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Molecular genetics of colorectal cancer

Authors
Harold Frucht, MD
Aimee L Lucas, MD, MS
Section Editors
Richard M Goldberg, MD
Benjamin A Raby, MD, MPH
Deputy Editor
Diane MF Savarese, MD

INTRODUCTION

Colorectal cancer (CRC) is a common disease. Approximately 134,490 new cases are diagnosed each year in the United States, of which 95,270 originate in the colon and the rest in the rectum [1]. Annually, approximately 49,190 Americans die of CRC, accounting for approximately 9 percent of all cancer deaths; in the United States, CRC ranks third in both incidence and cause of cancer death in both men and women. Global, country-specific data on incidence and mortality are available from the World Health Organization GLOBOCAN database.

The risk factors for CRC are both environmental and inherited. The mode of presentation of CRC follows one of three patterns that are reflective of these differing risk factors: sporadic, inherited, and familial:

Sporadic disease, in which there is no family history, accounts for approximately 70 percent of all CRCs. It is most common over the age of 50, and dietary and environmental factors have been etiologically implicated. (See "Colorectal cancer: Epidemiology, risk factors, and protective factors".)

Fewer than 10 percent of patients have a true inherited predisposition to CRC, and these cases are subdivided according to whether or not colonic polyps are a major disease manifestation. The diseases with polyposis include familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), and the hamartomatous polyposis syndromes (eg, Peutz-Jeghers, juvenile polyposis [2], phosphatase and tensin homolog [PTEN] hamartoma tumor [Cowden] syndrome), while those without polyposis are referred to as hereditary nonpolyposis CRC (HNPCC; Lynch syndrome). These conditions are all associated with a high risk of developing CRC. In many cases, the causative genetic mutation has been identified, and a test is available. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis" and "MUTYH-associated polyposis" and "Peutz-Jeghers syndrome: Epidemiology, clinical manifestations, and diagnosis" and "Juvenile polyposis syndrome" and "PTEN hamartoma tumor syndrome, including Cowden syndrome" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

The third and least well understood pattern is known as "familial" CRC, which accounts for up to 25 percent of cases. Affected patients have a family history of CRC, but the pattern is not consistent with one of the inherited syndromes described above. Individuals from these families are at increased risk of developing CRC, although the risk is not as high as with the inherited syndromes. Having a single affected first-degree relative (ie, parent, child, sibling) increases the risk of developing CRC 1.7-fold over that of the general population. The risk is further increased if two first-degree relatives have CRC or if the index case is diagnosed before age 55. (See "Colorectal cancer: Epidemiology, risk factors, and protective factors".)

                        

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References
Top
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66:7.
  2. Wirtzfeld DA, Petrelli NJ, Rodriguez-Bigas MA. Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations. Ann Surg Oncol 2001; 8:319.
  3. Lindor NM. Familial colorectal cancer type X: the other half of hereditary nonpolyposis colon cancer syndrome. Surg Oncol Clin N Am 2009; 18:637.
  4. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61:759.
  5. Zauber AG, Winawer SJ, O'Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 2012; 366:687.
  6. Noffsinger AE. Serrated polyps and colorectal cancer: new pathway to malignancy. Annu Rev Pathol 2009; 4:343.
  7. Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 2006; 38:787.
  8. Das PM, Singal R. DNA methylation and cancer. J Clin Oncol 2004; 22:4632.
  9. Shen L, Kondo Y, Rosner GL, et al. MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst 2005; 97:1330.
  10. van Engeland M, Derks S, Smits KM, et al. Colorectal cancer epigenetics: complex simplicity. J Clin Oncol 2011; 29:1382.
  11. Goel A, Nagasaka T, Arnold CN, et al. The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology 2007; 132:127.
  12. Rajagopalan H, Bardelli A, Lengauer C, et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002; 418:934.
  13. 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.
  14. Samowitz WS, Albertsen H, Sweeney C, et al. Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. J Natl Cancer Inst 2006; 98:1731.
  15. French AJ, Sargent DJ, Burgart LJ, et al. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin Cancer Res 2008; 14:3408.
  16. Ogino S, Nosho K, Kirkner GJ, et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 2009; 58:90.
  17. Spring KJ, Zhao ZZ, Karamatic R, et al. High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy. Gastroenterology 2006; 131:1400.
  18. Chan TL, Zhao W, Leung SY, et al. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res 2003; 63:4878.
  19. Lynch JP, Hoops TC. The genetic pathogenesis of colorectal cancer. Hematol Oncol Clin North Am 2002; 16:775.
  20. Sherr CJ. Cancer cell cycles. Science 1996; 274:1672.
  21. Cancer Genetics and Cancer Predisposition Testing. In: American Society of Clinical Oncology Curriculum, American Society of Clinical Oncology (Ed), Alexandria, VA 1998.
  22. Forgacs I. Oncogenes and gastrointestinal cancer. Gut 1988; 29:417.
  23. Cartwright C. Intestinal cell growth control: role of Src tyrosine kinases. Gastroenterology 1998; 114:1335.
  24. Hamilton SR. The molecular genetics of colorectal neoplasia. Gastroenterology 1993; 105:3.
  25. Kapitanović S, Radosević S, Kapitanović M, et al. The expression of p185(HER-2/neu) correlates with the stage of disease and survival in colorectal cancer. Gastroenterology 1997; 112:1103.
  26. Irby RB, Mao W, Coppola D, et al. Activating SRC mutation in a subset of advanced human colon cancers. Nat Genet 1999; 21:187.
  27. Takayama T, Ohi M, Hayashi T, et al. Analysis of K-ras, APC, and beta-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial adenomatous polyposis. Gastroenterology 2001; 121:599.
  28. Shibata D, Schaeffer J, Li ZH, et al. Genetic heterogeneity of the c-K-ras locus in colorectal adenomas but not in adenocarcinomas. J Natl Cancer Inst 1993; 85:1058.
  29. Tortola S, Marcuello E, González I, et al. p53 and K-ras gene mutations correlate with tumor aggressiveness but are not of routine prognostic value in colorectal cancer. J Clin Oncol 1999; 17:1375.
  30. Shirasawa S, Furuse M, Yokoyama N, Sasazuki T. Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 1993; 260:85.
  31. Bourne HR, Sanders DA, McCormick F. The GTPase superfamily: conserved structure and molecular mechanism. Nature 1991; 349:117.
  32. Moon BS, Jeong WJ, Park J, et al. Role of oncogenic K-Ras in cancer stem cell activation by aberrant Wnt/β-catenin signaling. J Natl Cancer Inst 2014; 106:djt373.
  33. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988; 319:525.
  34. Frattini M, Balestra D, Suardi S, et al. Different genetic features associated with colon and rectal carcinogenesis. Clin Cancer Res 2004; 10:4015.
  35. Harada K, Hiraoka S, Kato J, et al. Genetic and epigenetic alterations of Ras signalling pathway in colorectal neoplasia: analysis based on tumour clinicopathological features. Br J Cancer 2007; 97:1425.
  36. Giehl K. Oncogenic Ras in tumour progression and metastasis. Biol Chem 2005; 386:193.
  37. Miranda E, Destro A, Malesci A, et al. Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer. Br J Cancer 2006; 95:1101.
  38. Pretlow TP, Brasitus TA, Fulton NC, et al. K-ras mutations in putative preneoplastic lesions in human colon. J Natl Cancer Inst 1993; 85:2004.
  39. Losi L, Roncucci L, di Gregorio C, et al. K-ras and p53 mutations in human colorectal aberrant crypt foci. J Pathol 1996; 178:259.
  40. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Fecal DNA versus fecal occult blood for colorectal-cancer screening in an average-risk population. N Engl J Med 2004; 351:2704.
  41. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971; 68:820.
  42. Knudson AG Jr. Hereditary cancer, oncogenes, and antioncogenes. Cancer Res 1985; 45:1437.
  43. Vogelstein B, Fearon ER, Kern SE, et al. Allelotype of colorectal carcinomas. Science 1989; 244:207.
  44. Laken SJ, Petersen GM, Gruber SB, et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet 1997; 17:79.
  45. Drucker L, Shpilberg O, Neumann A, et al. Adenomatous polyposis coli I1307K mutation in Jewish patients with different ethnicity: prevalence and phenotype. Cancer 2000; 88:755.
  46. Spirio LN, Samowitz W, Robertson J, et al. Alleles of APC modulate the frequency and classes of mutations that lead to colon polyps. Nat Genet 1998; 20:385.
  47. Lamlum H, Ilyas M, Rowan A, et al. The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson's 'two-hit' hypothesis. Nat Med 1999; 5:1071.
  48. Su LK, Vogelstein B, Kinzler KW. Association of the APC tumor suppressor protein with catenins. Science 1993; 262:1734.
  49. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000; 103:311.
  50. Fearnhead NS, Britton MP, Bodmer WF. The ABC of APC. Hum Mol Genet 2001; 10:721.
  51. Uthoff SM, Eichenberger MR, McAuliffe TL, et al. Wingless-type frizzled protein receptor signaling and its putative role in human colon cancer. Mol Carcinog 2001; 31:56.
  52. Korinek V, Barker N, Morin PJ, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science 1997; 275:1784.
  53. Morin PJ, Sparks AB, Korinek V, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997; 275:1787.
  54. Goss KH, Groden J. Biology of the adenomatous polyposis coli tumor suppressor. J Clin Oncol 2000; 18:1967.
  55. van de Wetering M, Sancho E, Verweij C, et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 2002; 111:241.
  56. Shih IM, Wang TL, Traverso G, et al. Top-down morphogenesis of colorectal tumors. Proc Natl Acad Sci U S A 2001; 98:2640.
  57. Kim PJ, Plescia J, Clevers H, et al. Survivin and molecular pathogenesis of colorectal cancer. Lancet 2003; 362:205.
  58. Fodde R, Kuipers J, Rosenberg C, et al. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 2001; 3:433.
  59. Soussi T. The p53 tumor suppressor gene: from molecular biology to clinical investigation. Ann N Y Acad Sci 2000; 910:121.
  60. Baker SJ, Preisinger AC, Jessup JM, et al. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res 1990; 50:7717.
  61. Kikuchi-Yanoshita R, Konishi M, Ito S, et al. Genetic changes of both p53 alleles associated with the conversion from colorectal adenoma to early carcinoma in familial adenomatous polyposis and non-familial adenomatous polyposis patients. Cancer Res 1992; 52:3965.
  62. Russo A, Bazan V, Iacopetta B, et al. The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment. J Clin Oncol 2005; 23:7518.
  63. Kirsch DG, Kastan MB. Tumor-suppressor p53: implications for tumor development and prognosis. J Clin Oncol 1998; 16:3158.
  64. Kastan MB, Onyekwere O, Sidransky D, et al. Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991; 51:6304.
  65. Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci U S A 1992; 89:7491.
  66. Woods DB, Vousden KH. Regulation of p53 function. Exp Cell Res 2001; 264:56.
  67. Lane DP. Cancer. p53, guardian of the genome. Nature 1992; 358:15.
  68. Yurgelun MB, Masciari S, Joshi VA, et al. Germline TP53 Mutations in Patients With Early-Onset Colorectal Cancer in the Colon Cancer Family Registry. JAMA Oncol 2015; 1:214.
  69. Hamid O, Varterasian ML, Wadler S, et al. Phase II trial of intravenous CI-1042 in patients with metastatic colorectal cancer. J Clin Oncol 2003; 21:1498.
  70. Warren RS, Kirn DH. Liver-directed viral therapy for cancer p53-targeted adenoviruses and beyond. Surg Oncol Clin N Am 2002; 11:571.
  71. Raj K, Ogston P, Beard P. Virus-mediated killing of cells that lack p53 activity. Nature 2001; 412:914.
  72. Watanabe T, Sullenger BA. Induction of wild-type p53 activity in human cancer cells by ribozymes that repair mutant p53 transcripts. Proc Natl Acad Sci U S A 2000; 97:8490.
  73. Fearon ER, Cho KR, Nigro JM, et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 1990; 247:49.
  74. Hedrick L, Cho KR, Fearon ER, et al. The DCC gene product in cellular differentiation and colorectal tumorigenesis. Genes Dev 1994; 8:1174.
  75. Chan SS, Zheng H, Su MW, et al. UNC-40, a C. elegans homolog of DCC (Deleted in Colorectal Cancer), is required in motile cells responding to UNC-6 netrin cues. Cell 1996; 87:187.
  76. Thiagalingam S, Lengauer C, Leach FS, et al. Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nat Genet 1996; 13:343.
  77. Cho KR, Oliner JD, Simons JW, et al. The DCC gene: structural analysis and mutations in colorectal carcinomas. Genomics 1994; 19:525.
  78. Popat S, Houlston RS. A systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status and colorectal cancer prognosis. Eur J Cancer 2005; 41:2060.
  79. Sun XF, Rütten S, Zhang H, Nordenskjöld B. Expression of the deleted in colorectal cancer gene is related to prognosis in DNA diploid and low proliferative colorectal adenocarcinoma. J Clin Oncol 1999; 17:1745.
  80. Goyette MC, Cho K, Fasching CL, et al. Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer. Mol Cell Biol 1992; 12:1387.
  81. Reiss M, Santoro V, de Jonge RR, Vellucci VF. Transfer of chromosome 18 into human head and neck squamous carcinoma cells: evidence for tumor suppression by Smad4/DPC4. Cell Growth Differ 1997; 8:407.
  82. Riggins GJ, Thiagalingam S, Rozenblum E, et al. Mad-related genes in the human. Nat Genet 1996; 13:347.
  83. Eppert K, Scherer SW, Ozcelik H, et al. MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 1996; 86:543.
  84. MacGrogan D, Pegram M, Slamon D, Bookstein R. Comparative mutational analysis of DPC4 (Smad4) in prostatic and colorectal carcinomas. Oncogene 1997; 15:1111.
  85. Xie W, Rimm DL, Lin Y, et al. Loss of Smad signaling in human colorectal cancer is associated with advanced disease and poor prognosis. Cancer J 2003; 9:302.
  86. Zhou XP, Woodford-Richens K, Lehtonen R, et al. Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Am J Hum Genet 2001; 69:704.
  87. Markowitz S, Wang J, Myeroff L, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 1995; 268:1336.
  88. Chung DC, Rustgi AK. DNA mismatch repair and cancer. Gastroenterology 1995; 109:1685.
  89. Papadopoulos N, Nicolaides NC, Liu B, et al. Mutations of GTBP in genetically unstable cells. Science 1995; 268:1915.
  90. Baker SM, Bronner CE, Zhang L, et al. Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis. Cell 1995; 82:309.
  91. Papadopoulos N, Nicolaides NC, Wei YF, et al. Mutation of a mutL homolog in hereditary colon cancer. Science 1994; 263:1625.
  92. Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998; 58:5248.
  93. Syngal S, Weeks JC, Schrag D, et al. Benefits of colonoscopic surveillance and prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer mutations. Ann Intern Med 1998; 129:787.
  94. Shibata D, Peinado MA, Ionov Y, et al. Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation. Nat Genet 1994; 6:273.
  95. Sourrouille I, Coulet F, Lefevre JH, et al. Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors. Fam Cancer 2013; 12:27.
  96. Mensenkamp AR, Vogelaar IP, van Zelst-Stams WA, et al. Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 2014; 146:643.
  97. Rodríguez-Soler M, Pérez-Carbonell L, Guarinos C, et al. Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology 2013; 144:926.
  98. Ku CS, Cooper DN, Wu M, et al. Gene discovery in familial cancer syndromes by exome sequencing: prospects for the elucidation of familial colorectal cancer type X. Mod Pathol 2012; 25:1055.
  99. Klarskov L, Holck S, Bernstein I, Nilbert M. Hereditary colorectal cancer diagnostics: morphological features of familial colorectal cancer type X versus Lynch syndrome. J Clin Pathol 2012; 65:352.
  100. Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 2005; 293:1979.
  101. Shiovitz S, Copeland WK, Passarelli MN, et al. Characterisation of familial colorectal cancer Type X, Lynch syndrome, and non-familial colorectal cancer. Br J Cancer 2014; 111:598.
  102. Therkildsen C, Jönsson G, Dominguez-Valentin M, et al. Gain of chromosomal region 20q and loss of 18 discriminates between Lynch syndrome and familial colorectal cancer. Eur J Cancer 2013; 49:1226.
  103. Middeldorp A, van Eijk R, Oosting J, et al. Increased frequency of 20q gain and copy-neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas. Int J Cancer 2012; 130:837.
  104. Ionov Y, Peinado MA, Malkhosyan S, et al. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993; 363:558.
  105. Fujiwara T, Stolker JM, Watanabe T, et al. Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences. Am J Pathol 1998; 153:1063.
  106. Schwitalle Y, Kloor M, Eiermann S, et al. Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 2008; 134:988.
  107. Hatch SB, Lightfoot HM Jr, Garwacki CP, et al. Microsatellite instability testing in colorectal carcinoma: choice of markers affects sensitivity of detection of mismatch repair-deficient tumors. Clin Cancer Res 2005; 11:2180.
  108. de la Chapelle A, Hampel H. Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol 2010; 28:3380.
  109. Mueller J, Gazzoli I, Bandipalliam P, et al. Comprehensive molecular analysis of mismatch repair gene defects in suspected Lynch syndrome (hereditary nonpolyposis colorectal cancer) cases. Cancer Res 2009; 69:7053.
  110. Thibodeau SN, French AJ, Cunningham JM, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res 1998; 58:1713.
  111. Haugen AC, Goel A, Yamada K, et al. Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer. Cancer Res 2008; 68:8465.
  112. Halford S, Sasieni P, Rowan A, et al. Low-level microsatellite instability occurs in most colorectal cancers and is a nonrandomly distributed quantitative trait. Cancer Res 2002; 62:53.
  113. Halford SE, Sawyer EJ, Lambros MB, et al. MSI-low, a real phenomenon which varies in frequency among cancer types. J Pathol 2003; 201:389.
  114. Whitehall VL, Walsh MD, Young J, et al. Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability. Cancer Res 2001; 61:827.
  115. Dong SM, Lee EJ, Jeon ES, et al. Progressive methylation during the serrated neoplasia pathway of the colorectum. Mod Pathol 2005; 18:170.
  116. Jass JR, Baker K, Zlobec I, et al. Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a 'fusion' pathway to colorectal cancer. Histopathology 2006; 49:121.
  117. Weinberg RA. Oncogenes and tumor suppressor genes. CA Cancer J Clin 1994; 44:160.
  118. Veigl ML, Kasturi L, Olechnowicz J, et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci U S A 1998; 95:8698.
  119. Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 1998; 95:6870.
  120. Cunningham JM, Kim CY, Christensen ER, et al. The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet 2001; 69:780.
  121. Cui H, Horon IL, Ohlsson R, et al. Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nat Med 1998; 4:1276.
  122. Nakagawa H, Chadwick RB, Peltomaki P, et al. Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer. Proc Natl Acad Sci U S A 2001; 98:591.
  123. Kane MF, Loda M, Gaida GM, et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 1997; 57:808.
  124. Esteller M, Fraga MF, Guo M, et al. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet 2001; 10:3001.
  125. Baylin SB, Esteller M, Rountree MR, et al. Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet 2001; 10:687.
  126. Tycko B. Epigenetic gene silencing in cancer. J Clin Invest 2000; 105:401.
  127. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003; 349:2042.
  128. Rhee I, Bachman KE, Park BH, et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 2002; 416:552.
  129. Cui H, Cruz-Correa M, Giardiello FM, et al. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 2003; 299:1753.
  130. Kuiper RP, Vissers LE, Venkatachalam R, et al. Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Hum Mutat 2011; 32:407.
  131. Ligtenberg MJ, Kuiper RP, Chan TL, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet 2009; 41:112.
  132. 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.
  133. Sieber OM, Lipton L, Crabtree M, et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 2003; 348:791.
  134. Sampson JR, Dolwani S, Jones S, et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 2003; 362:39.
  135. Wang L, Baudhuin LM, Boardman LA, et al. MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology 2004; 127:9.
  136. Ricciardiello L, Goel A, Mantovani V, et al. Frequent loss of hMLH1 by promoter hypermethylation leads to microsatellite instability in adenomatous polyps of patients with a single first-degree member affected by colon cancer. Cancer Res 2003; 63:787.
  137. Croitoru ME, Cleary SP, Di Nicola N, et al. Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. J Natl Cancer Inst 2004; 96:1631.
  138. Enholm S, Hienonen T, Suomalainen A, et al. Proportion and phenotype of MYH-associated colorectal neoplasia in a population-based series of Finnish colorectal cancer patients. Am J Pathol 2003; 163:827.
  139. Kambara T, Whitehall VL, Spring KJ, et al. Role of inherited defects of MYH in the development of sporadic colorectal cancer. Genes Chromosomes Cancer 2004; 40:1.
  140. Al-Tassan N, Chmiel NH, Maynard J, et al. Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Nat Genet 2002; 30:227.
  141. Farrington SM, Tenesa A, Barnetson R, et al. Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet 2005; 77:112.
  142. Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS. Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol 2009; 27:3975.
  143. Webb EL, Rudd MF, Houlston RS. Colorectal cancer risk in monoallelic carriers of MYH variants. Am J Hum Genet 2006; 79:768.
  144. Croitoru ME, Cleary SP, Berk T, et al. Germline MYH mutations in a clinic-based series of Canadian multiple colorectal adenoma patients. J Surg Oncol 2007; 95:499.
  145. Nielsen M, van Steenbergen LN, Jones N, et al. Survival of MUTYH-associated polyposis patients with colorectal cancer and matched control colorectal cancer patients. J Natl Cancer Inst 2010; 102:1724.
  146. Gupta RA, Brockman JA, Sarraf P, et al. Target genes of peroxisome proliferator-activated receptor gamma in colorectal cancer cells. J Biol Chem 2001; 276:29681.
  147. He TC, Chan TA, Vogelstein B, Kinzler KW. PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 1999; 99:335.
  148. Yang WL, Frucht H. Activation of the PPAR pathway induces apoptosis and COX-2 inhibition in HT-29 human colon cancer cells. Carcinogenesis 2001; 22:1379.
  149. Dobbie Z, Muller PY, Heinimann K, et al. Expression of COX-2 and Wnt pathway genes in adenomas of familial adenomatous polyposis patients treated with meloxicam. Anticancer Res 2002; 22:2215.
  150. Gupta RA, Tan J, Krause WF, et al. Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. Proc Natl Acad Sci U S A 2000; 97:13275.
  151. Sarraf P, Mueller E, Smith WM, et al. Loss-of-function mutations in PPAR gamma associated with human colon cancer. Mol Cell 1999; 3:799.