Skip to main content
SpringerLink
Log in

Molecular Mechanisms of Colorectal Carcinogenesis

  • Chapter
  • First Online:
Molecular Pathogenesis of Colorectal Cancer

Abstract

Colorectal cancer (CRC) presents in three major forms: inherited, sporadic, and familial. Although the mechanisms underlying familial CRC are poorly understood, a large body of evidence suggests that inherited and sporadic CRC are caused by sequential genetic and molecular events. There are three distinct pathways of CRC pathogenesis: the chromosomal instability pathway (CIN), the microsatellite instability pathway (MSI), and the serrated pathway. The majority of CRCs arise from the CIN pathway, which is characterized by defects in chromosomal segregation, telomere stability, and the DNA damage response. Microsatellite instability derives from the loss of DNA mismatch repair and is found in about 15 % of all CRCs, 3 % of which are associated with Lynch syndrome. The serrated pathway, recognized only in the last 15 years, describes the progression of serrated polyps to CRC. The goal of this chapter is to discuss the key genetic and molecular elements of each pathway from a historical perspective and to describe the relevance of this knowledge to the care of patients with CRC.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahrendt SA, Decker PA, Doffek K et al (2000) Microsatellite instability at selected tetranucleotide repeats is associated with p53 mutations in non-small cell lung cancer. Cancer Res 60(9):2488–2491

    PubMed  CAS  Google Scholar 

  • Akhoondi S, Sun D, von der Lehr N et al (2007) FBXW7/hCDC4 is a general tumor suppressor in human cancer. Cancer Res 67(19):9006–9012

    Article  PubMed  CAS  Google Scholar 

  • Albertini RJ, Nicklas JA, O’Neill JP, Robison SH (1990) In vivo somatic mutations in humans: measurement and analysis. Annu Rev Genet 24:305–326

    Article  PubMed  CAS  Google Scholar 

  • Aoki K, Aoki M, Sugai M et al (2007) Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells. Oncogene 26(24):3511–3520

    Article  PubMed  CAS  Google Scholar 

  • Arain MA, Sawhney M, Sheikh S et al (2010) CIMP status of interval colon cancers: another piece to the puzzle. Am J Gastroenterol 105(5):1189–1195

    Article  PubMed  Google Scholar 

  • Arber N, Eagle CJ, Spicak J et al (2006) Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 355(9):885–895

    Article  PubMed  CAS  Google Scholar 

  • Barbie DA, Tamayo P, Boehm JS et al (2009) Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462(7269):108–112

    Article  PubMed  CAS  Google Scholar 

  • Bardelli A, Cahill DP, Lederer G et al (2001) Carcinogen-specific induction of genetic instability. Proc Natl Acad Sci U S A 98(10):5770–5775

    Article  PubMed  CAS  Google Scholar 

  • Bardi G, Parada LA, Bomme L et al (1997) Cytogenetic comparisons of synchronous carcinomas and polyps in patients with colorectal cancer. Br J Cancer 76(6):765–769

    Article  PubMed  CAS  Google Scholar 

  • Baron JA, Sandler RS, Bresalier RS et al (2006) A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology 131(6):1674–1682

    Article  PubMed  CAS  Google Scholar 

  • Bassing CH, Suh H, Ferguson DO et al (2003) Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114(3):359–370

    Article  PubMed  CAS  Google Scholar 

  • Baxter NN, Goldwasser MA, Paszat LF, Saskin R, Urbach DR, Rabeneck L (2009) Association of colonoscopy and death from colorectal cancer. Ann Intern Med 150(1):1–8

    Article  PubMed  Google Scholar 

  • Benatti P, Gafà R, Barana D et al (2005) Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res 11(23):8332–8340

    Article  PubMed  CAS  Google Scholar 

  • Bertagnolli MM, Eagle CJ, Zauber AG et al (2006) Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 355(9):873–884

    Article  PubMed  CAS  Google Scholar 

  • Bertagnolli MM, Niedzwiecki D, Compton CC et al (2009) 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 27(11):1814–1821

    Article  PubMed  CAS  Google Scholar 

  • Bhattacharyya NP, Skandalis A, Ganesh A, Groden J, Meuth M (1994) Mutator phenotypes in human colorectal carcinoma cell lines. Proc Natl Acad Sci U S A 91(14):6319–6323

    Article  PubMed  CAS  Google Scholar 

  • Bird AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321(6067):209–213

    Article  PubMed  CAS  Google Scholar 

  • Blake C, Tsao J-L, Wu A, Shibata D (2001) Stepwise deletions of PolyA sequences in mismatch repair-deficient colorectal cancers. Am J Pathol 158(5):1867–1870

    Article  PubMed  CAS  Google Scholar 

  • Boland CR, Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138(6):2073–2087.e3

    Article  PubMed  CAS  Google Scholar 

  • Boland CR, Thibodeau SN, Hamilton SR et al (1998) 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 58(22):5248–5257

    PubMed  CAS  Google Scholar 

  • Bomme L, Bardi G, Pandis N, Fenger C, Kronborg O, Heim S (1994) Clonal karyotypic abnormalities in colorectal adenomas: clues to the early genetic events in the adenoma-carcinoma sequence. Genes Chromosomes Cancer 10(3):190–196

    Article  PubMed  CAS  Google Scholar 

  • Bondi J, Husdal A, Bukholm G, Nesland JM, Bakka A, Bukholm IRK (2005) Expression and gene amplification of primary (A, B1, D1, D3, and E) and secondary (C and H) cyclins in colon adenocarcinomas and correlation with patient outcome. J Clin Pathol 58(5):509–514

    Article  PubMed  CAS  Google Scholar 

  • Boparai KS, Dekker E, Van Eeden S et al (2008) Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis. Gastroenterology 135(6):2014–2018

    Article  PubMed  CAS  Google Scholar 

  • Boparai KS, Mathus-Vliegen EMH, Koornstra JJ et al (2010) Increased colorectal cancer risk during follow-up in patients with hyperplastic polyposis syndrome: a multicentre cohort study. Gut 59(8):1094–1100

    Article  PubMed  Google Scholar 

  • Boveri T (2008) Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris. J Cell Sci 121(Suppl 1):1–84

    Article  PubMed  Google Scholar 

  • Brenner H, Hoffmeister M, Arndt V, Stegmaier C, Altenhofen L, Haug U (2010) Protection from right- and left-sided colorectal neoplasms after colonoscopy: population-based study. J Natl Cancer Inst 102(2):89–95

    Article  PubMed  Google Scholar 

  • Brentnall TA, Crispin DA, Bronner MP et al (1996) Microsatellite instability in nonneoplastic mucosa from patients with chronic ulcerative colitis. Cancer Res 56(6):1237–1240

    PubMed  CAS  Google Scholar 

  • Bresalier RS, Sandler RS, Quan H et al (2005) Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352(11):1092–1102

    Article  PubMed  CAS  Google Scholar 

  • Bressler B, Paszat LF, Vinden C, Li C, He J, Rabeneck L (2004) Colonoscopic miss rates for right-sided colon cancer: a population-based analysis. Gastroenterology 127(2):452–456

    Article  PubMed  Google Scholar 

  • Buchanan DD, Sweet K, Drini M et al (2010) Phenotypic diversity in patients with multiple serrated polyps: a genetics clinic study. Int J Colorectal Dis 25(6):703–712

    Article  PubMed  Google Scholar 

  • Campisi J (2005) Suppressing cancer: the importance of being senescent. Science 309(5736):886–887

    Article  PubMed  CAS  Google Scholar 

  • Camps J, Nguyen QT, Padilla-Nash HM et al (2009) Integrative genomics reveals mechanisms of copy number alterations responsible for transcriptional deregulation in colorectal cancer. Genes Chromosomes Cancer 48(11):1002–1017

    Article  PubMed  CAS  Google Scholar 

  • Cardoso J, Molenaar L, De Menezes RX et al (2006) Chromosomal instability in MYH- and APC-mutant adenomatous polyps. Cancer Res 66(5):2514–2519

    Article  PubMed  CAS  Google Scholar 

  • Carragher LAS, Snell KR, Giblett SM et al (2010) V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a. EMBO Mol Med 2(11):458–471

    Article  PubMed  CAS  Google Scholar 

  • Castets M, Broutier L, Molin Y et al (2011) DCC constrains tumour progression via its dependence receptor activity. Nature 482(7386):534–537, Available from: http://www.ncbi.nlm.nih.gov/pubmed/22158121

    Article  PubMed  CAS  Google Scholar 

  • Castillo A, Morse HC III, Godfrey VL, Naeem R, Justice MJ (2007) Overexpression of Eg5 causes genomic instability and tumor formation in mice. Cancer Res 67(21):10138–10147

    Article  PubMed  CAS  Google Scholar 

  • Celeste A, Difilippantonio S, Difilippantonio MJ et al (2003) H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114(3):371–383

    Article  PubMed  CAS  Google Scholar 

  • Chadeneau C, Hay K, Hirte HW, Gallinger S, Bacchetti S (1995) Telomerase activity associated with acquisition of malignancy in human colorectal cancer. Cancer Res 55(12):2533–2536

    PubMed  CAS  Google Scholar 

  • Chalhoub N, Baker SJ (2009) PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 4:127–150

    Article  PubMed  CAS  Google Scholar 

  • Chan AT, Giovannucci EL (2010) Primary prevention of colorectal cancer. Gastroenterology 138(6):2029–2043.e10

    Article  PubMed  CAS  Google Scholar 

  • Chan AO-O, Issa J-PJ, Morris JS, Hamilton SR, Rashid A (2002) Concordant CpG island methylation in hyperplastic polyposis. Am J Pathol 160(2):529–536

    Article  PubMed  CAS  Google Scholar 

  • Chang CL, Marra G, Chauhan DP et al (2002) Oxidative stress inactivates the human DNA mismatch repair system. Am J Physiol Cell Physiol 283(1):C148–C154

    Article  PubMed  CAS  Google Scholar 

  • Chen Z, Trotman LC, Shaffer D et al (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436(7051):725–730

    Article  PubMed  CAS  Google Scholar 

  • Chirieac LR, Shen L, Catalano PJ, Issa J-P, Hamilton SR (2005) Phenotype of microsatellite-stable colorectal carcinomas with CpG island methylation. Am J Surg Pathol 29(4):429–436

    Article  PubMed  Google Scholar 

  • Chow E, Lipton L, Lynch E et al (2006) Hyperplastic polyposis syndrome: phenotypic presentations and the role of MBD4 and MYH. Gastroenterology 131(1):30–39

    Article  PubMed  CAS  Google Scholar 

  • Cianciulli A, Cosimelli M, Marzano R et al (2004) Genetic and pathologic significance of 1p, 17p, and 18q aneusomy and the ERBB2 gene in colorectal cancer and related normal colonic mucosa. Cancer Genet Cytogenet 151(1):52–59

    Article  PubMed  CAS  Google Scholar 

  • Cole BF, Logan RF, Halabi S et al (2009) Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. J Natl Cancer Inst 101(4):256–266

    Article  PubMed  CAS  Google Scholar 

  • Cottrell S, Bicknell D, Kaklamanis L, Bodmer WF (1992) Molecular analysis of APC mutations in familial adenomatous polyposis and sporadic colon carcinomas. Lancet 340(8820):626–630

    Article  PubMed  CAS  Google Scholar 

  • Cuilliere-Dartigues P, El-Bchiri J, Krimi A et al (2006) TCF-4 isoforms absent in TCF-4 mutated MSI-H colorectal cancer cells colocalize with nuclear CtBP and repress TCF-4-mediated transcription. Oncogene 25(32):4441–4448

    Article  PubMed  CAS  Google Scholar 

  • Curfman GD, Morrissey S, Drazen JM (2005) Expression of concern: Bombardier et al., “Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis”, N Engl J Med 2000;343:1520–8. N Engl J Med 353(26):2813–2814

    Article  PubMed  CAS  Google Scholar 

  • Davies H, Bignell GR, Cox C et al (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954

    Article  PubMed  CAS  Google Scholar 

  • de Vogel S, Weijenberg MP, Herman JG et al (2009) MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer: indications for distinct pathways and sequence of events. Ann Oncol 20(7):1216–1222

    Article  PubMed  Google Scholar 

  • de Vos tot Nederveen Cappel WH, Meulenbeld HJ, Kleibeuker JH et al (2004) Survival after adjuvant 5-FU treatment for stage III colon cancer in hereditary nonpolyposis colorectal cancer. Int J Cancer 109(3):468–471

    Article  PubMed  CAS  Google Scholar 

  • Des Guetz G, Lecaille C, Mariani P et al (2010) Prognostic impact of microsatellite instability in colorectal cancer patients treated with adjuvant FOLFOX. Anticancer Res 30(10):4297–4301

    PubMed  CAS  Google Scholar 

  • Di Vinci A, Infusini E, Peveri C, Risio M, Rossini FP, Giaretti W (1996) Deletions at chromosome 1p by fluorescence in situ hybridization are an early event in human colorectal tumorigenesis. Gastroenterology 111(1):102–107

    Article  PubMed  Google Scholar 

  • Diep CB, Thorstensen L, Meling GI, Skovlund E, Rognum TO, Lothe RA (2003) Genetic tumor markers with prognostic impact in Dukes’ stages B and C colorectal cancer patients. J Clin Oncol 21(5):820–829

    Article  PubMed  Google Scholar 

  • Dotan E, Meropol NJ, Zhu F et al (2012) Relationship of increased aurora kinase A gene copy number, prognosis and response to chemotherapy in patients with metastatic colorectal cancer. Br J Cancer 106(4):748–755, Available from: http://www.ncbi.nlm.nih.gov/pubmed/22240781

    Article  PubMed  CAS  Google Scholar 

  • Duesberg P, Fabarius A, Hehlmann R (2004) Aneuploidy, the primary cause of the multilateral genomic instability of neoplastic and preneoplastic cells. IUBMB Life 56(2):65–81

    Article  PubMed  CAS  Google Scholar 

  • East JE, Saunders BP, Jass JR (2008) Sporadic and syndromic hyperplastic polyps and serrated adenomas of the colon: classification, molecular genetics, natural history, and clinical management. Gastroenterol Clin North Am 37(1):25–46, v

    Google Scholar 

  • Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, Dubois RN (1994) Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107(4):1183–1188

    PubMed  CAS  Google Scholar 

  • Eilers M, Eisenman RN (2008) Myc’s broad reach. Genes Dev 22(20):2755–2766

    Article  PubMed  CAS  Google Scholar 

  • Elsaleh H, Joseph D, Grieu F, Zeps N, Spry N, Iacopetta B (2000) Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 355(9217):1745–1750

    Article  PubMed  CAS  Google Scholar 

  • Engelhardt M, Drullinsky P, Guillem J, Moore MAS (1997) Telomerase and telomere length in the development and progression of premalignant lesions to colorectal cancer. Clin Cancer Res 3(11):1931–1941

    PubMed  CAS  Google Scholar 

  • English DR, Young JP, Simpson JA et al (2008) Ethnicity and risk for colorectal cancers showing somatic BRAF V600E mutation or CpG island methylator phenotype. Cancer Epidemiol Biomarkers Prev 17(7):1774–1780

    Article  PubMed  CAS  Google Scholar 

  • Esteller M, Sparks A, Toyota M et al (2000) Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer. Cancer Res 60(16):4366–4371

    PubMed  CAS  Google Scholar 

  • Fallik D, Borrini F, Boige V et al (2003) Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer. Cancer Res 63(18):5738–5744

    PubMed  CAS  Google Scholar 

  • Farrar WD, Sawhney MS, Nelson DB, Lederle FA, Bond JH (2006) Colorectal cancers found after a complete colonoscopy. Clin Gastroenterol Hepatol 4(10):1259–1264

    Article  PubMed  Google Scholar 

  • Fazeli A, Dickinson SL, Hermiston ML et al (1997) Phenotype of mice lacking functional deleted in colorectal cancer (Dec) gene. Nature 386(6627):796–804

    Article  PubMed  CAS  Google Scholar 

  • Fearon ER (2011) Molecular genetics of colorectal cancer. Annu Rev Pathol 6:479–507

    Article  PubMed  CAS  Google Scholar 

  • Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767

    Article  PubMed  CAS  Google Scholar 

  • Fearon ER, Cho KR, Nigro JM et al (1990) Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247(4938):49–56

    Article  PubMed  CAS  Google Scholar 

  • Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M (1988) Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res 48(5):1159–1161

    PubMed  CAS  Google Scholar 

  • Ferrández A, Samowitz W, DiSario JA, Burt RW (2004) Phenotypic characteristics and risk of cancer development in hyperplastic polyposis: case series and literature review. Am J Gastroenterol 99(10):2012–2018

    Article  PubMed  Google Scholar 

  • Firestein R, Hahn WC (2009) Revving the throttle on an oncogene: CDK8 takes the driver seat. Cancer Res 69(20):7899–7901

    Article  PubMed  CAS  Google Scholar 

  • Firestein R, Bass AJ, Kim SY et al (2008) CDK8 is a colorectal cancer oncogene that regulates [bgr]-catenin activity. Nature 455(7212):547–551

    Article  PubMed  CAS  Google Scholar 

  • Firestein R, Shima K, Nosho K et al (2010) CDK8 expression in 470 colorectal cancers in relation to β-catenin activation, other molecular alterations and patient survival. Int J Cancer 126(12):2863–2873

    PubMed  CAS  Google Scholar 

  • Fodde R, Kuipers J, Rosenberg C et al (2001) Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 3(4):433–438

    Article  PubMed  CAS  Google Scholar 

  • Fujita K, Yamamoto H, Matsumoto T et al (2011) Sessile serrated adenoma with early neoplastic progression: a clinicopathologic and molecular study. Am J Surg Pathol 35(2):295–304

    Article  PubMed  Google Scholar 

  • Ganem NJ, Godinho SA, Pellman D (2009) A mechanism linking extra centrosomes to chromosomal instability. Nature 460(7252):278–282

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Albeniz X, Chan AT (2011) Aspirin for the prevention of colorectal cancer. Best Pract Res Clin Gastroenterol 25(4–5):461–472

    Article  PubMed  CAS  Google Scholar 

  • Gasche C, Chang CL, Rhees J, Goel A, Boland CR (2001) Oxidative stress increases frameshift mutations in human colorectal cancer cells. Cancer Res 61(20):7444–7448

    PubMed  CAS  Google Scholar 

  • Gertler R, Rosenberg R, Stricker D et al (2004) Telomere length and human telomerase reverse transcriptase expression as markers for progression and prognosis of colorectal carcinoma. J Clin Oncol 22(10):1807–1814

    Article  PubMed  CAS  Google Scholar 

  • Glazer E, Golla V, Forman R, Zhu H, Levi G, Bodenheimer HC Jr (2008) Serrated adenoma is a risk factor for subsequent adenomatous polyps. Dig Dis Sci 53(8):2204–2207

    Article  PubMed  Google Scholar 

  • Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP (1985) Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 228(4696):187–190

    Article  PubMed  CAS  Google Scholar 

  • Grady WM, Myeroff LL, Swinler SE et al (1999) Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. Cancer Res 59(2):320–324

    PubMed  CAS  Google Scholar 

  • Hadjihannas MV, Brückner M, Jerchow B, Birchmeier W, Dietmaier W, Behrens J (2006) Aberrant Wnt/β-catenin signaling can induce chromosomal instability in colon cancer. Proc Natl Acad Sci U S A 103(28):10747–10752

    Article  PubMed  CAS  Google Scholar 

  • Hahn E, Kraus S, Arber N (2010) Role of cyclooxygenase-2 in pathogenesis and prevention of colorectal cancer. Dig Dis 28(4–5):585–589

    Article  PubMed  Google Scholar 

  • Haigis KM, Kendall KR, Wang Y et al (2008) Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet 40(5):600–608

    Article  PubMed  CAS  Google Scholar 

  • Hampel H, Frankel WL, Martin E et al (2005) Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352(18):1851–1860

    Article  PubMed  CAS  Google Scholar 

  • Hawkins NJ, Ward RL (2001) Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas. J Natl Cancer Inst 93(17):1307–1313

    Article  PubMed  CAS  Google Scholar 

  • Hawkins N, Norrie M, Cheong K et al (2002) CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology 122(5):1376–1387

    Article  PubMed  CAS  Google Scholar 

  • He T-C, Sparks AB, Rago C et al (1998) Identification of c-MYC as a target of the APC pathway. Science 281(5382):1509–1512

    Article  PubMed  CAS  Google Scholar 

  • Herz C, Schlürmann F, Batarello D et al (2011) Occurrence of Aurora A positive multipolar mitoses in distinct molecular classes of colorectal carcinomas and effect of Aurora A inhibition. Mol Carcinog 51(9):696–710, Available from: http://www.ncbi.nlm.nih.gov/pubmed/21739483

    Article  PubMed  CAS  Google Scholar 

  • Hezel AF, Bardeesy N (2008) LKB1; linking cell structure and tumor suppression. Oncogene 27(55):6908–6919

    Article  PubMed  CAS  Google Scholar 

  • Higuchi T, Sugihara K, Jass JR (2005) Demographic and pathological characteristics of serrated polyps of colorectum. Histopathology 47(1):32–40

    Article  PubMed  CAS  Google Scholar 

  • Hiraoka S, Kato J, Fujiki S, et al (2010) The presence of large serrated polyps increases risk for colorectal cancer. Gastroenterology 139(5):1503–1510, 1510.e1–3

    Google Scholar 

  • Höglund M, Gisselsson D, Hansen GB, Säll T, Mitelman F, Nilbert M (2002) Dissecting karyotypic patterns in colorectal tumors: two distinct but overlapping pathways in the adenoma-carcinoma transition. Cancer Res 62(20):5939–5946

    PubMed  Google Scholar 

  • Hornick JL, Odze RD (2009) Polyps of the large intestine, 2nd edn. Elsevier, Philadelphia

    Google Scholar 

  • Hung KE, Maricevich MA, Richard LG et al (2010) Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment. Proc Natl Acad Sci U S A 107(4):1565–1570

    Article  PubMed  CAS  Google Scholar 

  • Imperiale TF, Wagner DR, Lin CY, Larkin GN, Rogge JD, Ransohoff DF (2002) Results of screening colonoscopy among persons 40 to 49 years of age. N Engl J Med 346(23):1781–1785

    Article  PubMed  Google Scholar 

  • Infante JR, Kurzrock R, Spratlin J et al (2012) A phase I study to assess the safety, tolerability, and pharmacokinetics of AZD4877, an intravenous Eg5 inhibitor in patients with advanced solid tumors. Cancer Chemother Pharmacol 69(1):165–172

    Article  PubMed  CAS  Google Scholar 

  • Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363(6429):558–561

    Article  PubMed  CAS  Google Scholar 

  • Iwatsuki M, Mimori K, Ishii H et al (2010) Loss of FBXW7, a cell cycle regulating gene, in colorectal cancer: clinical significance. Int J Cancer 126(8):1828–1837

    PubMed  CAS  Google Scholar 

  • Jani JP, Arcari J, Bernardo V et al (2010) PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy. Mol Cancer Ther 9(4):883–894

    Article  PubMed  CAS  Google Scholar 

  • Jaramillo E, Tamura S, Mitomi H (2005) Endoscopic appearance of serrated adenomas in the colon. Endoscopy 37(3):254–260

    Article  PubMed  CAS  Google Scholar 

  • Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50(1):113–130

    Article  PubMed  CAS  Google Scholar 

  • Jass JR, Iino H, Ruszkiewicz A et al (2000) Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum. Gut 47(1):43–49

    Article  PubMed  CAS  Google Scholar 

  • Jass JR, Baker K, Zlobec I et al (2006) Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a “fusion” pathway to colorectal cancer. Histopathology 49(2):121–131

    Article  PubMed  CAS  Google Scholar 

  • Jeevaratnam P, Cottier DS, Browett PJ, Van De Water NS, Pokos V, Jass JR (1996) Familial giant hyperplastic polyposis predisposing to colorectal cancer: a new hereditary bowel cancer syndrome. J Pathol 179(1):20–25

    Article  PubMed  CAS  Google Scholar 

  • Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90

    Article  PubMed  Google Scholar 

  • Ji W, Hernandez R, Zhang XY et al (1997) DNA demethylation and pericentromeric rearrangements of chromosome 1. Mutat Res 379(1):33–41

    Article  PubMed  CAS  Google Scholar 

  • Ji B-T, Weissfeld JL, Chow W-H, Huang W-Y, Schoen RE, Hayes RB (2006) Tobacco smoking and colorectal hyperplastic and adenomatous polyps. Cancer Epidemiol Biomarkers Prev 15(5):897–901

    Article  PubMed  CAS  Google Scholar 

  • Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21(2):163–167

    Article  PubMed  CAS  Google Scholar 

  • Jover R, Zapater P, Castells A et al (2006) Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer. Gut 55(6):848–855

    Article  PubMed  CAS  Google Scholar 

  • Jung B, Smith EJ, Doctolero RT et al (2006) Influence of target gene mutations on survival, stage and histology in sporadic microsatellite unstable colon cancers. Int J Cancer 118(10): 2509–2513

    Article  PubMed  CAS  Google Scholar 

  • Jung BH, Beck SE, Cabral J et al (2007) Activin type 2 receptor restoration in MSI-H colon cancer suppresses growth and enhances migration with activin. Gastroenterology 132(2):633–644

    Article  PubMed  CAS  Google Scholar 

  • Kakar S, Burgart LJ, Thibodeau SN et al (2003) Frequency of loss of hMLH1 expression in colorectal carcinoma increases with advancing age. Cancer 97(6):1421–1427

    Article  PubMed  CAS  Google Scholar 

  • Kambara T, Simms LA, Whitehall VLJ et al (2004) BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53(8):1137–1144

    Article  PubMed  CAS  Google Scholar 

  • Kane MF, Loda M, Gaida GM et al (1997) 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 57(5):808–811

    PubMed  CAS  Google Scholar 

  • Kaplan KB, Burds AA, Swedlow JR, Bekir SS, Sorger PK, Näthke IS (2001) A role for the adenomatous polyposis coli protein in chromosome segregation. Nat Cell Biol 3(4):429–432

    Article  PubMed  CAS  Google Scholar 

  • Karapetis CS, Khambata-Ford S, Jonker DJ et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359(17):1757–1765

    Article  PubMed  CAS  Google Scholar 

  • Katayama H, Ota T, Jisaki F et al (1999a) Mitotic kinase expression and colorectal cancer progression. J Natl Cancer Inst 91(13):1160–1162

    Article  PubMed  CAS  Google Scholar 

  • Katayama S, Shiota G, Oshimura M, Kawasaki H (1999b) Clinical usefulness of telomerase activity and telomere length in the preoperative diagnosis of gastric and colorectal cancer. J Cancer Res Clin Oncol 125(7):405–410

    Article  PubMed  CAS  Google Scholar 

  • Khanna KK, Jackson SP (2001) DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 27(3):247–254

    Article  PubMed  CAS  Google Scholar 

  • Kim GP, Colangelo LH, Wieand HS et al (2007) Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol 25(7):767–772

    Article  PubMed  CAS  Google Scholar 

  • Kim MS, Lee J, Sidransky D (2010a) DNA methylation markers in colorectal cancer. Cancer Metastasis Rev 29(1):181–206

    Article  PubMed  CAS  Google Scholar 

  • Kim K-M, Lee EJ, Kim Y-H, Chang DK, Odze RD (2010b) KRAS mutations in traditional serrated adenomas from Korea herald an aggressive phenotype. Am J Surg Pathol 34(5):667–675

    PubMed  Google Scholar 

  • Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87(2):159–170

    Article  PubMed  CAS  Google Scholar 

  • Kirley SD, D’Apuzzo M, Lauwers GY, Graeme-Cook F, Chung DC, Zukerberg LR (2005) The cables gene on chromosome 18Q regulates colon cancer progression in vivo. Cancer Biol Ther 4(8):861–863

    Article  PubMed  CAS  Google Scholar 

  • Lambert R, Kudo SE, Vieth M et al (2009) Pragmatic classification of superficial neoplastic colorectal lesions. Gastrointest Endosc 70(6):1182–1199

    Article  PubMed  Google Scholar 

  • Lammi L, Arte S, Somer M et al (2004) Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet 74(5):1043–1050

    Article  PubMed  CAS  Google Scholar 

  • Lanza G, Gafà R, Santini A, Maestri I, Guerzoni L, Cavazzini L (2006) Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol 24(15):2359–2367

    Article  PubMed  CAS  Google Scholar 

  • Leary RJ, Lin JC, Cummins J et al (2008) Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers. Proc Natl Acad Sci 105(42):16224–16229

    Article  PubMed  CAS  Google Scholar 

  • Lee S-H, Chang DK, Goel A et al (2003) Microsatellite instability and suppressed DNA repair enzyme expression in rheumatoid arthritis. J Immunol 170(4):2214–2220

    PubMed  CAS  Google Scholar 

  • Leggett B, Whitehall V (2010) Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology 138(6):2088–2100

    Article  PubMed  CAS  Google Scholar 

  • Leggett BA, Cornwell M, Thomas LR et al (1997) Characteristics of metachronous colorectal carcinoma occurring despite colonoscopic surveillance. Dis Colon Rectum 40(5):603–608

    Article  PubMed  CAS  Google Scholar 

  • Leggett BA, Devereaux B, Biden K, Searle J, Young J, Jass J (2001) Hyperplastic polyposis: association with colorectal cancer. Am J Surg Pathol 25(2):177–184

    Article  PubMed  CAS  Google Scholar 

  • Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386(6625):623–627

    Article  PubMed  CAS  Google Scholar 

  • Lengauer C, Kinzler KW, Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396(6712):643–649

    Article  PubMed  CAS  Google Scholar 

  • Leslie A, Carey FA, Pratt NR, Steele RJC (2002) The colorectal adenoma-carcinoma sequence. Br J Surg 89(7):845–860

    Article  PubMed  CAS  Google Scholar 

  • Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88(3):323–331

    Article  PubMed  CAS  Google Scholar 

  • Li D, Jin C, McCulloch C et al (2009) Association of large serrated polyps with synchronous advanced colorectal neoplasia. Am J Gastroenterol 104(3):695–702

    Article  PubMed  Google Scholar 

  • Li H-T, Lu Y-Y, An Y-X, Wang X, Zhao Q-C (2011) KRAS, BRAF and PIK3CA mutations in human colorectal cancer: relationship with metastatic colorectal cancer. Oncol Rep 25(6):1691–1697, Available from: http://www.ncbi.nlm.nih.gov/pubmed/21424126

    PubMed  CAS  Google Scholar 

  • Loeb LA, Loeb KR, Anderson JP (2003) Multiple mutations and cancer. Proc Natl Acad Sci U S A 100(3):776–781

    Article  PubMed  CAS  Google Scholar 

  • Longacre TA, Fenoglio-Preiser CM (1990) Mixed hyperplastic adenomatous polyps/serrated adenomas. A distinct form of colorectal neoplasia. Am J Surg Pathol 14(6):524–537

    Article  PubMed  CAS  Google Scholar 

  • Lothe RA, Andersen SN, Hofstad B et al (1995) Deletion of 1p loci and microsatellite instability in colorectal polyps. Genes Chromosomes Cancer 14(3):182–188

    Article  PubMed  CAS  Google Scholar 

  • Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348(10):919–932

    Article  PubMed  CAS  Google Scholar 

  • Mäkinen MJ, George SM, Jernvall P, Mäkelä J, Vihko P, Karttunen TJ (2001) Colorectal carcinoma associated with serrated adenoma—prevalence, histological features, and prognosis. J Pathol 193(3):286–294

    Article  PubMed  Google Scholar 

  • Malumbres M, Barbacid M (2003) RAS oncogenes: the first 30 years. Nat Rev Cancer 3(6):459–465

    Article  PubMed  CAS  Google Scholar 

  • Mann B, Gelos M, Siedow A et al (1999) Target genes of β-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. Proc Natl Acad Sci U S A 96(4):1603–1608

    Article  PubMed  CAS  Google Scholar 

  • Markowitz S, Wang J, Myeroff L et al (1995) Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268(5215):1336–1338

    Article  PubMed  CAS  Google Scholar 

  • Mehlen P, Fearon ER (2004) Role of the dependence receptor DCC in colorectal cancer pathogenesis. J Clin Oncol 22(16):3420–3428

    Article  PubMed  CAS  Google Scholar 

  • Mehlen P, Rabizadeh S, Snipas SJ, Assa-Munt N, Salvesen GS, Bredesen DE (1998) The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 395(6704):801–804

    Article  PubMed  CAS  Google Scholar 

  • Merg A, Howe JR (2004) Genetic conditions associated with intestinal juvenile polyps. Am J Med Genet C Semin Med Genet 129C(1):44–55

    Article  PubMed  Google Scholar 

  • Meylan E, Dooley AL, Feldser DM et al (2009) Requirement for NF-B signalling in a mouse model of lung adenocarcinoma. Nature 462(7269):104–107

    Article  PubMed  CAS  Google Scholar 

  • Minoo P, Jass JR (2006) Senescence and serration: a new twist to an old tale. J Pathol 210(2):137–140

    Article  PubMed  CAS  Google Scholar 

  • Minoo P, Baker K, Goswami R et al (2006) Extensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis. Gut 55(10):1467–1474

    Article  PubMed  CAS  Google Scholar 

  • Mirabelli-Primdahl L, Gryfe R, Kim H et al (1999) Beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway. Cancer Res 59(14):3346–3351

    PubMed  CAS  Google Scholar 

  • Miyaki M, Konishi M, Kikuchi-Yanoshita R et al (1994) Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res 54(11):3011–3020

    PubMed  CAS  Google Scholar 

  • Miyaki M, Iijima T, Kimura J et al (1999) Frequent mutation of beta-catenin and APC genes in primary colorectal tumors from patients with hereditary nonpolyposis colorectal cancer. Cancer Res 59(18):4506–4509

    PubMed  CAS  Google Scholar 

  • Miyoshi Y, Nagase H, Ando H et al (1992) Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet 1(4):229–233

    Article  PubMed  CAS  Google Scholar 

  • Morson B (1974) President’s address. The polyp-cancer sequence in the large bowel. Proc R Soc Med 67(6 Pt 1):451–457

    PubMed  CAS  Google Scholar 

  • Munro AJ, Lain S, Lane DP (2005) P53 abnormalities and outcomes in colorectal cancer: a systematic review. Br J Cancer 92(3):434–444

    PubMed  CAS  Google Scholar 

  • Nakamura K-I, Furugori E, Esaki Y et al (2000) Correlation of telomere lengths in normal and cancers tissue in the large bowel. Cancer Lett 158(2):179–184

    Article  PubMed  CAS  Google Scholar 

  • Negrini S, Gorgoulis VG, Halazonetis TD (2010) Genomic instability—an evolving hallmark of cancer. Nat Rev Mol Cell Biol 11(3):220–228

    Article  PubMed  CAS  Google Scholar 

  • Nowak MA, Komarova NL, Sengupta A et al (2002) The role of chromosomal instability in tumor initiation. Proc Natl Acad Sci U S A 99(25):16226–16231

    Article  PubMed  CAS  Google Scholar 

  • O’Brien MJ (2007) Hyperplastic and serrated polyps of the colorectum. Gastroenterol Clin North Am 36(4):947–968, viii

    Google Scholar 

  • O’Brien MJ, Yang S, Clebanoff JL et al (2004) Hyperplastic (serrated) polyps of the colorectum: relationship of CpG island methylator phenotype and K-ras mutation to location and histologic subtype. Am J Surg Pathol 28(4):423–434

    Article  PubMed  Google Scholar 

  • O’Brien MJ, Yang S, Mack C et al (2006) Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am J Surg Pathol 30(12):1491–1501

    Article  PubMed  Google Scholar 

  • Ogino S, Kawasaki T, Kirkner GJ, Loda M, Fuchs CS (2006a) CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations. J Mol Diagn 8(5):582–588

    Article  PubMed  CAS  Google Scholar 

  • Ogino S, Odze RD, Kawasaki T et al (2006b) Correlation of pathologic features with CpG island methylator phenotype (CIMP) by quantitative DNA methylation analysis in colorectal carcinoma. Am J Surg Pathol 30(9):1175–1183

    Article  PubMed  Google Scholar 

  • Ogino S, Kawasaki T, Kirkner GJ, Suemoto Y, Meyerhardt JA, Fuchs CS (2007) Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer. Gut 56(11):1564–1571

    Article  PubMed  CAS  Google Scholar 

  • Ogino S, Nosho K, Kirkner GJ et al (2009a) CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 58(1):90–96

    Article  PubMed  Google Scholar 

  • Ogino S, Nosho K, Irahara N et al (2009b) Prognostic significance and molecular associations of 18q loss of heterozygosity: a cohort study of microsatellite stable colorectal cancers. J Clin Oncol 27(27):4591–4598

    Article  PubMed  Google Scholar 

  • Ogino S, Nosho K, Irahara N et al (2009c) Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin Cancer Res 15(20):6412–6420

    Article  PubMed  CAS  Google Scholar 

  • Ogino S, Shima K, Meyerhardt J et al (2011) Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803. Clin Cancer Res 18(3):890–900, Available from: http://www.ncbi.nlm.nih.gov/pubmed/22147942

    Article  PubMed  Google Scholar 

  • Oshima M, Murai N, Kargman S et al (2001) Chemoprevention of intestinal polyposis in the ApcΔ716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. Cancer Res 61(4):1733–1740

    PubMed  CAS  Google Scholar 

  • Park DY, Sakamoto H, Kirley SD et al (2007) The cables gene on chromosome 18q is silenced by promoter hypermethylation and allelic loss in human colorectal cancer. Am J Pathol 171(5):1509–1519

    Article  CAS  Google Scholar 

  • Peddibhotla S, Lam MH, Gonzalez-Rimbau M, Rosen JM (2009) The DNA-damage effector checkpoint kinase 1 is essential for chromosome segregation and cytokinesis. Proc Natl Acad Sci U S A 106(13):5159–5164

    Article  PubMed  CAS  Google Scholar 

  • Pérez R, Lasa A, Toro DH, Cruz-Correa M, Martinez-Souss J (2010) Relationship between sporadic hyperplastic polyps and colorectal neoplasia in Hispanic veterans. P R Health Sci J 29(4):372–376

    PubMed  Google Scholar 

  • Phillips SM, Banerjea A, Feakins R, Li SR, Bustin SA, Dorudi S (2004) Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br J Surg 91(4):469–475

    Article  PubMed  CAS  Google Scholar 

  • Pino MS, Chung DC (2010) The chromosomal instability pathway in colon cancer. Gastroenterology 138(6):2059–2072

    Article  PubMed  CAS  Google Scholar 

  • Plentz RR, Wiemann SU, Flemming P et al (2003) Telomere shortening of epithelial cells characterises the adenoma-carcinoma transition of human colorectal cancer. Gut 52(9):1304–1307

    Article  PubMed  CAS  Google Scholar 

  • Popat S, Hubner R, Houlston RS (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23(3):609–618

    Article  PubMed  CAS  Google Scholar 

  • Powell SM, Zilz N, Beazer-Barclay Y et al (1992) APC mutations occur early during colorectal tumorigenesis. Nature 359(6392):235–237

    Article  PubMed  CAS  Google Scholar 

  • Pretlow TP, Pretlow TG (2005) Mutant KRAS in aberrant crypt foci (ACF): initiation of colorectal cancer? Biochim Biophys Acta 1756(2):83–96

    PubMed  CAS  Google Scholar 

  • Pruitt K, Der CJ (2001) Ras and Rho regulation of the cell cycle and oncogenesis. Cancer Lett 171(1):1–10

    Article  PubMed  CAS  Google Scholar 

  • Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE (2002) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418(6901):934

    Article  PubMed  CAS  Google Scholar 

  • Rajagopalan H, Jallepalli PV, Rago C et al (2004) Inactivation of hCDC4 can cause chromosomal instability. Nature 428(6978):77–81

    Article  PubMed  CAS  Google Scholar 

  • Rashid A, Houlihan PS, Booker S, Petersen GM, Giardiello FM, Hamilton SR (2000) Phenotypic and molecular characteristics of hyperplastic polyposis. Gastroenterology 119(2):323–332

    Article  PubMed  CAS  Google Scholar 

  • Ribic CM, Sargent DJ, Moore MJ et al (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349(3):247–257

    Article  PubMed  CAS  Google Scholar 

  • Roper J, Richardson MP, Wang WV et al (2011) The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer. PLoS One 6(9):e25132

    Article  PubMed  CAS  Google Scholar 

  • Roschke AV, Glebov OK, Lababidi S, Gehlhaus KS, Weinstein JN, Kirsch IR (2008) Chromosomal instability is associated with higher expression of genes implicated in epithelial-mesenchymal transition, cancer invasiveness, and metastasis and with lower expression of genes involved in cell cycle checkpoints, DNA repair, and chromatin maintenance. Neoplasia 10(11):1222–1230

    PubMed  CAS  Google Scholar 

  • Rubio CA, Stemme S, Jaramillo E, Lindblom A (2006) Hyperplastic polyposis coli syndrome and colorectal carcinoma. Endoscopy 38(3):266–270

    Article  PubMed  CAS  Google Scholar 

  • Ruder EH, Laiyemo AO, Graubard BI, Hollenbeck AR, Schatzkin A, Cross AJ (2011) Non-steroidal anti-inflammatory drugs and colorectal cancer risk in a large, prospective cohort. Am J Gastroenterol 106(7):1340–1350

    Article  PubMed  CAS  Google Scholar 

  • Rudolph KL, Millard M, Bosenberg MW, DePinho RA (2001) Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet 28(2):155–159

    Article  PubMed  CAS  Google Scholar 

  • Russo A, Bazan V, Iacopetta B, Kerr D, Soussi T, Gebbia N (2005) 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 23(30):7518–7528

    Article  PubMed  CAS  Google Scholar 

  • Samowitz WS, Albertsen H, Herrick J et al (2005a) Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 129(3):837–845

    Article  PubMed  CAS  Google Scholar 

  • Samowitz WS, Sweeney C, Herrick J et al (2005b) Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 65(14):6063–6069

    Article  PubMed  CAS  Google Scholar 

  • Samowitz WS, Albertsen H, Sweeney C et al (2006) Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. J Natl Cancer Inst 98(23):1731–1738

    Article  PubMed  CAS  Google Scholar 

  • Samuels Y, Wang Z, Bardelli A et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554

    Article  PubMed  CAS  Google Scholar 

  • Samuels Y, Diaz LA, Schmidt-Kittler O et al (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7(6):561–573

    Article  PubMed  CAS  Google Scholar 

  • Sandmeier D, Benhattar J, Martin P, Bouzourene H (2009) Serrated polyps of the large intestine: a molecular study comparing sessile serrated adenomas and hyperplastic polyps. Histopathology 55(2):206–213

    Article  PubMed  Google Scholar 

  • Sawhney MS, Farrar WD, Gudiseva S et al (2006) Microsatellite instability in interval colon cancers. Gastroenterology 131(6):1700–1705

    Article  PubMed  Google Scholar 

  • Schöffski P, Awada A, Dumez H et al (2012) A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours. Eur J Cancer 48(2):179–186

    Article  PubMed  CAS  Google Scholar 

  • Schreiner MA, Weiss DG, Lieberman DA (2010) Proximal and large hyperplastic and nondysplastic serrated polyps detected by colonoscopy are associated with neoplasia. Gastroenterology 139(5):1497–1502

    Article  PubMed  Google Scholar 

  • Shia J (2008) Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. J Mol Diagn 10(4):293–300

    Article  PubMed  Google Scholar 

  • Shih I-M, Zhou W, Goodman SN, Lengauer C, Kinzler KW, Vogelstein B (2001) Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res 61(3):818–822

    PubMed  CAS  Google Scholar 

  • Shima K, Morikawa T, Yamauchi M et al (2011) TGFBR2 and BAX mononucleotide tract mutations, microsatellite instability, and prognosis in 1072 colorectal cancers. PLoS One 6(9):e25062

    Article  PubMed  CAS  Google Scholar 

  • Shirasawa S, Furuse M, Yokoyama N, Sasazuki T (1993) Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 260(5104):85–88

    Article  PubMed  CAS  Google Scholar 

  • Shrubsole MJ, Wu H, Ness RM, Shyr Y, Smalley WE, Zheng W (2008) Alcohol drinking, cigarette smoking, and risk of colorectal adenomatous and hyperplastic polyps. Am J Epidemiol 167(9):1050–1058

    Article  PubMed  Google Scholar 

  • Sinicrope FA, Rego RL, Halling KC et al (2006) Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients. Gastroenterology 131(3):729–737

    Article  PubMed  CAS  Google Scholar 

  • Snover DC, Jass JR, Fenoglio-Preiser C, Batts KP (2005) Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept. Am J Clin Pathol 124(3):380–391

    Article  PubMed  Google Scholar 

  • Souglakos J, Philips J, Wang R et al (2009) Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer 101(3):465–472

    Article  PubMed  CAS  Google Scholar 

  • Sparks AB, Morin PJ, Vogelstein B, Kinzler KW (1998) Mutational analysis of the APC/β-catenin/Tcf pathway in colorectal cancer. Cancer Res 58(6):1130–1134

    PubMed  CAS  Google Scholar 

  • Spring KJ, Zhao ZZ, Karamatic R et al (2006) High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy. Gastroenterology 131(5):1400–1407

    Article  PubMed  CAS  Google Scholar 

  • Stoler DL, Chen N, Basik M et al (1999) The onset and extent of genomic instability in sporadic colorectal tumor progression. Proc Natl Acad Sci U S A 96(26):15121–15126

    Article  PubMed  CAS  Google Scholar 

  • Storojeva I, Boulay J-L, Heinimann K et al (2005) Prognostic and predictive relevance of microsatellite instability in colorectal cancer. Oncol Rep 14(1):241–249

    PubMed  CAS  Google Scholar 

  • Stryker SJ, Wolff BG, Culp CE, Libbe SD, Ilstrup DM, MacCarty RL (1987) Natural history of untreated colonic polyps. Gastroenterology 93(5):1009–1013

    PubMed  CAS  Google Scholar 

  • Suzuki H, Harpaz N, Tarmin L et al (1994) Microsatellite instability in ulcerative colitis-associated colorectal dysplasias and cancers. Cancer Res 54(18):4841–4844

    PubMed  CAS  Google Scholar 

  • Suzuki H, Igarashi S, Nojima M et al (2010) IGFBP7 is a p53-responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype. Carcinogenesis 31(3):342–349

    Article  PubMed  CAS  Google Scholar 

  • Takagi Y, Kohmura H, Futamura M et al (1996) Somatic alterations of the DPC4 gene in human colorectal cancers in vivo. Gastroenterology 111(5):1369–1372

    Article  PubMed  CAS  Google Scholar 

  • Takagi Y, Koumura H, Futamura M et al (1998) Somatic alterations of the SMAD-2 gene in human colorectal cancers. Br J Cancer 78(9):1152–1155

    Article  PubMed  CAS  Google Scholar 

  • Takagi S, Kinouchi Y, Hiwatashi N et al (1999) Telomere shortening and the clinicopathologic characteristics of human colorectal carcinomas. Cancer 86(8):1431–1436

    Article  PubMed  CAS  Google Scholar 

  • Takahashi T, Sano B, Nagata T et al (2003) Polo-like kinase 1 (PLK1) is overexpressed in primary colorectal cancers. Cancer Sci 94(2):148–152

    Article  PubMed  CAS  Google Scholar 

  • Takayama T, Katsuki S, Takahashi Y et al (1998) Aberrant crypt foci of the colon as precursors of adenoma and cancer. N Engl J Med 339(18):1277–1284

    Article  PubMed  CAS  Google Scholar 

  • Tan Y, Sangfelt O, Spruck C (2008) The Fbxw7/hCdc4 tumor suppressor in human cancer. Cancer Lett 271(1):1–12

    Article  PubMed  CAS  Google Scholar 

  • Tanaka K, Yanoshita R, Konishi M et al (1993) Suppression of tumourigenicity in human colon carcinoma cells by introduction of normal chromosome 1p36 region. Oncogene 8(8):2253–2258

    PubMed  CAS  Google Scholar 

  • Tateyama H, Li W, Takahashi E, Miura Y, Sugiura H, Eimoto T (2002) Apoptosis index and apoptosis-related antigen expression in serrated adenoma of the colorectum: the saw-toothed structure may be related to inhibition of apoptosis. Am J Surg Pathol 26(2):249–256

    Article  PubMed  Google Scholar 

  • Tatsumoto N, Hiyama E, Murakami Y et al (2000) High telomerase activity is an independent prognostic indicator of poor outcome in colorectal cancer. Clin Cancer Res 6(7):2696–2701

    PubMed  CAS  Google Scholar 

  • Taylor SS, McKeon F (1997) Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell 89(5):727–735

    Article  PubMed  CAS  Google Scholar 

  • Tedesco FJ, Hendrix JC, Pickens CA, Brady PG, Mills LR (1982) Diminutive polyps: histopathology, spatial distribution, and clinical significance. Gastrointest Endosc 28(1):1–5

    Article  PubMed  CAS  Google Scholar 

  • Thiagalingam S, Laken S, Willson JKV et al (2001) Mechanisms underlying losses of heterozygosity in human colorectal cancers. Proc Natl Acad Sci U S A 98(5):2698–2702

    Article  PubMed  CAS  Google Scholar 

  • Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260(5109):816–819

    Article  PubMed  CAS  Google Scholar 

  • Tol J, Nagtegaal ID, Punt CJA (2009) BRAF mutation in metastatic colorectal cancer. N Engl J Med 361(1):98–99

    Article  PubMed  CAS  Google Scholar 

  • Torlakovic E, Snover DC (1996) Serrated adenomatous polyposis in humans. Gastroenterology 110(3):748–755

    Article  PubMed  CAS  Google Scholar 

  • Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM (2003) Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 27(1):65–81

    Article  PubMed  Google Scholar 

  • Torlakovic EE, Gomez JD, Driman DK et al (2008) Sessile serrated adenoma (SSA) vs. traditional serrated adenoma (TSA). Am J Surg Pathol 32(1):21–29

    Article  PubMed  Google Scholar 

  • Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 96(15):8681–8686

    Article  PubMed  CAS  Google Scholar 

  • Tran B, Kopetz S, Tie J et al (2011) Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer 117(20):4623–4632, Available from: http://www.ncbi.nlm.nih.gov/pubmed/21456008

    Article  PubMed  CAS  Google Scholar 

  • Van Cutsem E, Köhne C-H, Láng I et al (2011) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29(15):2011–2019

    Article  PubMed  CAS  Google Scholar 

  • Vasen HFA (2005) Clinical description of the Lynch syndrome [hereditary nonpolyposis colorectal cancer (HNPCC)]. Fam Cancer 4(3):219–225

    Article  PubMed  CAS  Google Scholar 

  • Vasen HFA, Mecklin J-P, Meera Khan P, Lynch HT (1991) The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34(5):424–425

    Article  PubMed  CAS  Google Scholar 

  • Vasen HFA, Watson P, Mecklin J-P, Lynch HT (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 116(6):1453–1456

    Article  PubMed  CAS  Google Scholar 

  • Veigl ML, Kasturi L, Olechnowicz J et al (1998) Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci U S A 95(15):8698–8702

    Article  PubMed  CAS  Google Scholar 

  • Vogelstein B, Fearon ER, Hamilton SR et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319(9):525–532

    Article  PubMed  CAS  Google Scholar 

  • Vogelstein B, Fearon E, Kern S et al (1989) Allelotype of colorectal carcinomas. Science 244(4901):207–211

    Article  PubMed  CAS  Google Scholar 

  • Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408(6810):307–310

    Article  PubMed  CAS  Google Scholar 

  • Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR (2008) Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132(3):363–374

    Article  PubMed  CAS  Google Scholar 

  • Wallace K, Grau MV, Ahnen D et al (2009) The association of lifestyle and dietary factors with the risk for serrated polyps of the colorectum. Cancer Epidemiol Biomarkers Prev 18(8):2310–2317

    Article  PubMed  Google Scholar 

  • Wang L, Cunningham JM, Winters JL et al (2003) BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res 63(17):5209–5212

    PubMed  CAS  Google Scholar 

  • Wang Z, Cummins JM, Shen D et al (2004) Three classes of genes mutated in colorectal cancers with chromosomal instability. Cancer Res 64(9):2998–3001

    Article  PubMed  CAS  Google Scholar 

  • Ward R, Meagher A, Tomlinson I et al (2001) Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut 48(6):821–829

    Article  PubMed  CAS  Google Scholar 

  • Ward RL, Cheong K, Ku S-L, Meagher A, O’Connor T, Hawkins NJ (2003) Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. J Clin Oncol 21(20):3729–3736

    Article  PubMed  CAS  Google Scholar 

  • Warthin A (1913) Heredity with reference to carcinoma—as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895–1913. Arch Intern Med 12(5):546–555

    Article  Google Scholar 

  • Weisenberger DJ, Siegmund KD, Campan M et al (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38(7):787–793

    Article  PubMed  CAS  Google Scholar 

  • Whitehall VL, Walsh MD, Young J, Leggett BA, Jass JR (2001) Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability. Cancer Res 61(3):827–830

    PubMed  CAS  Google Scholar 

  • Winawer SJ, Zauber AG, Ho MN et al (1993) Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med 329(27):1977–1981

    Article  PubMed  CAS  Google Scholar 

  • Wood LD, Parsons DW, Jones S et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318(5853):1108–1113

    Article  PubMed  CAS  Google Scholar 

  • Wu JM, Montgomery EA, Iacobuzio-Donahue CA (2008) Frequent beta-catenin nuclear labeling in sessile serrated polyps of the colorectum with neoplastic potential. Am J Clin Pathol 129(3):416–423

    Article  PubMed  CAS  Google Scholar 

  • Wynter CVA, Walsh MD, Higuchi T, Leggett BA, Young J, Jass JR (2004) Methylation patterns define two types of hyperplastic polyp associated with colorectal cancer. Gut 53(4):573–580

    Article  PubMed  CAS  Google Scholar 

  • Yachida S, Mudali S, Martin SA, Montgomery EA, Iacobuzio-Donahue CA (2009) Beta-catenin nuclear labeling is a common feature of sessile serrated adenomas and correlates with early neoplastic progression after BRAF activation. Am J Surg Pathol 33(12):1823–1832

    Article  PubMed  Google Scholar 

  • Yang S, Farraye FA, Mack C, Posnik O, O’Brien MJ (2004) BRAF and KRAS Mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status. Am J Surg Pathol 28(11):1452–1459

    Article  PubMed  Google Scholar 

  • Young J, Jass JR (2006) The case for a genetic predisposition to serrated neoplasia in the colorectum: hypothesis and review of the literature. Cancer Epidemiol Biomarkers Prev 15(10): 1778–1784

    Article  PubMed  CAS  Google Scholar 

  • Young J, Jenkins M, Parry S et al (2007) Serrated pathway colorectal cancer in the population: genetic consideration. Gut 56(10):1453–1459

    Article  PubMed  Google Scholar 

  • Yuen ST, Davies H, Chan TL et al (2002) Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 62(22):6451–6455

    PubMed  CAS  Google Scholar 

  • Yun J, Rago C, Cheong I et al (2009) Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325(5947):1555–1559

    Article  PubMed  CAS  Google Scholar 

  • Zha S, Sekiguchi J, Brush JW, Bassing CH, Alt FW (2008) Complementary functions of ATM and H2AX in development and suppression of genomic instability. Proc Natl Acad Sci U S A 105(27):9302–9306

    Article  PubMed  CAS  Google Scholar 

  • Zhang L (2008) Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part II. The utility of microsatellite instability testing. J Mol Diagn 10(4):301–307

    Article  PubMed  CAS  Google Scholar 

  • Zhou W, Goodman SN, Galizia G et al (2002) Counting alleles to predict recurrence of early-stage colorectal cancers. Lancet 359(9302):219–225

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, Tufts Medical Center, 800 Washington Street, #233, Boston, MA, 02111, USA

    Jatin Roper M.D. & Kenneth E. Hung M.D., Ph.D.

Authors
  1. Jatin Roper M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kenneth E. Hung M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth E. Hung M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Molecular Pathology Unit, Harvard Medical School, Charlestown, Massachusetts, USA

    Kevin M. Haigis, Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Roper, J., Hung, K.E. (2013). Molecular Mechanisms of Colorectal Carcinogenesis. In: Haigis, Ph.D., K. (eds) Molecular Pathogenesis of Colorectal Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8412-7_2

Download citation

Publish with us

Policies and ethics

Search

Navigation