Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third most common cause of cancer death in men and women in the USA and accounts for 9 % of all new cancer cases and of all cancer deaths. In contrast, the incidence of small bowel cancer is low and accounts for 0.4 % of all new cases and 0.2 % of all cancer deaths. It is currently believed that most sporadic colorectal cancers arise from preexisting precursor lesions, including adenoma, dysplasia and recently serrated polyps, but a small percentage of colorectal cancers can arise de novo without identifiable precursor lesions. The majority of colorectal cancers develop through an “adenoma–carcinoma sequence” beginning from transformation of normal colorectal epithelium to an adenomatous intermediate and then to adenocarcinoma. The molecular pathogenesis of colorectal cancer including genetic and epigenetic alterations has been extensively studied in the past two decades and is among one the best understood among human neoplasms.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Jemal A, Siegel R, Xu J, et al. Cancer Statistics, 2010. CA Cancer J Clin. 2010;60:277–300.
Morson B. President’s address: the polyp-cancer sequence in the large bowel. Proc R Soc Med. 1974;67:451–457.
Fearon E, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–767.
Toyota M, Ho C, Ahuja N, et al. Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res. 1999;59:2307–2312.
Toyota M, Ohe-Toyota M, Ahuja N, et al. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc Natl Acad Sci USA. 2000;97:710–715.
Toyota M, Ahuja N, Ohe-Toyota M, et al. CpG Island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA. 1999;96:8681–8686.
Ionov Y, Peinado MA, Malkhosyan S, et al. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993;363:558–561.
Thibodeau SN, Berg G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816–819.
Peltomaki P, Lothe RA, Aaltonen LA, et al. Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal cancer syndrome. Cancer Res. 1993;53:5853–5855.
Wood LD, Parsons DW, Jones S, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007;318:1108–1113.
Leary R, Lin J, Cummins J, et al. Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers. Proc Natl Acad Sci USA. 2008;105:16226–16229.
Powell S, Zilz N, Beazer-Barclay Y, et al. APC mutations occur early during colorectal tumoriogenesis. Nature. 1992;359:235–237.
Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87:159–170.
Benhattar J, Losi L, Chaubert P, et al. Prognostic significance of K-ras mutations in colorectal carcinoma. Gastroenterology. 1993;104:1044–1048.
Moerkerk P, Arends JW, van Driel M, et al. Type and number of Ki-ras point mutations relate to stage of human colorectal cancer. Cancer Res. 1994;54:3376–3378.
Santini D, Loupakis F, Vincenzi B, et al. High concordance of KRAS status between primary colorectal tumors and related metastatic sites: implications for clinical practice. Oncologist. 2008;13:1270–1275.
Nigro JM, Baker SJ, Preisinger AC, et al. Mutations in the p53 gene occur in diverse tumor types. Nature. 1989;342:705–708.
Baker SJ, Preisinger AC, Jessup JM, et al. p53 gene mutations occur in combination with 17p allelic deletions as late event in colorectal tumorigenesis. Cancer Res. 1990;50:7717–7722.
Fearon ER, Cho KR, Nigro JM, et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990;247:49–56.
Thiagalingam S, Lengauer C, Leach FS, et al. Evaluation of candidate tumor suppressor genes on chromosome 18 in colorectal cancers. Nat Genet. 1996;13:343–346.
Bacolod MD, Barany F. Gene dysregulation driven by somatic copy number aberrations-biological and clinical implications in colon tumors: a paper from the 2009 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diag. 2010;12:552–561.
Cottrell S, Bicknell D, Kaklamanis L, et al. Molecular analysis of APC mutations in familial adenomatous polyposis and sporadic colon carcinomas. Lancet. 1992;340:626–630.
Miyaki M, Konishi M, Kikuchi-Yanoshita R, et al. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res. 1994;54:3011–3020.
Miyoshi Y, Nagase H, Ando H, et al. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet. 1992;1:229–233.
Otori K, Konishi M, Sugiyama K, et al. Infrequent somatic mutation of the adenomatous polyposis coli gene in aberrant crypt foci of human colon tissue. Cancer. 1998;83:896–900.
Esteller M, Sparks A, Toyota M, et al. Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer. Cancer Res. 2000;60:4366–4371.
Rubinfeld B, Albert I, Porfiri E, et al. Binding of GSK3b to the APC-b-catenin complex and regulation of complex assembly. Science. 1996;272:1023–1026.
Mann B, Gelos M, Siedow A, et al. Target genes of beta-catenin-T-cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. Proc Natl Acad Sci USA. 1999;96: 1603–1608.
Sparks A, Morin P, Vogelstein B, et al. Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res. 1998;58:1130–1134.
Shimizu Y, Ikeda S, Fujimori M, et al. Frequent alterations in the Wnt signaling pathway in colorectal cancer with microsatellite instability. Genes Chromosomes Cancer. 2002;3:73–81.
Leslie A, Carey F, Pratt N, et al. The colorectal adenoma-carcinoma sequence. Br J Surg. 2002;89:845–860.
Vogelstein B, Lane D, Levine A. Surfing the p53 network. Nature. 2000;408:307–310.
Levine A. p53, the cellular gatekeeper for growth and division. Cell. 1997;88:323–331.
Menendez D, Inga A, Resnick MA. The expanding universe of p53 targets. Nat Rev Cancer. 2009;9:724–737.
Beroud C, Soussi T. The UMD-p53 database: new mutations and analysis tools. Hum Mutat. 2003;21:176–181.
Cho K, Oliner J, Simons J, et al. The DCC gene: structural analysis and mutations in colorectal carcinomas. Genomics. 1994;19: 525–531.
Takagi Y, Kohmura H, Futamura M, et al. Somatic alterations of the DPC4 gene in human colorectal cancers in vivo. Gastroenterology. 1996;111:1369–1372.
Takagi Y, Koumura H, Futamura M, et al. Somatic alterations of the SMAD-2 gene in human colorectal cancers. Br J Cancer. 1995;78:1152–1155.
Wu C, Kirley S, Xiao H, et al. Cables enhances cdk2 tyrosine 152 phosphorylation by Wee1, inhibits cell growth, and is lost in many human colon and squamous cancers. Cancer Res. 2001;61:7325–7332.
Park do Y, Sakamoto H, Kirley S, et al. The Cables gene on chromosomes 18q is silences by promoter hypermethylation and allelic loss in human colorectal cancer. Am J Pathol. 2007;171:1509–1519.
Chan TL, Zhao W, Leung SY, et al. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res. 2003;63:4878–4881.
Samuels Y, Wang Z, Bardelli A, et al. High frequency if mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.
Samuels Y, Velculescu VE. Oncogenic mutations of PIK3CA in human cancers. Cell Cycle. 2004;3:1221–1224.
Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science. 2001;293:1068–1070.
Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16:6–21.
Baylin SB, Herman JG, Graff JR, et al. Alterations in DNA methylation—A fundamental aspect of neoplasia. Adv Cancer Res. 1998;72:141–196.
Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983;301:89–92.
Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet. 1999;21:163–167.
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;57:808–811.
Merlo A, Herman JG, Mao L, et al. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995;1:686–692.
Ahuja N, Li Q, Mohan AL, et al. Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res. 1998;58:5489–5494.
Issa JP, Ottaviano YL, Celano P, et al. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet. 1994;7:536–540.
Suzuki H, Gabrielson E, Chen W, et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet. 2002;31:141–149.
Costello JF, Fruhwald MC, Smiraglia DJ, et al. Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet. 2000;24:132–138.
Toyota M, Shen L, Ohe-Toyota M, et al. Aberrant methylation of the Cyclooxygenase 2 CpG island in colorectal tumors. Cancer Res. 2000;60:4044–4048.
Devereux TR, Horikawa I, Anna CH, et al. DNA methylation analysis of the promoter region of the human telomerase reverse transcriptase (hTERT) gene. Cancer Res. 1999;59:6087–6090.
Ahuja N, Mohan AL, Li Q, et al. Association between CpG island methylation and microsatellite instability in colorectal cancer. Cancer Res. 1997;57:3370–3374.
Hawkins N, Norrie M, Cheong K, et al. CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology. 2002;122:1376–1387.
Whitehall VL, Wynter CV, Walsh MD, et al. Morphological and molecular heterogeneity within nonmicrosatellite instability-high colorectal cancer. Cancer Res. 2002;62:6011–6014.
Koinuma K, Shitoh K, Miyakura Y, et al. Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas. Int J Cancer. 2004;108:237–242.
Wang L, Cunningham JM, Winters JL, et al. BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res. 2003;63:5209–5212.
Esteller M, Toyota M, Sanchez-Cespedes M, et al. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res. 2000;60:2368–2371.
Rashid A, Shen L, Morris JS, et al. CpG island methylation in colorectal adenomas. Am J Pathol. 2001;159:1129–1135.
Chan AO, Broaddus RR, Houlihan PS, et al. CpG island methylation in aberrant crypt foci of the colorectum. Am J Pathol. 2002;160:1823–1830.
Li H, Myeroff L, Smiraglia D, et al. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci USA. 2003;100:8412–8417.
Torlakovic E, Snover DC. Serrated adenomatous polyposis in humans. Gastroenterology. 1996;110:748–755.
Rashid A, Houlihan PS, Booker S, et al. Phenotypic and molecular characteristics of hyperplastic polyposis. Gastroenterology. 2000;119:323–332.
Jeevaratnam P, Cottier DS, Browett PJ, et al. Familial giant hyperplastic polyposis predisposing to colorectal cancer: a new hereditary bowel cancer syndrome. J Pathol. 1996;179:20–25.
Park SJ, Rashid A, Lee JH, et al. Frequent CpG island methylation in serrated adenomas of the colorectum. Am J Pathol. 2003;162:815–822.
Chan AO, Issa JP, Morris JS, et al. Concordant CpG island methylation in hyperplastic polyposis. Am J Pathol. 2002;160:529–536.
Jass JR. Serrated route to colorectal cancer: back street or super highway? J Pathol. 2001;193:283–285.
Hawkins NJ, Bariol C, Ward RL. The serrated neoplasia pathway. Pathology. 2002;34:548–555.
Hawkins NJ, Ward RL. Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas. J Natl Cancer Inst. 2001;93:1307–1313.
Bronner CE, Baker SM, Morrison PT, et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature. 1994;368:258–261.
Papadopoulos N, Nicolaides NC, Wei YF, et al. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994;263:1625–1629.
Leach FS, Nicolaides NC, Papadopoulos N, et al. Mutation of a Muts D homolog in hereditary nonpolyposis colorectal cancer. Cell. 1993;75:1215–1225.
Fishel R, Lescoe MK, Rao MR, et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell. 1993;75:1027–1038 [Erratum, Cell 1994;77:167].
Miyaki M, Konishi M, Tanaka K, et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet. 1997;17:271–272.
Koldner RD, Tytell JD, Schmeits JL, et al. Germ-line msh6 mutations in colorectal cancer families. Cancer Res. 1999;59:5068–5074.
Nicolaides NC, Papadopoulos N, Liu B, et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature. 1994;371:75–80.
Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA. 1998;95:6870–6875.
Veigel ML, Kasturi L, Olechnowicz J, et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing MSI cancers. Proc Natl Acad Sci USA. 1998;95:8698–8702.
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 detection of microsatellite instability in colorectal cancer. Cancer Res. 1998;58:5248–5275.
Malkhosyan SR, Yamamoto H, Piao Z, et al. Late onset and high incidence of colon cancer of the mutator phenotype with hypermethylated hMLH1 gene in women. Gastroenterology. 2000; 119:598.
Wright CM, Dent OF, Barker M, et al. The prognostic significance of extensive microsatellite instability in sporadic clinicopathologic stage C colorectal cancer. Br J Surg. 2000;87:1197–1202.
Alexander J, Watanabe T, Wu TT, et al. Histopathologic identification of colon cancer with microsatellite instability. Am J Pathol. 2001;98:527–735.
Kim H, Jen J, Vogelstein B, et al. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol. 1994;145:148–156.
Rüschoff J, Dietmaier W, Lüttges J, et al. Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics. Am J Pathol. 1997;150: 1815–1825.
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;153:1063–1078.
Samowitz WS, Holden JA, Curtin K, et al. Inverse relationship between microsatellite instability and K-ras and p53 gene alteration in colon cancer. Am J Pathol. 2001;158:1517–1524.
Mirabelli-Primdahl L, Gryfe R, Kim H, et al. Beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway. Cancer Res. 1999;59:3346–3351.
Deng G, Bell I, Crawley S, et al. BRAF mutation is frequently present in sporadic cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res. 2004;10:191–195.
Markowitz S, Wang J, Myeroff L, et al. Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability. Science. 1995;268:1336–1338.
Souza RF, Appel R, Yin J, et al. The insulin-like growth factor II receptor gene is a target of microsatellite instability in human gastrointestinal tumors. Nat Genet. 1996;14:255–257.
Yamamoto H, Sawai H, Weber TK, et al. Somatic frameshift mutations in hereditary nonpolyposis colorectal cancer. Cancer Res. 1998;58:997–1003.
Parsons R, Myeroff L, Liu B, et al. Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res. 1995;55:5548–5550.
Jen J, Kim H, Piantadosi S, et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med. 1994;331:213–221.
Watanabe T, Wu T-T, Catalano PJ, et al. Molecular predictors of survival after chemotherapy for colon cancer. N Engl J Med. 2001;344:1196–1206.
Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77.
Shen L, Catalano PJ, Benson AB III, et al. Association between DNA methylation and shortened survival in patients with advanced colorectal cancer treated with 5-fluorouracil based chemotherapy. Clin Cancer Res. 2007;13:6093–6098.
Samowitz WS, Albertsen H, Herrick J, et al. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology. 2005;129:837–845.
Jover R, Nguyen T-P, Perez-Carbonell L, et al. 5-Fluorouracil adjuvant chemotherapy does not increase survival with CpG adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer. Gastroenterology. 2011;140:1174–1181.
Rubic 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.
Liévre A, Bachet JB, Le Corre D, et al. KRAS mutation is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66:3992–3995.
Liévre A, Bachet JB, Boige V, et al. KRAS mutation as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374–379.
Jhawer M, Goel S, Wilson AJ, et al. PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 2008;68:1953–1961 [Erratum, Cancer Res 2008;68:6859.].
Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009;27:5924–5930.
van Cutsem E, Köhne C-H, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Eng J Med. 2009;360:1408–1417.
De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, AND PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11:753–762.
Warth A, Kloor M, Schirmacher P, et al. Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP. Mod Pathol. 2011;24:564–570.
Diosdado B, Buffart TE, Watkins R, et al. High-resolution array comparative genomic hybridization in sporadic and celiac disease-related small bowel adenocarcinomas. Clin Cancer Res. 2010;16:1391–1401.
Blaker H, von Herbay A, Penzel R, et al. Genetics of adenocarcinomas of the small intestine: frequent deletions at chromosome 18q and mutations of the SMAD4 gene. Oncogene. 2002;21:158–164.
Berkhout M, Nagtegaal ID, Cornelissen SJ, et al. Chromosomal and methylation alterations in sporadic and familial adenomatous polyposis-related duodenal carcinomas. Mod Pathol. 2007;20: 1253–1262.
Rashid A, Hamilton SR. Genetic alterations in sporadic and Crohn’s-associated adenocarcinomas of the small intestine. Gastroenterology. 1997;113:127–135.
Wheeler JM, Warren BF, Mortensen NJ, et al. An insight into the genetic pathway of adenocarcinoma of the small intestine. Gut. 2002;50:218–223.
Arai M, Shimizu S, Imai Y, et al. Mutations of the Ki-ras, p53 and APC genes in adenocarcinomas of the human small intestine. Int J Cancer. 1997;70:390–395.
Zhang MQ, Chen ZM, Wang HL. Immunohistochemical investigation of tumorigenic pathways in small intestinal adenocarcinoma: a comparison with colorectal adenocarcinoma. Mod Pathol. 2006;19:573–580.
Younes N, Fulton N, Tanaka R, et al. The presence of K-12 ras mutations in duodenal adenocarcinomas and the absence of ras mutations in other small bowel adenocarcinomas and carcinoid tumors. Cancer. 1997;79:1804–1808.
Muneyuki T, Watanabe M, Yamanaka M, et al. Combination analysis of genetic alterations and cell proliferation in small intestinal carcinomas. Dig Dis Sci. 2000;45:2022–2028.
Schonleben F, Qiu W, Allendorf JD, et al. Molecular analysis of PIK3CA, BRAF, and RAS oncogenes in periampullary and ampullary adenomas and carcinomas. J Gastrointest Surg. 2009;13:1510–1516.
Kim SG, Chan AOO, Wu TT, et al. Epigenetic and genetic alterations in duodenal carcinomas are distinct from biliary and ampullary carcinomas. Gastroenterology. 2003;124:1300–1310.
Overman MJ, Pozadzides J, Kopetz S, et al. Immunophenotype and molecular characterization of adenocarcinoma of the small intestine. Br J Cancer. 2010;102:144–150.
Lynch HT, Lynch JF, Lynch PM, et al. Hereditary colorectal cancer syndromes: molecular genetics, genetic counseling, diagnosis and management. Fam Cancer. 2008;7:27–39.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Rashid, A. (2013). Molecular Pathology of Colon and Small Bowel Cancers: Sporadic Type. In: Sepulveda, A., Lynch, J. (eds) Molecular Pathology of Neoplastic Gastrointestinal Diseases. Molecular Pathology Library, vol 7. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-6015-2_8
Download citation
DOI: https://doi.org/10.1007/978-1-4614-6015-2_8
Published:
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4614-6014-5
Online ISBN: 978-1-4614-6015-2
eBook Packages: MedicineMedicine (R0)