Tumor Biology

, Volume 35, Issue 6, pp 5067–5082 | Cite as

Genetic unraveling of colorectal cancer

  • Sabha Rasool
  • Vamiq Rasool
  • Tahira Naqvi
  • Bashir A. Ganai
  • Bhahwal Ali Shah


Colorectal cancer is a common disease in both men and women (being the third most common cancer in men and the second most common among women) and thus represents an important and serious public health issue, especially in the western world. Although it is a well-established fact that cancers of the large intestine produce symptoms relatively earlier at a stage that can be easily cured by resection, a large number of people lose their lives to this deadly disease each year. Recent times have seen an important change in the incidence of colorectal cancer in different parts of the world. The etiology of colorectal cancer is multifactorial and is likely to involve the actions of genes at multiple levels along the multistage carcinogenesis process. Exhaustive efforts have been made out in the direction of unraveling the role of various environmental factors, gene mutations, and polymorphisms worldwide (as well as in Kashmir—“a valley of gastrointestinal cancers”) that have got a role to play in the development of this disease so that antitumor drugs could be developed against this cancer, first, and, finally, the responsiveness or resistance to these agents could be understood for combating this global issue.


Colorectal cancer Gene mutations Molecular oncology 


Conflicts of interest



  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedGoogle Scholar
  2. 2.
    Boyle P, Elena M. Epidemiology of colorectal cancer. British Med Bull. 2002;64:1–25.Google Scholar
  3. 3.
    World Health Organization (February 2006). Retrieved 24 May 2007.Google Scholar
  4. 4.
    Paula MC, Harold F. The genetics of CRC. Ann Intern Med. 2002;137:603–12.Google Scholar
  5. 5.
    Umar A, Greenwald P. Alarming colorectal cancer incidence trends: a case for early detection and prevention. Cancer Epidemiol Biomarkers Prev. 2009;18:1672–3.PubMedGoogle Scholar
  6. 6.
    Levin B, Lieberman DA, McFarland B, Smith RA, Brooks D, Andrews KS, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. 2008;58:130–60.PubMedGoogle Scholar
  7. 7.
    Fatemi SR, Shivarani S, Malek FN, Vahedi M, Maserat E, Iranpour Y, et al. Colonoscopy screening results in at risk Iranian population. Asian Pac J Cancer Prev. 2010;11:1801–4.PubMedGoogle Scholar
  8. 8.
    Moghimi-Dehkordi B, Safaee A. An overview of colorectal cancer survival rates and prognosis in Asia. World J Gastrointest Oncol. 2012;4(4):71–5.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Sameer AS, Shah ZA, Syeed N, Banday MZ, Bashir SM, Bhat BA, et al. TP53 Pro47Ser and Arg72Pro polymorphisms and colorectal cancer predisposition in an ethnic Kashmiri population. Genet Mol Res. 2010;9:651–60.PubMedGoogle Scholar
  10. 10.
    Sameer AS, ul Rehman S, Pandith AA, Syeed N, Shah ZA, Chowdhri NA, et al. Molecular gate keepers succumb to gene aberrations in colorectal cancer in Kashmiri population, revealing a high incidence area. Saudi J Gastroenterol. 2009;15:244–52.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Rasool S, Ganai BA, Sameer AS, Masood A. Esophageal cancer: associated factors with special reference to the Kashmir Valley. Tumori. 2012;98:191–203.PubMedGoogle Scholar
  12. 12.
    Jenkins TD, Rustgi AK: Genetics of colorectal carcinoma. In: cancer of the lower gastrointestinal tract. Ed. Willet C.G. London 2001;33–44.Google Scholar
  13. 13.
    Young GP, Hu Y, Le Leu RK, Nyskohus L. Dietary fibre and colorectal cancer: a model for environment–gene interactions. Mol Nutr Food Res. 2005;49(6):571–84.PubMedGoogle Scholar
  14. 14.
    Kinzler KW, Vogelstein B. Colorectal tumors. In: Vogelstein B, Kinzler KW, editors. The genetic basis of human cancer. 2nd ed. New York: McGraw-Hill; 2002. p. 583–612.Google Scholar
  15. 15.
    Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol Mech Dis. 2011;6:479–507.Google Scholar
  16. 16.
    Kupfer SS, Anderson JR, Hooker S, Skol A, Kittles RA, Keku TO, Sandler RS, Ellis NA. Genetic heterogeneity in colorectal cancer associations between African and European Americans. Gastroenterol. 2010;139(5):1677--85.Google Scholar
  17. 17.
    Kang GH. Four molecular subtypes of colorectal cancer and their precursor lesions. Arch Pathol Lab Med. 2011;135(6):698–703.PubMedGoogle Scholar
  18. 18.
    Lee AJX, Endesfelder D, Rowan A, Walther A, Birkbak NJ, Futreal PA, et al. Chromosomal instability confers intrinsic multidrug resistance. Cancer Res. 2011;71:1858–70.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Markowitz SD, Bertagnolli MM. Molecular basis of colorectal cancer. N Engl J Med. 2009;361:2449–60.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Arends JW. Molecular interactions in the Vogelstein model of colorectal carcinoma. J Pathol. 2000;190(4):412–6.PubMedGoogle Scholar
  21. 21.
    Lenglauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers. Nature. 1997;386:623–7.Google Scholar
  22. 22.
    Benatti P, Gafà R, Barana D, Marino M, Scarselli A, Pedroni M, et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res. 2005;11(23):8332–40.PubMedGoogle Scholar
  23. 23.
    Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58(22):5248.PubMedGoogle Scholar
  24. 24.
    World Cancer Research Fund and American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington, DC: American Institute for Cancer Research; 2007.Google Scholar
  25. 25.
    Papadopoulos N, Nicolaides NC, Wei YF, et al. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994;263(5153):1625–9.PubMedGoogle Scholar
  26. 26.
    Wilmink ABM. Overview of the epidemiology of colorectal cancer. Dis Colon Rectum. 1997;40(4):483–93.PubMedGoogle Scholar
  27. 27.
    Jeter JM, Kohlmann W, Gruber SB. Genetics of colorectal cancer. Oncology. 2006;20(3):269–76.PubMedGoogle Scholar
  28. 28.
    Ruschoff J, Dietmaier W, Luttges J, et al. Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics. Am J Pathol. 1997;150:1815–25.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Cederquist, K. (2005). Genetic and epidemiological studies of hereditary colorectal cancer. Norrlands UniversitetssjukhusGoogle Scholar
  30. 30.
    Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science. 1993;260:812–6.PubMedGoogle Scholar
  31. 31.
    Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352:1851–60.PubMedGoogle Scholar
  32. 32.
    Vilar E & Gruber SB. Microsatellite instability in colorectal cancer—the stable evidence Nat Rev Clin Oncol. 2010;7(3):153--62.Google Scholar
  33. 33.
    Issa JP. CpG island methylator phenotype in cancer. Nat Rev Cancer. 2004;4:988–93.PubMedGoogle Scholar
  34. 34.
    Kondo Y, Issa JP. Epigenetic changes in colorectal cancer. Cancer Metastasis Rev. 2004;23:29–39.PubMedGoogle Scholar
  35. 35.
    Ang PW, Loh M, Liem N, Lim PL, Grieu F, Vaithilingam A, et al. Comprehensive profiling of DNA methylation in colorectal cancer reveals subgroups with distinct clinicopathological and molecular features. BMC Cancer. 2010;10:227.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Toyota M, Ahuja N, Ohe-Toyota M, Herman J, Baylin SB, Issa JP. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A. 1999;96:8681–6.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Nosho K, Irahara N, Shima K, et al. Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample. PLoS One. 2008;3(11):e3698.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006;38:787–93.PubMedGoogle Scholar
  39. 39.
    Barault L, Charon-Barra C, Jooste V, de la Vega MF, Martin L, Roignot P, et al. Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. Cancer Res. 2008;68(20):8541–6.PubMedGoogle Scholar
  40. 40.
    Hawkins N, Norrie M, Cheong K, Mokany E, Ku SL, Meagher A, et al. CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology. 2002;122(5):1376–87.PubMedGoogle Scholar
  41. 41.
    Fleming NI, Jorissen RN, Mouradov D, Christie M, Sakthianandeswaren A, Palmieri M et al. SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. Cancer Res. 2013;73(2):725–35.Google Scholar
  42. 42.
    Rustgi AK. The genetics of hereditary colon cancer. Genes Dev. 2007;21:2525–38.PubMedGoogle Scholar
  43. 43.
    Ahnen DJ. The genetic basis of colorectal cancer risk. Adv Intern Med. 1996;41:531–52.PubMedGoogle Scholar
  44. 44.
    Yeatman TJ: Colon cancer. Encyclopedia of Life Sciences; 2001. Macmillan Publishers. p. 1–6.Google Scholar
  45. 45.
    Pappou EP and Ahuja N. The role of oncogenes in gastrointestinal cancer. Gastrointest. Cancer Res. 2010;2(Suppl 1):S2–S15.Google Scholar
  46. 46.
    Renkonen ET. Genetic basis of hereditary colorectal cancers. Helsinki University Biomedical Dissertations #75,9–12.Google Scholar
  47. 47.
    Klingelhutz AJ, Hedrick L, Cho KR, McDougall JK. The DCC gene suppresses the malignant phenotype of transformed human epithelial cells. Oncogene. 1995;10:1581–6.PubMedGoogle Scholar
  48. 48.
    Bishop JM. The enemies within: the genesis of retrovirus oncogenes. Cell. 1982;23:5–7.Google Scholar
  49. 49.
    Olivero M, Valente G, Bardelli A, Longati P, Ferrero N, Cracco C, et al. Novel mutation in the ATP-binding site of the MET oncogene tyrosine kinase in a HPRCC family. Int J Cancer. 1999;82:640–3.PubMedGoogle Scholar
  50. 50.
    Alitalo K, Schwab M, Lin CC, Varmus HE, Bishop JM. Homogenously staining chromosomal regions contain amplified copies of an abundant expressed cellular oncogene (c-myc) in malignant neuroendocrine cells from a human colon carcinoma. Proc Natl Acad Sci U S A. 1983;80:1707.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Boxer LM, Dang CV. Translocations involving c-myc and c-myc function. Oncogene. 2001;20:5595–610.PubMedGoogle Scholar
  52. 52.
    Rabbitts TH. Chromosomal translocations in human cancer. Nature. 1994;372:143.PubMedGoogle Scholar
  53. 53.
    Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3:459–65.PubMedGoogle Scholar
  54. 54.
    Forrester K, Almoguera C, Han K, et al. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature. 1987;327:298–303.PubMedGoogle Scholar
  55. 55.
    Shirasawa S, Furuse M, Yokoyama N, Sasazuki T. Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science. 1993;260:85–8.PubMedGoogle Scholar
  56. 56.
    Takayama T, Miyanishi K, Hayashi T, Sato Y, Niitsu Y. Colorectal cancer: genetics of development and metastasis. J Gastroenterol. 2006;41(3):185–92.PubMedGoogle Scholar
  57. 57.
    Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.PubMedGoogle Scholar
  58. 58.
    Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007;318:1108–13.PubMedGoogle Scholar
  59. 59.
    Chan TL, Zhao W, Leung SY, Yuen ST. Cancer Genome Project. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res. 2003;63:4878–81.PubMedGoogle Scholar
  60. 60.
    Lorentz O, Cadoret A, Duluc I, et al. Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras. Oncogene. 1999;18:87–92.PubMedGoogle Scholar
  61. 61.
    Guan RJ, Fu Y, Holt PR, Pardee AB. Association of Kras mutations with p16 methylation in human colon cancer. Gastroenterology. 1999;116:1063–71.PubMedGoogle Scholar
  62. 62.
    Sameer AS, Chowdri NA, Abdullah S, Shah ZA, Siddiqi MA. Mutation pattern of K-ras gene in colorectal cancer patients of Kashmir: a report. Indian J Cancer. 2009;46:219–25.PubMedGoogle Scholar
  63. 63.
    Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002;418:934.PubMedGoogle Scholar
  64. 64.
    Siena S, Sartore-Bianchi A, Di Nicolantonio F, Balfour J, Bardelli A. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst. 2009;101:1308–24.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Calistri D, Rengucci C, Seymour I, Leonardi E, Truini M, Malacarne D, et al. KRAS, p53 and BRAF gene mutations and aneuploidy in sporadic colorectal cancer progression. Anal Cell Pathol. 2006;28(4):161–6.Google Scholar
  66. 66.
    Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA, et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005;65(14):6063.PubMedGoogle Scholar
  67. 67.
    Sameer AS. Colorectal cancer: a researcher’s perspective of the molecular angel’s gone eccentric in the Vale of Kashmir. Tumor Biol. 2013;34(3):1301–15.Google Scholar
  68. 68.
    Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene. 2008;27:5486–96.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.PubMedGoogle Scholar
  70. 70.
    Carson JD, AllerG V, Lehr R, Sinnamon RH, Kirkpatrick RB, et al. Effects of oncogenic p110α subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase. J Biochem. 2008;409:519–24.Google Scholar
  71. 71.
    Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9:550–62.PubMedGoogle Scholar
  72. 72.
    Gardner L, Lee L, and Dang C. The c-Myc oncogenic transcription factor. Encyclopedia of Cancer. p. 1–13.Google Scholar
  73. 73.
    De Pinho R et al. Myc family of cellular oncogenes. J Cell Biochem. 1987;33(4):257–66.Google Scholar
  74. 74.
    Nesbit CE, Tersak JM, Prochownik EV. MYC oncogenes and human neoplastic disease. Oncogene. 1999;18(19):3004–16.PubMedGoogle Scholar
  75. 75.
    Dang CV et al. The c-Myc target gene network. Semin Cancer Biol. 2006;16(4):253–64.PubMedGoogle Scholar
  76. 76.
    Fernandez PC et al. Genomic targets of the human c-Myc protein. Genes Dev. 2003;17(9):1115–29.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Erisman MD et al. Deregulation of c-myc gene expression in human colon carcinoma is not accompanied by amplification or rearrangement of the gene. Mol Cell Biol. 1985;5(8):1969–76.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Sikora K et al. c-myc oncogene expression in colorectal cancer. Cancer. 1987;59(7):1289–95.PubMedGoogle Scholar
  79. 79.
    Monnat M et al. Prognostic implications of expression of the cellular genes myc, fos, Ha-ras and Ki-ras in colon carcinoma. Int J Cancer. 1987;40(3):293–9.PubMedGoogle Scholar
  80. 80.
    Yokota J et al. Alterations of myc, myb, and rasHa proto-oncogenes in cancers are frequent and show clinical correlation. Science. 1986;231(4735):261–5.PubMedGoogle Scholar
  81. 81.
    He TC et al. Identification of c-MYC as a target of the APC pathway. Science. 1998;281(5382):1509–12.PubMedGoogle Scholar
  82. 82.
    Stewart J et al. Detection of the c-myc oncogene product in colonic polyps and carcinomas. Br J Cancer. 1986;53(1):1–6.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Pavelic ZP et al. High c-myc protein expression in benign colorectal lesions correlates with the degree of dysplasia. Anticancer Res. 1992;12(1):171–5.PubMedGoogle Scholar
  84. 84.
    Sundaresan V et al. Abnormal distribution of c-myc oncogene product in familial adenomatous polyposis. J Clin Pathol. 1987;40(11):1274–81.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Rochlitz CF, Herrmann R, de Kant E. Overexpression and amplification of c-myc during progression of human colorectal cancer. Oncology. 1996;53(6):448–54.PubMedGoogle Scholar
  86. 86.
    Heerdt BG et al. Aggressive subtypes of human colorectal tumors frequently exhibit amplification of the c-myc gene. Oncogene. 1991;6(1):125–9.PubMedGoogle Scholar
  87. 87.
    Alao JP. The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention. Mol Cancer. 2007;6:24.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R, et al. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A. 1999;96:5522–7.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999;398:422–6.PubMedGoogle Scholar
  90. 90.
    Arber N et al. Increased expression of cyclin D1 is an early event in multistage colorectal carcinogenesis. Gastroenterology. 1996;110(3):669–74.PubMedGoogle Scholar
  91. 91.
    Mc Kay JA et al. Cyclin D1 protein expression and gene polymorphism in colorectal cancer. Aberdeen Colorectal Initiative. Int J Cancer. 2000;88(1):77–81.Google Scholar
  92. 92.
    Nosho K et al. Cyclin D1 is frequently overexpressed in microsatellite unstable colorectal cancer, independent of CpG island methylator phenotype. Histopathology. 2008;53(5):588–98.PubMedCentralPubMedGoogle Scholar
  93. 93.
    Ogino S et al. A cohort study of cyclin D1 expression and prognosis in 602 colon cancer cases. Clin Cancer Res. 2009;15(13):4431–8.PubMedCentralPubMedGoogle Scholar
  94. 94.
    Sameer AS, Parray FQ, Dar MA, Nissar S, Banday MZ, Rasool S, GM Gulzar, Chowdri NA and Siddiqi MA. Cyclin D1 G870A polymorphism and risk of colorectal cancer: a case control study. Mol Med Reports; 2013;7(3):811--5.Google Scholar
  95. 95.
    Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature. 1984;309(5967):418–25.PubMedGoogle Scholar
  96. 96.
    Brand TM, Iida M, Li C, Wheeler DL. The nuclear epidermal growth factor receptor signaling network and its role in cancer. Discovery Medicine, 2011;12(66):419--32Google Scholar
  97. 97.
    Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;22:337–45.Google Scholar
  98. 98.
    Saltz LB, Meropol NJ, Loehrer PJ, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004;22:1201–8.PubMedGoogle Scholar
  99. 99.
    Goldstein NS, Armin M. Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer stage IV colon adenocarcinoma: implications for a standardized scoring system. Cancer. 2001;92:1331–46.PubMedGoogle Scholar
  100. 100.
    Sirvent A, Benistant C, Roche S. Oncogenic signaling by tyrosine kinases of the SRC family in advanced colorectal cancer. Am J Cancer Res. 2012;2(4):357–71.PubMedCentralPubMedGoogle Scholar
  101. 101.
    Thomas SM, Brugge JS. Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol. 1997;13:513–609.PubMedGoogle Scholar
  102. 102.
    Summy JM, Gallick GE. Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev. 2003;22:337–58.PubMedGoogle Scholar
  103. 103.
    Han NM, Curley SA, Gallick GE. Differential activation of pp 60(c-src) and pp62(c-yes) in human colorectal carcinoma liver metastases. Clin Cancer Res. 1996;2:1397–404.PubMedGoogle Scholar
  104. 104.
    Aligayer H, Boyd DD, Heiss MM, Abdalla EK, Curley SA, Gallick GE. Activation of Src kinase in primary colorectal carcinoma: an indicator of poor clinical prognosis. Cancer. 2002;94:344–51.PubMedGoogle Scholar
  105. 105.
    Park WS, Oh RR, Park JY, Kim PJ, Shin MS, Lee JH, et al. Nuclear localization of beta-catenin is an important prognostic factor in hepatoblastoma. J Pathol. 2001;193:483–90.PubMedGoogle Scholar
  106. 106.
    Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R, et al. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science. 1998;280:596–9.PubMedGoogle Scholar
  107. 107.
    Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P. Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol. 1998;8:573–81.PubMedGoogle Scholar
  108. 108.
    Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J. 1998;17:1371–84.PubMedCentralPubMedGoogle Scholar
  109. 109.
    Yost C, Torres M, Miller JR, Huang E, Kimelman D, Moon RT. The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev. 1996;10:1443–54.PubMedGoogle Scholar
  110. 110.
    Fevr T, Robine S, Louvard D, Huelsken J. Wnt/beta-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells. Mol Cell Biol. 2007;27:7551–9.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787–90.PubMedGoogle Scholar
  112. 112.
    Wagenaar RA, Crawford HC, Matrisian LM. Stabilized beta-catenin immortalizes colonic epithelial cells. Cancer Res. 2001;61:2097–104.PubMedGoogle Scholar
  113. 113.
    Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res. 1998;58:1130–4.PubMedGoogle Scholar
  114. 114.
    Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108:837–47.PubMedGoogle Scholar
  115. 115.
    Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14:1837–51.PubMedGoogle Scholar
  116. 116.
    Sameer AS, Shah ZA, Abdullah S, Chowdri NA, Siddiqi MA. Analysis of molecular aberrations of Wnt pathway gladiators in colorectal cancer in the Kashmiri population. Hum Genomics. 2011;5(5):441–52.PubMedCentralGoogle Scholar
  117. 117.
    Payne SR, Kemp CJ. Tumor suppressor genetics. Carcinogenesis. 2005;26:2031–45.PubMedGoogle Scholar
  118. 118.
    Knudson AG. Hereditary cancer, oncogenes and antioncogenes. Cancer Res. 1985;45:1437–43.PubMedGoogle Scholar
  119. 119.
    Knudson AG. Antioncogenes and human cancer. Proc Natl Acad Sci U S A. 1993;90(109):14–21.Google Scholar
  120. 120.
    Levitt NC, Hickson ID. Caretaker tumour suppressor genes that defend genome integrity. Trends Mol Med. 2002;8:179–86.PubMedGoogle Scholar
  121. 121.
    Goss KH, Groden J. Biology of the adenomatous polyposis coli tumor suppressor. J Clin Oncol. 2000;18:1967–79.PubMedGoogle Scholar
  122. 122.
    Polakis P. The many ways of Wnt in cancer. Curr Opin Genet Dev. 2007;17:45–51.PubMedGoogle Scholar
  123. 123.
    Brocardo M, Henderson S. APC shuttling to the membrane, nucleus, and beyond. Trends Cell Biol. 2009;18:587–96.Google Scholar
  124. 124.
    Lynch HT, De La Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348:919–32.PubMedGoogle Scholar
  125. 125.
    Worthley DL, Whitehall VL, Spring KJ, Leggett BA. Colorectal carcinogenesis: road maps to cancer. World J Gastroenterol. 2007;13:3784–91.PubMedGoogle Scholar
  126. 126.
    Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science. 1990;249:912–25.PubMedGoogle Scholar
  127. 127.
    Vazquez A, Bond EE, Levine AJ, Bond GL. The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov. 2008;7:979–87.PubMedGoogle Scholar
  128. 128.
    Baker SJ, Fearon ER, Nigro JM, et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989;244:217–21.PubMedGoogle Scholar
  129. 129.
    Harris SL, Levine AJ. The p53 pathway: positive and negative feedback loops. Oncogenes. 2005;24:2899–908.Google Scholar
  130. 130.
    Hung J, Anderson R. p53: functions, mutations and sarcomas. Acta Orthop Scand Suppl. 1997;273:68–73.PubMedGoogle Scholar
  131. 131.
    Sameer AS, ul Rehman AA, Pandith AA, Syeed N, Shah ZA, Chowdhri NA, et al. Molecular gate keepers succumb to gene aberrations in colorectal cancer in Kashmiri population, revealing a high incidence area. Saudi J Gastroenterol. 2009;15(4):244–52.PubMedCentralPubMedGoogle Scholar
  132. 132.
    Molecular mechanisms involved in colorectal cancer initiation and progression. Oncology Programme 2007 Scientific Report, pp. 118–121.Google Scholar
  133. 133.
    Muñoz NM, Upton M, Rojas A, Washington MK, Lin L, Chytil A, et al. Transforming growth factor beta receptor type II inactivation induces the malignant transformation of intestinal neoplasms initiated by APC mutation. Cancer Res. 2006;66(20):9837–44.PubMedGoogle Scholar
  134. 134.
    Massagué J, Blain SW, Lo RS. TGFβ signaling in growth control, cancer, and heritable disorders. Cell. 2000;103:295–309.PubMedGoogle Scholar
  135. 135.
    Grady WM, Rajput A, Myeroff L, Liu DF, Kwon K, Willis J, et al. Mutation of the type II transforming growth factor-beta receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. Cancer Res. 1998;58(14):3101–4.PubMedGoogle Scholar
  136. 136.
    Samanta D, Datta PK. Alterations in the Smad pathway in human cancers. Front Biosci. 2012;17:1281–93.Google Scholar
  137. 137.
    Engel ME, Datta PK, Moses HL. Signal transduction by transforming growth factor-beta: a cooperative paradigm with extensive negative regulation. J Cell Biochem Suppl. 1998;30–31:111–22.PubMedGoogle Scholar
  138. 138.
    Zhang B, Halder SK, Kashikar ND, Cho YJ, Datta A, Gorden DL, et al. Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology. 2010;138(3):969–80.PubMedCentralPubMedGoogle Scholar
  139. 139.
    Alazzouzi H, Alhopuro P, Salovaara R, Sammalkorpi H, Jarvinen H, Mecklin JP, et al. SMAD4 as a prognostic marker in colorectal cancer. Clin Cancer Res. 2005;11:2606–11.PubMedGoogle Scholar
  140. 140.
    Sameer AS, Chowdri NA, Syeed N, Banday MZ, Shah ZA, Siddiqi MA. SMAD4—molecular gladiator of the TGF-beta signaling is trampled upon by mutational insufficiency in colorectal carcinoma of Kashmiri population: an analysis with relation to KRAS proto-oncogene. BMC Cancer. 2010;10:300.PubMedCentralPubMedGoogle Scholar
  141. 141.
    Morán A, Ortega P, de Juan C, Fernández-Marcelo T, Frías C, Sánchez-Pernaute A, et al. Differential colorectal carcinogenesis: molecular basis and clinical relevance. World J Gastrointest Oncol. 2010;2(3):151–8.PubMedCentralPubMedGoogle Scholar
  142. 142.
    Akkiprik M, Ataizi-Çelikel Ç, Düşünceli F, Sönmez Ö, Güllüoglu BM, Sav A, et al. Clinical significance of p53 K-ras and DCC gene alterations in the stage I–II colorectal cancers. J Gastrointest Liver Dis. 2007;16:11–7.Google Scholar
  143. 143.
    Itoh F, Hinoda Y, Ohe M, et al. Decreased expression of DCC mRNA in human colorectal cancers. Int J Cancer. 1993;53:260–3.PubMedGoogle Scholar
  144. 144.
    Iino H, Fukayama M, Maeda Y, et al. Molecular genetics for clinical management of colorectal carcinoma. Cancer. 1994;73:1324–31.PubMedGoogle Scholar
  145. 145.
    Saito M, Yamaguchi A, Goi T, et al. Expression of DCC protein in colorectal tumors and its relationship to tumor progression and metastasis. Oncology. 1999;56:134–41.PubMedGoogle Scholar
  146. 146.
    Gotley DC, Reeder JA, Fawcett J, et al. The deleted in colon cancer (DCC) gene is consistently expressed in colorectal cancers and metastases. Oncogene. 1996;13:787–95.PubMedGoogle Scholar
  147. 147.
    Tanaka K, Oshimura M, Kikuchi R, Seki M, Hayashi T, Miyaki M. Suppression of tumourigenicity in human colon carcinoma cells by introduction of normal chromosome 5 or 18. Nature. 1991;349:340–2.PubMedGoogle Scholar
  148. 148.
    Kathleen RC, Jonathan DO, Jonathan WS, Lora H, Eric RF, Antonette CP, et al. The DCC gene: structural analysis and mutations in colorectal carcinoma. Genomics. 1994;19:525–31.Google Scholar
  149. 149.
    Christelle F, Xin Y, Laure G, Ve'ronique C, Hwain S, Dale EB, et al. The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation. PNAS. 2001;98:3416–21.Google Scholar
  150. 150.
    Adrienne VD, Joseph S, Ellen F, Molly DS. The Drosophila netrin receptor frazzled/DCC functions as an invasive tumor suppressor. BMC Dev Biol. 2011;11:41.Google Scholar
  151. 151.
    Meimei L, Peiling L, Baoxin L, Changmin L, Rujin Z, Chunjie H. Lost expression of DCC gene in ovarian cancer and its inhibition in ovarian cancer cells. Med. Oncol. 2011;28(1):282–9.Google Scholar
  152. 152.
    Mustafa A, Çigdem A, Fikret D, Özgür S, Bahadýr MG, Aydin S, et al. Clinical significance of p53, K-ras and DCC gene alterations in the stage I–II colorectal cancers. J Gastrointest Liver Dis. 2007;16:11–7.Google Scholar
  153. 153.
    Shekarabi M, Kennedy TE. The netrin-1 receptor DCC promotes filopodia formation and cell spreading by activating Cdc42 and Rac1. Mol Cell Neurosci. 2002;19:1–17.PubMedGoogle Scholar
  154. 154.
    Khan NP, Pandith AA, Hussain MU, Yousuf A, Khan MS, Siddiqi MA, et al. Loss of heterozygosity (LOH) of deleted in colorectal cancer (DCC) gene and predisposition to colorectal cancer: significant association in colorectal cancer patients of Kashmir. J Cancer Res Exp Oncol. 2011;3(8):88–94.Google Scholar
  155. 155.
    Naguib A, Cooke JC, Happerfield L, Kerr L, Gay LJ, Luben RN, et al. Alterations in PTEN and PIK3CA in colorectal cancers in the EPIC Norfolk Study: associations with clinicopathological and dietary factors. BMC Cancer. 2011;11:123.PubMedCentralPubMedGoogle Scholar
  156. 156.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–7.PubMedGoogle Scholar
  157. 157.
    Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15:356–62.PubMedGoogle Scholar
  158. 158.
    Li DM, Sun H. TEP1 encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor β. Cancer Res. 1997;57:2124–9.PubMedGoogle Scholar
  159. 159.
    Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16:64–7.PubMedGoogle Scholar
  160. 160.
    Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin RJ, et al. Germline mutations in PTEN are present in Bannayan–Zonana syndrome. Nat Genet. 1997;16:333–4.PubMedGoogle Scholar
  161. 161.
    Chang JG, Chen YJ, Perng LI, Wang NM, Kao MC, Yang TY, et al. Mutation analysis of the PTEN/MMAC1 gene in cancers of the digestive tract. Eur J Cancer. 1999;35(4):647–51.PubMedGoogle Scholar
  162. 162.
    Danielsen SA, Lind GE, Bjornslett M, Meling GI, Rognum TO, Heim S, Lothe RA: Novel mutations of the suppressor gene PTEN in colorectal carcinomas stratified by microsatellite instability- and TP53 mutation status. Hum Mutat. 2008;29(11):E252--62.Google Scholar
  163. 163.
    Dicuonzo G, Angeletti S, Garcia-Foncillas J, Brugarolas A, Okrouzhnov Y, Santini D, et al. Colorectal carcinomas and PTEN/MMAC1 gene mutations. Clin Cancer Res. 2001;7(12):4049–53.PubMedGoogle Scholar
  164. 164.
    Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, et al. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 2004;64(9):3014–21.PubMedGoogle Scholar
  165. 165.
    Nassif NT, Lobo GP, Wu X, Henderson CJ, Morrison CD, Eng C, et al. PTEN mutations are common in sporadic microsatellite stable colorectal cancer. Oncogene. 2004;23(2):617–28.PubMedGoogle Scholar
  166. 166.
    Wang ZJ, Taylor F, Churchman M, Norbury G, Tomlinson I. Genetic pathways of colorectal carcinogenesis rarely involve the PTEN and LKB1 genes outside the inherited hamartoma syndromes. Am J Pathol. 1998;153(2):363–6.PubMedCentralPubMedGoogle Scholar
  167. 167.
    Guanti G, Resta N, Simone C, Cariola F, Demma I, Fiorente P, et al. Involvement of PTEN mutations in the genetic pathways of colorectal cancerogenesis. Hum Mol Genet. 2000;9(2):283–7.PubMedGoogle Scholar
  168. 168.
    Zhou XP, Loukola A, Salovaara R, Nystrom-Lahti M, Peltomaki P, de la Chapelle A, et al. PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. Am J Pathol. 2002;161(2):439–47.PubMedCentralPubMedGoogle Scholar
  169. 169.
    Watson AJM. Apoptosis and colorectal cancer. Gut. 2004;53:1701–9.PubMedCentralPubMedGoogle Scholar
  170. 170.
    Chiou SK, Jones MK, Tarnawski AS. Survivin—an anti-apoptosis protein: its biological roles and implications for cancer and beyond. Med Sci Monit. 2003;9(4):143–7.Google Scholar
  171. 171.
    Miller L. An exegesis of IAPs: salvation and surprises from BIR motifs. Trends Cell Biol. 1999;9:323–8.PubMedGoogle Scholar
  172. 172.
    O’Connor DS, Grossman D, Plescia J, et al. Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc Natl Acad Sci U S A. 2000;97:13103–7.PubMedCentralPubMedGoogle Scholar
  173. 173.
    Ikeguchi M, Yamaguchi K, Kaibara N. Survivin gene expression positively correlates with proliferative activity of cancer cells in esophageal cancer. Tumour Biol. 2003;24:40–5.PubMedGoogle Scholar
  174. 174.
    Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, et al. IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases and anticancer drugs. Cancer Res. 1998;58:15–20.Google Scholar
  175. 175.
    Kawasaki H, Toyoda M, Shinohara H, et al. Expression of surviving correlates with apoptosis, proliferation, and angiogenesis during human colorectal tumorigenesis. Cancer. 2001;91:2026–32.PubMedGoogle Scholar
  176. 176.
    Gianani R, Jarboe E, Orlicky D, et al. Expression of survivin in normal, hyperplastic, and neoplastic colonic mucosa. Hum Pathol. 2001;32:119–25.PubMedGoogle Scholar
  177. 177.
    Hernandez JM, Farma JM, Coppola D, Hakam A, Fulp WJ, Chen DT, et al. Expression of the antiapoptotic protein survivin in colon cancer. Clin Colorectal Cancer. 2011;10:188–93.PubMedGoogle Scholar
  178. 178.
    Ofner D, Riehemann K, Maier H, Reidmann B, Nehoda H, Totsch M, et al. Immunohistochemically detectable Bcl-2 expression in colorectal carcinoma: correlation with tumor stage and patient survival. Br J Cancer. 1995;72:981–5.PubMedCentralPubMedGoogle Scholar
  179. 179.
    Baretton GB, Diebold G, Christoforis G, Vogt M, Muller C, Dopfer K, et al. Apoptosis and immunohistochemical bcl-2 expression in colorectal adenomas and carcinomas. Cancer (Phila). 1996;77:255–64.Google Scholar
  180. 180.
    Sinicrope FA, Hart J, Michelassi F, Lee JJ. Prognostic value of bcl-2 oncoprotein expression in stage II colon carcinoma. Clin Cancer Res. 1995;1:1103–10.PubMedGoogle Scholar
  181. 181.
    Srivastava S, Verma M, Henson DE. Biomarkers for early detection of colon cancer. Clin Cancer Res. 2001;7:11–8.Google Scholar
  182. 182.
    Pritchard DM, Potten CS, Korsmeyer SJ, et al. Damage-induced apoptosis in intestinal epithelia from bcl-2-null and bax-null mice: investigations of the mechanistic determinants of epithelial apoptosis in vivo. Oncogene. 1999;18:7287–93.PubMedGoogle Scholar
  183. 183.
    Pritchard DM, Print C, O’Reilly L, et al. Bcl-w is an important determinant of damage-induced apoptosis in epithelia of small and large intestine. Oncogene. 2000;19(34):3955–9.PubMedGoogle Scholar
  184. 184.
    Pathan N, Marusawa H, Krajewska M, et al. TUCAN, an antiapoptotic caspase-associated recruitment domain family protein overexpressed in cancer. JBC. 2001;276:32220–9.Google Scholar
  185. 185.
    Poirier MC, Santella RM, Weston A. Carcinogen macromolecular adducts and their measurement. Carcinogenesis. 2000;21:353–9.PubMedGoogle Scholar
  186. 186.
    Kawajiri K, Nakachi K, Imai K, Watanabe J, Hayashi S. Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer. Carcinogenesis. 1993;14:1085–9.PubMedGoogle Scholar
  187. 187.
    Bozina N, Bradamante V, Lovric M. Genetic polymorphisms of metabolic enzymes P450 (CYP) as a susceptibility factor for drug response, toxicity and cancer risk. Arh Hig Rada Toksikol. 2009;60:217–42.PubMedGoogle Scholar
  188. 188.
    Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, et al. Environmental and heritable factors in the causation of cancer analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343:78–85.PubMedGoogle Scholar
  189. 189.
    Kury S, Buecher B, Robiou-du-Pont S, Scoul C, Sebille V, Colman H, et al. Combinations of cytochrome P450 gene polymorphisms enhancing the risk for sporadic colorectal cancer related to red meat consumption. Cancer Epidemiol Biomarkers Prev. 2007;16:1460–7.PubMedGoogle Scholar
  190. 190.
    Cotterchio M et al. Red meat intake, doneness, polymorphisms in genes that encode carcinogen-metabolizing enzymes, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 2008;17:3098–107.PubMedCentralPubMedGoogle Scholar
  191. 191.
    Bethke L et al. Polymorphisms in the cytochrome P450 genes CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1, CYP19A1 and colorectal cancer risk. BMC Cancer. 2007;7:123.PubMedCentralPubMedGoogle Scholar
  192. 192.
    Zhong S, Wyllie AH, Barnes D, Wolf CR, Spurr NK. Carcinogenesis. 1993;14:1821–4.PubMedGoogle Scholar
  193. 193.
    Brockmoller J, Kerb R, Drakoulis N, Staffeldt B, Roots I. Cancer Res. 1994;54:4103–11.PubMedGoogle Scholar
  194. 194.
    Seidegård J, Pero RW, Markowitz MM, Roush G, Miller DG, Beattie EJ. Carcinogenesis. 1990;11:33–6.PubMedGoogle Scholar
  195. 195.
    Kodate C, Fukushi A, Narita T, Kudo H, Soma Y, Sato K. Jpn J Cancer Res. 1988;77:226–9.Google Scholar
  196. 196.
    Zhao ZQ, Guan QK, Yang FY, Zhao P, Zhou B, Chen ZJ. System review and meta-analysis of the relationships between five metabolic gene polymorphisms and colorectal adenoma risk. Tumour Biol. 2012;33(2):523–35.PubMedGoogle Scholar
  197. 197.
    Hein DW, Doll MA, Rustan TD, Gray K, Feng Y, Ferguson RJ, et al. Metabolic activation and deactivation of arylamine carcinogens by recombinant human NAT1 and polymorphic NAT2 acetyltransferases. Carcinogenesis. 1993;14:1633.PubMedGoogle Scholar
  198. 198.
    Ilett KF, David BM, Detchon P, Castleden WM, Kwa R. Acetylation phenotype in colorectal carcinoma. Cancer Res. 1987;47:1466.PubMedGoogle Scholar
  199. 199.
    Sameer AS, Nissar S, Qadri Q, Alam S, Baba SM, Siddiqi MA. Role of CYP2E1 genotypes in susceptibility to colorectal cancer in Kashmiri population. Hum Genomics. 2011;5(6):530–7.PubMedCentralPubMedGoogle Scholar
  200. 200.
    Sameer AS, Qadri A, Siddiqi MA. GSTP1 I105V polymorphism and susceptibility to colorectal cancer in Kashmiri population. DNA Cell Biol. 2012;31(1):74–9.PubMedGoogle Scholar
  201. 201.
    Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Willett WC. Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med. 1994;121:241–6.PubMedGoogle Scholar
  202. 202.
    Williams CS, Mann M, DuBios RN. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene. 1999;18:7908–16.PubMedGoogle Scholar
  203. 203.
    Egil F. Biochemistry of cyclooxygenase (COX-2) inhibitors and molecular pathology of COX-2 in neoplasia. Crit Rev Clin Lab Sci. 2000;37:431–502.Google Scholar
  204. 204.
    Subbaramaiah K, Dannenberg AJ. Cyclooxygenase2: a molecular target for cancer prevention and, treatment. Trends Pharmacol Sci. 2003;24:96–102.PubMedGoogle Scholar
  205. 205.
    Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994;107:1183–8.PubMedGoogle Scholar
  206. 206.
    Gupta RA, DuBois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer. 2001;1:11–21.PubMedGoogle Scholar
  207. 207.
    Marnett LJ, DuBois RN. COX-2: a target for colon cancer prevention. Annu Rev Pharmacol Toxicol. 2002;42:55–80.PubMedGoogle Scholar
  208. 208.
    Ogino S, Kirkner GJ, Nosho K, Irahara N, Kure S, Shima K, et al. Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin Cancer Res. 2008;14:8221–7.PubMedCentralPubMedGoogle Scholar
  209. 209.
    Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell. 1996;87:803–9.PubMedGoogle Scholar
  210. 210.
    Wang D, DuBois RN. The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene. 2010;29(6):781–8.PubMedCentralPubMedGoogle Scholar
  211. 211.
    Arico S, Pattingre S, Bauvy C, Gane P, Barbat A, Codogno P, et al. Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line. J Biol Chem. 2002;277:27613–21.PubMedGoogle Scholar
  212. 212.
    Chen WS, Liu JH, Wei SJ, Liu JM, Hong CY, Yang WK. Colon cancer cells with high invasive potential are susceptible to induction of apoptosis by a selective COX-2 inhibitor. Cancer Sci. 2003;94:253–8.PubMedGoogle Scholar
  213. 213.
    Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med. 2006;355:873–84.PubMedGoogle Scholar
  214. 214.
    Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med. 2003;348:883–90.PubMedGoogle Scholar
  215. 215.
    Wang D, Dubois RN. Prostaglandins and cancer. Gut. 2006;55:115–22.PubMedCentralPubMedGoogle Scholar
  216. 216.
    Wang D, Wang H, Brown J, Daikoku T, Ning W, Shi Q, et al. CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer. J Exp Med. 2006;203:941–51.PubMedCentralPubMedGoogle Scholar
  217. 217.
    Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin–beta-catenin signaling axis. Science. 2005;310:1504–10.PubMedGoogle Scholar
  218. 218.
    Wu AW, Gu J, Ji JF, Li ZF, Xu GW. Role of COX-2 in carcinogenesis of colorectal cancer and its relationship with tumor biological characteristics and patients prognosis. World J Gastroenterol. 2003;9(9):1990–4.PubMedGoogle Scholar
  219. 219.
    Müller-Decker K, Fürstenberger G. The cyclooxygenase-2-mediated prostaglandin signaling is causally related to epithelial carcinogenesis. Mol Carcinog. 2007;46:705–10.PubMedGoogle Scholar
  220. 220.
    The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7.Google Scholar
  221. 221.
    Kim TM, Lee SH, Chung YJ. Clinical applications of next-generation sequencing in colorectal cancers. World J Gastroenterol. 2013;19(40):6784–93.PubMedCentralPubMedGoogle Scholar
  222. 222.
    Biancolella M, K Fortini B, Tring S, Plummer SJ, Mendoza-Fandino GA, et al. Identification and characterization of functional risk variants for colorectal cancer mapping to chromosome 11q23.1. Hum Mol Genet. 2013; doi: 10.1093/hmg/ddt584.
  223. 223.
    Javid G, Zargar SA, Rather S, Khan AR, Khan BA, Yattoo GN, et al. Incidence of colorectal cancer in Kashmir Valley, India. Indian J Gastroenterol. 2011;30(1):7–11.PubMedGoogle Scholar
  224. 224.
    Fernandez-Rozadilla C, Cazier JB, Tomlinson I, Brea-Fernández A, Lamas MJ, et al. The EPICOLON Consortium, Hemminki K, Bessa X, Andreu M, Jover R, Xicola R, Llor X, Moreno V, Castells A, Castellví-Bel S, Carracedo A, Ruiz-Ponte C. A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer. Hum Genet. 2013; doi: 10.1007/s00439-013-1390-4
  225. 225.
    Rasool S, Kadla SA, Khan T, Qazi F, Shah NA, Basu J, et al. Association of a VDR gene polymorphism with risk of colorectal cancer in Kashmir. Asian Pac J Cancer Prev. 2013;14:5833–7.PubMedGoogle Scholar
  226. 226.
    Malik MA, Gupta A, Zargar SA, Mittal B. Role of genetic variants of deleted in colorectal carcinoma (DCC) polymorphisms and esophageal and gastric cancers risk in Kashmir Valley and meta-analysis. Tumour Biol. 2013;34:3049–57.PubMedGoogle Scholar
  227. 227.
    Nissar S, Lone TA, Banday MZ, Rasool R, Chowdri NA, Parray FQ, et al. Arg399Gln polymorphism of XRCC1 gene and risk of colorectal cancer in Kashmir: a case control study. Oncol Lett. 2013;5:959–63.PubMedCentralPubMedGoogle Scholar
  228. 228.
    Wani HA, Beigh MA, Amin S, Bhat AA, Bhat S, Khan H, et al. Methylation profile of promoter region of p16 gene in colorectal cancer patients of Kashmir Valley. J Biol Regul Homeost Agents. 2013;27(2):297–307.PubMedGoogle Scholar
  229. 229.
    Khan NP, Pandith AA, Yousuf A, Khan NS, Khan MS, Bhat IA, et al. The XRCC1 Arg399Gln gene polymorphism and risk of colorectal cancer: a study in Kashmir. Asian Pac J Cancer Prev. 2013;14(11):6779–82.PubMedGoogle Scholar
  230. 230.
    Wani M, Afroze D, Makhdoomi M, Hamid I, Wani B, Bhat G, et al. Promoter methylation status of DNA repair gene (hMLH1) in gastric carcinoma patients of the Kashmir Valley. Asian Pac J Cancer Prev. 2012;13(8):4177–81.PubMedGoogle Scholar
  231. 231.
    Shah MA, Shaff SM, Lone GN, Jan SM. Lack of influence of MGMT codon Leu84Phe and codon Ileu143Val polymorphisms on esophageal cancer risk in the Kashmir Valley. Asian Pac J Cancer Prev. 2012;13(7):3047–52.PubMedGoogle Scholar
  232. 232.
    Shafia S, Qasim I, Aziz SA, Bhat IA, Nisar S, Shah ZA. Role of vitamin D receptor (VDR) polymorphisms in susceptibility to multiple myeloma in ethnic Kashmiri population. Blood Cells Mol Dis. 2013;51(1):56–60.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Sabha Rasool
    • 1
  • Vamiq Rasool
    • 2
  • Tahira Naqvi
    • 3
  • Bashir A. Ganai
    • 1
  • Bhahwal Ali Shah
    • 4
  1. 1.Department of BiochemistryUniversity of KashmirSrinagarIndia
  2. 2.Department of PediatricsGovernment Medical CollegeSrinagarIndia
  3. 3.Department of ChemistryGovernment Higher Secondary SchoolSrinagarIndia
  4. 4.Department of Natural Product Chemistry (Microbes) Division, CSIR-IIIMJammuIndia

Personalised recommendations