Molecular Pathways, Screening and Follow-up of Colorectal Carcinogenesis: An Overview

Author(s): Eskandar Taghizadeh, Seyed M.G. Hayat, Rhonda J. Rosengren, Daryoush Rostami, Hamed Abdolkarimi, Amirhossein Sahebkar*

Journal Name: Current Cancer Therapy Reviews

Volume 16 , Issue 2 , 2020

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Graphical Abstract:


Colorectal cancer (CRC) is the development of cancer from the colon or rectum. This kind of cancer presents with a broad spectrum of neoplasms from benign to metastatic forms. The development of the majority of colon cancers appears from adenomatous polyps or adenomas systematically. At least three molecular pathways are involved in CRC pathogenesis including chromosomal instability (CIN), microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). Methods such as fecal occult blood tests (FOBTs), colonoscopy, flexible sigmoidoscopy (FOS), computed tomographic colonography (CTC), and fecal DNA are commonly used for CRC screening. The current review discusses the signs and symptoms associated with CRC, molecular pathways related to CRC and some strategies for current screening, diagnosis and treatment.

Keywords: Colorectal cancer (CRC), CIN pathway, MSI pathway, CIMP pathway, diabetes, carcinogens.

Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin 2017; 67(3): 177-93.
[] [PMID: 28248415]
Thanikachalam K, Khan G. Colorectal cancer and nutrition. Nutrients 2019; 11(1): 164.
[] [PMID: 30646512]
Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 2001; 96(10): 2992-3003.
[] [PMID: 11693338]
Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017; 66(4): 683-91.
[] [PMID: 26818619]
Haiman CA, Le Marchand L, Yamamato J, et al. A common genetic risk factor for colorectal and prostate cancer. Nat Genet 2007; 39(8): 954-6.
[] [PMID: 17618282]
Ather HM, Sarfraz M, Anwaar T. Colorectal Cancer (CRC). Prof Med J 2016; 23: 364-9.
Nassiri M, Kooshyar MM, Roudbar Z, Mahdavi M, Doosti M. Genes and SNPs associated with non-hereditary and hereditary colorectal cancer. Asian Pac J Cancer Prev 2013; 14(10): 5609-14.
[] [PMID: 24289550]
Vargas AJ, Thompson PA. Diet and nutrient factors in colorectal cancer risk. Nutr Clin Pract 2012; 27(5): 613-23.
[] [PMID: 22892274]
Petti S. Lifestyle risk factors for oral cancer. Oral Oncol 2009; 45(4-5): 340-50.
[] [PMID: 18674956]
Irigaray P, Newby JA, Clapp R, et al. Lifestyle-related factors and environmental agents causing cancer: an overview. Biomed Pharmacother 2007; 61(10): 640-58.
[] [PMID: 18055160]
Dorundi S, Bannerjea A. Signs and symptoms of colorectal cancer. Surgery 2008; 8: 323-8.
Walling AM, Weeks JC, Kahn KL, et al. Symptom prevalence in lung and colorectal cancer patients. J Pain Symptom Manage 2015; 49(2): 192-202.
[] [PMID: 24973624]
Dunne JR, Gannon CJ, Osborn TM, Taylor MD, Malone DL, Napolitano LM. Preoperative anemia in colon cancer: assessment of risk factors. Am Surg 2002; 68(6): 582-7.
[PMID: 12079143]
Adelstein B-A, Macaskill P, Katelaris PH, Irwig L. Bowel symptoms in relation to colorectal cancer. In: Olsson L, Eds. Timely diagnosis of colorectal cancer . Springer, Cham, Switzerland 2018; pp. 21-38.
Sung JJ, Ng SC, Chan FK, et al. Asia Pacific Working Group. An updated Asia Pacific Consensus Recommendations on colorectal cancer screening. Gut 2015; 64(1): 121-32.
[] [PMID: 24647008]
Fijten GH, Starmans R, Muris JW, Schouten HJ, Blijham GH, Knottnerus JA. Predictive value of signs and symptoms for colorectal cancer in patients with rectal bleeding in general practice. Fam Pract 1995; 12(3): 279-86.
[] [PMID: 8536830]
John SK, George S, Primrose JN, Fozard JB. Symptoms and signs in patients with colorectal cancer. Colorectal Dis 2011; 13(1): 17-25.
[] [PMID: 20105201]
Parsons DW, Wang T-L, Samuels Y, et al. Colorectal cancer: mutations in a signalling pathway. Nature 2005; 436(7052): 792-2.
[] [PMID: 16094359]
Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol 2011; 6: 479-507.
[] [PMID: 21090969]
Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology 2010; 138(6): 2059-72.
[] [PMID: 20420946]
Matsuzaki K, Deng G, Tanaka H, Kakar S, Miura S, Kim YS. The relationship between global methylation level, loss of heterozygosity, and microsatellite instability in sporadic colorectal cancer. Clin Cancer Res 2005; 11(24 Pt 1): 8564-9.
[] [PMID: 16361538]
Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000; 103(2): 311-20.
[] [PMID: 11057903]
Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 2001; 1(1): 55-67.
[] [PMID: 11900252]
Lemieux E, Cagnol S, Beaudry K, Carrier J, Rivard N. Oncogenic KRAS signalling promotes the Wnt/β-catenin pathway through LRP6 in colorectal cancer. Oncogene 2015; 34(38): 4914-27.
[] [PMID: 25500543]
Scott N, Sagar P, Stewart J, Blair GE, Dixon MF, Quirke P. p53 in colorectal cancer: clinicopathological correlation and prognostic significance. Br J Cancer 1991; 63(2): 317-9.
[] [PMID: 1997114]
Smith G, Carey FA, Beattie J, et al. Mutations in APC, Kirsten-ras, and p53--alternative genetic pathways to colorectal cancer. Proc Natl Acad Sci USA 2002; 99(14): 9433-8.
[] [PMID: 12093899]
Geiersbach KB, Samowitz WS. Microsatellite instability and colorectal cancer. Arch Pathol Lab Med 2011; 135(10): 1269-77.
[] [PMID: 21970482]
Armaghany T, Wilson JD, Chu Q, Mills G. Genetic alterations in colorectal cancer. Gastrointest Cancer Res 2012; 5(1): 19-27.
[PMID: 22574233]
Kuismanen SA, Holmberg MT, Salovaara R, de la Chapelle A, Peltomäki P. Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers. Am J Pathol 2000; 156(5): 1773-9.
[] [PMID: 10793088]
Parsons R, Myeroff LL, Liu B, et al. Microsatellite instability and mutations of the transforming growth factor β type II receptor gene in colorectal cancer. Cancer Res 1995; 55(23): 5548-50.
[PMID: 7585632]
Sinicrope FA, Sargent DJ. Molecular pathways: microsatellite instability in colorectal cancer: prognostic, predictive, and therapeutic implications. Clin Cancer Res 2012; 18(6): 1506-12.
[] [PMID: 22302899]
Mundade R, Imperiale TF, Prabhu L, Loehrer PJ, Lu T. Genetic pathways, prevention, and treatment of sporadic colorectal cancer. Oncoscience 2014; 1(6): 400-6.
[] [PMID: 25594038]
Chung DC. The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis. Gastroenterology 2000; 119(3): 854-65.
[] [PMID: 10982779]
Murphy KM, Zhang S, Geiger T, et al. Comparison of the microsatellite instability analysis system and the Bethesda panel for the determination of microsatellite instability in colorectal cancers. J Mol Diagn 2006; 8(3): 305-11.
[] [PMID: 16825502]
Imai K, Yamamoto H. Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. Carcinogenesis 2008; 29(4): 673-80.
[] [PMID: 17942460]
Copija A, Waniczek D, Witkoś A, Walkiewicz K, Nowakowska-Zajdel E. Clinical significance and prognostic relevance of microsatellite instability in sporadic colorectal cancer patients. Int J Mol Sci 2017; 18(1): 18.
[] [PMID: 28067827]
Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 1999; 96(15): 8681-6.
[] [PMID: 10411935]
Hawkins N, Norrie M, Cheong K, et al. CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology 2002; 122(5): 1376-87.
[] [PMID: 11984524]
Barault L, Charon-Barra C, Jooste V, et al. Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. Cancer Res 2008; 68(20): 8541-6.
[] [PMID: 18922929]
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(3): 837-45.
[] [PMID: 16143123]
Arain MA, Sawhney M, Sheikh S, et al. CIMP status of interval colon cancers: another piece to the puzzle. Am J Gastroenterol 2010; 105(5): 1189-95.
[] [PMID: 20010923]
Park SJ, Rashid A, Lee JH, Kim SG, Hamilton SR, Wu TT. Frequent CpG island methylation in serrated adenomas of the colorectum. Am J Pathol 2003; 162(3): 815-22.
[] [PMID: 12598316]
Shen L, Toyota M, Kondo Y, et al. Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci USA 2007; 104(47): 18654-9.
[] [PMID: 18003927]
Suehiro Y, Wong CW, Chirieac LR, et al. Epigenetic-genetic interactions in the APC/WNT, RAS/RAF, and P53 pathways in colorectal carcinoma. Clin Cancer Res 2008; 14(9): 2560-9.
[] [PMID: 18451217]
Ogino S, Cantor M, Kawasaki T, et al. CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies. Gut 2006; 55(7): 1000-6.
[] [PMID: 16407376]
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(7): 787-93.
[] [PMID: 16804544]
Issa J-P. Colon cancer: It's CIN or CIMP. Clin Cancer Res 2008; 14(19): 5939-40.
[] [PMID: 18829469]
Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology 2010; 138(6): 2088-100.
[] [PMID: 20420948]
Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol 2011; 42(1): 1-10.
[] [PMID: 20869746]
Lièvre A, Bachet J-B, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006; 66(8): 3992-5.
[] [PMID: 16618717]
Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010; 138: 2073-2087.e3.
Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C. The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer 2003; 3(9): 695-701.
[] [PMID: 12951588]
Kahi CJ, Anderson JC. Colorectal cancer screening and surveillance. In: Clinical gastrointestinal endoscopy. 3rd ed. Elsevier 2019; pp. 392-401.
Issa IA, Noureddine M. Colorectal cancer screening: An updated review of the available options. World J Gastroenterol 2017; 23(28): 5086-96.
[] [PMID: 28811705]
Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin 2018; 68(4): 250-81.
[] [PMID: 29846947]
Bond JH. Practice Parameters Committee of the American College of Gastroenterology. Polyp guideline: diagnosis, treatment, and surveillance for patients with colorectal polyps. Am J Gastroenterol 2000; 95(11): 3053-63.
[] [PMID: 11095318]
Winawer S, Fletcher R, Rex D, et al. Gastrointestinal Consortium Panel. Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology 2003; 124(2): 544-60.
[] [PMID: 12557158]
Burt RW. Colon cancer screening. Gastroenterology 2000; 119(3): 837-53.
[] [PMID: 10982778]
Ferrández A, DiSario JA. Hereditary colorectal cancer: screening and management. Curr Treat Options Oncol 2002; 3(6): 459-74.
[] [PMID: 12392636]
Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993; 328(19): 1365-71.
[] [PMID: 8474513]
Hardcastle JD, Chamberlain JO, Robinson MHE, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996; 348(9040): 1472-7.
[] [PMID: 8942775]
Nishihara R, Wu K, Lochhead P, et al. Long-term colorectal-cancer incidence and mortality after lower endoscopy. N Engl J Med 2013; 369(12): 1095-105.
[] [PMID: 24047059]
Brenner H, Stock C, Hoffmeister M. Effect of screening sigmoidoscopy and screening colonoscopy on colorectal cancer incidence and mortality: systematic review and meta-analysis of randomised controlled trials and observational studies. BMJ 2014; 348: g2467.
[] [PMID: 24922745]
Brenner H, Chang-Claude J, Seiler CM, Rickert A, Hoffmeister M. Protection from colorectal cancer after colonoscopy: a population-based, case-control study. Ann Intern Med 2011; 154(1): 22-30.
[] [PMID: 21200035]
Singh H, Nugent Z, Demers AA, Kliewer EV, Mahmud SM, Bernstein CN. The reduction in colorectal cancer mortality after colonoscopy varies by site of the cancer. Gastroenterology 2010; 139(4): 1128-37.
[] [PMID: 20600026]
Neugut AI, Lebwohl B. Colonoscopy vs sigmoidoscopy screening: getting it right. JAMA 2010; 304(4): 461-2.
[] [PMID: 20664047]
Allison JE, Fraser CG, Halloran SP, Young GP. Population screening for colorectal cancer means getting FIT: the past, present, and future of colorectal cancer screening using the fecal immunochemical test for hemoglobin (FIT). Gut Liver 2014; 8(2): 117-30.
[] [PMID: 24672652]
Lee JK, Liles EG, Bent S, Levin TR, Corley DA. Accuracy of fecal immunochemical tests for colorectal cancer: systematic review and meta-analysis. Ann Intern Med 2014; 160(3): 171-81.
[] [PMID: 24658694]
Massat NJ, Moss SM, Halloran SP, Duffy SW. Screening and primary prevention of colorectal cancer: a review of sex-specific and site-specific differences. J Med Screen 2013; 20(3): 125-48.
[] [PMID: 24197771]
van Rossum LG, van Rijn AF, Laheij RJ, et al. Cutoff value determines the performance of a semi-quantitative immunochemical faecal occult blood test in a colorectal cancer screening programme. Br J Cancer 2009; 101(8): 1274-81.
[] [PMID: 19755997]
Ahlquist DA. Multi-target stool DNA test: a new high bar for noninvasive screening. Dig Dis Sci 2015; 60(3): 623-33.
[] [PMID: 25492503]
Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med 2014; 370(14): 1287-97.
[] [PMID: 24645800]
Ladabaum U, Mannalithara A. Comparative effectiveness and cost effectiveness of a multitarget stool DNA test to screen for colorectal neoplasia. Gastroenterology 2016; 151: 427-439.e6.
Ranasinghe I, Parzynski CS, Searfoss R, et al. Differences in colonoscopy quality among facilities: Development of a post-colonoscopy risk-standardized rate of unplanned hospital visits. Gastroenterology 2016; 150(1): 103-13.
[] [PMID: 26404952]
Ziemlewicz TJ, Binkley N, Pickhardt PJ. Opportunistic osteoporosis screening: addition of quantitative CT bone mineral density evaluation to CT colonography. J Am Coll Radiol 2015; 12(10): 1036-41.
[] [PMID: 26435117]
Martín-López JE, Beltrán-Calvo C, Rodríguez-López R, Molina-López T. Comparison of the accuracy of CT colonography and colonoscopy in the diagnosis of colorectal cancer. Colorectal Dis 2014; 16(3): O82-9.
[] [PMID: 24299052]
Romero L, Pazol K, Warner L, Gavin L, Moskosky S, Besera G. Centers for Disease Control and Prevention (CDC). Vital signs: Trends in use of long-acting contraception among teens aged 15-19 seeking contraceptive services-United States, 2005-2013. MMWR Morb Mortal Wkly Rep 2015; 64: 363-9.
[PMID: 25856258]
deVos T, Tetzner R, Model F, et al. Circulating methylated SEPT9 DNA in plasma is a biomarker for colorectal cancer. Clin Chem 2009; 55(7): 1337-46.
[] [PMID: 19406918]
Grützmann R, Molnar B, Pilarsky C, et al. Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay. PLoS One 2008; 3(11): e3759
[] [PMID: 19018278]
Lofton-Day C, Model F, Devos T, et al. DNA methylation biomarkers for blood-based colorectal cancer screening. Clin Chem 2008; 54(2): 414-23.
[] [PMID: 18089654]
Stokes M. Colon cancer: Current and emerging trends in detection and treatment. The Rosen Publishing Group, NY, USA, 2005.
Promrat K, Aziz K, Wu GY. Screening for colorectal cancer. In: Screening. Springer; Berlin, Germany 2001; pp. 87-109.
Calistri D, Rengucci C, Casadei Gardini A, et al. Fecal DNA for noninvasive diagnosis of colorectal cancer in immunochemical fecal occult blood test-positive individuals. Cancer Epidemiol Biomarkers Prev 2010; 19(10): 2647-54.
[] [PMID: 20929882]
Levin B, Rozen P, Spann SJ, Young GP. Colorectal cancer in clinical practice: Prevention, early detection and management Florida:. CRC Press, Cleveland, USA 2005.
McLeod RS. Canadian Task Force on Preventive Health Care. Screening strategies for colorectal cancer: a systematic review of the evidence. Can J Gastroenterol 2001; 15(10): 647-60.
[] [PMID: 11694901]
Jeffery M, Hickey BE, Hider PN. Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev 2007; 1: CD002200
[] [PMID: 17253476]
Bilimoria KY, Stewart AK, Winchester DP, Ko CY. The National Cancer Data Base: a powerful initiative to improve cancer care in the United States. Ann Surg Oncol 2008; 15(3): 683-90.
[] [PMID: 18183467]
Figueredo A, Rumble RB, Maroun J, et al. Gastrointestinal Cancer Disease Site Group of Cancer Care Ontario’s Program in Evidence-based Care. Follow-up of patients with curatively resected colorectal cancer: a practice guideline. BMC Cancer 2003; 3: 26.
[] [PMID: 14529575]
Godhi S, Godhi A, Bhat R, Saluja S. Colorectal cancer: Postoperative follow-up and surveillance. Indian J Surg 2017; 79(3): 234-7.
[] [PMID: 28659677]
Rosen M, Chan L, Beart RW Jr, Vukasin P, Anthone G. Follow-up of colorectal cancer: a meta-analysis. Dis Colon Rectum 1998; 41(9): 1116-26.
[] [PMID: 9749495]
Van Cutsem E, Cervantes A, Nordlinger B, Arnold D. ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25(Suppl. 3): 1-9.
[] [PMID: 25190710]
Meyerhardt JA, Mangu PB, Flynn PJ, et al. American Society of Clinical Oncology. Follow-up care, surveillance protocol, and secondary prevention measures for survivors of colorectal cancer: American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol 2013; 31(35): 4465-70.
[] [PMID: 24220554]

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Year: 2020
Page: [88 - 96]
Pages: 9
DOI: 10.2174/1573394715666190730111946

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