22694276.

14. Legolvan MP, Taliano RJ, Resnick MB. Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach. Hum Pathol. 2012; 43:1157–1168. PMID: 22658275.

15. Walther A, Houlston R, Tomlinson I. Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis. Gut. 2008; 57:941–950. PMID: 18364437.

16. Bardhan K, Liu K. Epigenetics and colorectal cancer pathogenesis. Cancers (Basel). 2013; 5:676–713. PMID: 24216997.

17. Armaghany T, Wilson JD, Chu Q, Mills G. Genetic alterations in colorectal cancer. Gastrointest Cancer Res. 2012; 5:19–27. PMID: 22574233.

18. Umar A, Risinger JI, Hawk ET, Barrett JC. Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer. 2004; 4:153–158. PMID: 14964310.

19. Narayan S, Roy D. Role of APC and DNA mismatch repair genes in the development of colorectal cancers. Mol Cancer. 2003; 2:41. PMID: 14672538.

20. Kloor M, Staffa L, Ahadova A, von Knebel Doeberitz M. Clinical significance of microsatellite instability in colorectal cancer. Langenbecks Arch Surg. 2014; 399:23–31. PMID: 24048684.

21. Suk KT, Kim HS, Lee JH, et al. Clinicopathological characteristics of colorectal cancer according to microsatellite instability. Intest Res. 2009; 7:14–21.

22. Schnekenburger M, Diederich M. Epigenetics offer new horizons for colorectal cancer prevention. Curr Colorectal Cancer Rep. 2012; 8:66–81. PMID: 22389639.

23. Wu WK, Sung JJ. MicroRNA dysregulations in gastrointestinal cancers: pathophysiological and clinical perspectives. Intest Res. 2012; 10:324–331.

24. Esteller M. Aberrant DNA methylation as a cancer-inducing mechanism. Annu Rev Pharmacol Toxicol. 2005; 45:629–656. PMID: 15822191.

25. Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007; 8:286–298. PMID: 17339880.

26. Daniel FI, Cherubini K, Yurgel LS, de Figueiredo MA, Salum FG. The role of epigenetic transcription repression and DNA methyltransferases in cancer. Cancer. 2011; 117:677–687. PMID: 20945317.

27. Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene. 2001; 20:3139–3155. PMID: 11420731.

28. Sharp AJ, Stathaki E, Migliavacca E, et al. DNA methylation profiles of human active and inactive X chromosomes. Genome Res. 2011; 21:1592–1600. PMID: 21862626.

29. Anier K, Malinovskaja K, Aonurm-Helm A, Zharkovsky A, Kalda A. DNA methylation regulates cocaine-induced behavioral sensitization in mice. Neuropsychopharmacology. 2010; 35:2450–2461. PMID: 20720536.

30. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3:415–428. PMID: 12042769.

31. Domingo E, Niessen RC, Oliveira C, et al. BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes. Oncogene. 2005; 24:3995–3998. PMID: 15782118.

32. Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002; 418:934. PMID: 12198537.

33. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990; 61:759–767. PMID: 2188735.

34. Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol. 2001; 96:2992–3003. PMID: 11693338.

35. Gala M, Chung DC. Hereditary colon cancer syndromes. Semin Oncol. 2011; 38:490–499. PMID: 21810508.

36. Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010; 138:2044–2058. PMID: 20420945.

37. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008; 26:5783–5788. PMID: 18809606.

38. Boland CR, Troncale FJ. Familial colonic cancer without antecedent polyposis. Ann Intern Med. 1984; 100:700–701. PMID: 6712034.

39. Marra G, Boland CR. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst. 1995; 87:1114–1125. PMID: 7674315.

40. Bonis PA, Trikalinos TA, Chung M, et al. Evidence Report/Technology Assessment No. 150. Hereditary nonpolyposis colorectal cancer: diagnostic strategies and their implications. Rockville, MD: Agency for Healthcare Research and Quality;2007.

41. Peltomaki P. Lynch syndrome genes. Fam Cancer. 2005; 4:227–232. PMID: 16136382.

42. Kastrinos F, Stoffel EM, Balmana J, Steyerberg EW, Mercado R, Syngal S. Phenotype comparison of MLH1 and MSH2 mutation carriers in a cohort of 1,914 individuals undergoing clinical genetic testing in the United States. Cancer Epidemiol Biomarkers Prev. 2008; 17:2044–2051. PMID: 18708397.

43. Kovacs ME, Papp J, Szentirmay Z, Otto S, Olah E. Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat. 2009; 30:197–203. PMID: 19177550.

44. Niessen RC, Hofstra RM, Westers H, et al. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer. 2009; 48:737–744. PMID: 19455606.

45. Syngal S, Fox EA, Eng C, Kolodner RD, Garber JE. Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1. J Med Genet. 2000; 37:641–645. PMID: 10978352.

46. Pritchard CC, Grady WM. Colorectal cancer molecular biology moves into clinical practice. Gut. 2011; 60:116–129. PMID: 20921207.

47. Burt RW, Leppert MF, Slattery ML, et al. Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology. 2004; 127:444–451. PMID: 15300576.

48. Bjork J, Akerbrant H, Iselius L, et al. Periampullary adenomas and adenocarcinomas in familial adenomatous polyposis: cumulative risks and APC gene mutations. Gastroenterology. 2001; 121:1127–1135. PMID: 11677205.

49. Bulow S, Bjork J, Christensen IJ, et al. Duodenal adenomatosis in familial adenomatous polyposis. Gut. 2004; 53:381–386. PMID: 14960520.

50. Dobbie Z, Spycher M, Mary JL, et al. Correlation between the development of extracolonic manifestations in FAP patients and mutations beyond codon 1403 in the APC gene. J Med Genet. 1996; 33:274–280. PMID: 8730280.

51. Nagy R, Sweet K, Eng C. Highly penetrant hereditary cancer syndromes. Oncogene. 2004; 23:6445–6470. PMID: 15322516.

52. Bisgaard ML, Fenger K, Bulow S, Niebuhr E, Mohr J. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat. 1994; 3:121–125. PMID: 8199592.

53. Schreibman IR, Baker M, Amos C, McGarrity TJ. The hamartomatous polyposis syndromes: a clinical and molecular review. Am J Gastroenterol. 2005; 100:476–490. PMID: 15667510.

54. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology. 2000; 119:1447–1453. PMID: 11113065.

55. Howe JR, Mitros FA, Summers RW. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol. 1998; 5:751–756. PMID: 9869523.

56. Hemminki A, Markie D, Tomlinson I, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 1998; 391:184–187. PMID: 9428765.

57. Howe JR, Roth S, Ringold JC, et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science. 1998; 280:1086–1088. PMID: 9582123.

58. Aretz S. The differential diagnosis and surveillance of hereditary gastrointestinal polyposis syndromes. Dtsch Arztebl Int. 2010; 107:163–173. PMID: 20358032.

59. Briggs S, Tomlinson I. Germline and somatic polymerase epsilon and delta mutations define a new class of hypermutated colorectal and endometrial cancers. J Pathol. 2013; 230:148–153. PMID: 23447401.

60. Church JM. Polymerase proofreading-associated polyposis: a new, dominantly inherited syndrome of hereditary colorectal cancer predisposition. Dis Colon Rectum. 2014; 57:396–397. PMID: 24509466.

61. Seshagiri S. The burden of faulty proofreading in colon cancer. Nat Genet. 2013; 45:121–122. PMID: 23358219.

62. Palles C, Cazier JB, Howarth KM, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013; 45:136–144. PMID: 23263490.

63. Jaeger E, Leedham S, Lewis A, et al. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet. 2012; 44:699–703. PMID: 22561515.

64. Tomlinson IP, Carvajal-Carmona LG, Dobbins SE, et al. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLoS Genet. 2011; 7:e1002105. PMID: 21655089.

65. Wakefield LM, Hill CS. Beyond TGFbeta: roles of other TGFbeta superfamily members in cancer. Nat Rev Cancer. 2013; 13:328–341. PMID: 23612460.

66. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005; 23:609–618. PMID: 15659508.

67. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003; 349:247–257. PMID: 12867608.

68. Bertagnolli MM, Niedzwiecki D, Compton CC, et al. Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and Leukemia Group B Protocol 89803. J Clin Oncol. 2009; 27:1814–1821. PMID: 19273709.

69. Fallik D, Borrini F, Boige V, et al. Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer. Cancer Res. 2003; 63:5738–5744. PMID: 14522894.

70. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360:1408–1417. PMID: 19339720.

71. Lyseng-Williamson KA. Cetuximab: a guide to its use in combination with FOLFIRI in the first-line treatment of metastatic colorectal cancer in the USA. Mol Diagn Ther. 2012; 16:317–322. PMID: 23055389.

72. Xu Q, Xu AT, Zhu MM, Tong JL, Xu XT, Ran ZH. Predictive and prognostic roles of BRAF mutation in patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: a meta-analysis. J Dig Dis. 2013; 14:409–416. PMID: 23615046.

73. Leshno A, Gat-Harlap A, Arber N. Can an aspirin a day keep the colorectal cancer away? Intest Res. 2012; 10:229–234.

74. Nishihara R, Lochhead P, Kuchiba A, et al. Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA. 2013; 309:2563–2571. PMID: 23800934.

75. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012; 367:1596–1606. PMID: 23094721.