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Pharmacogenetics and biomarkers in colorectal cancer

The Pharmacogenomics Journal volume 9, pages 147–160 (2009)Cite this article

Abstract

The prognosis of patients with colorectal cancer (CRC) is affected by various factors at the time of diagnosis, including location of the tumor, gender, age and overall performance status of the patient. Predicting response and limiting drug-induced toxicity for patients with CRC are also critical. Interpatient differences in tumor response and drug toxicity are common during chemotherapy. Genomic variability of key metabolic enzyme complexes, drug targets and drug transport molecules are important contributing factors. At present, there is inconsistent and rather low use of pharmacogenetic testing in the clinical setting because of a lack of robust evidence or of resources. Patients’ selection and tailored treatments by the introduction of genetic testing will hopefully allow better response prediction and limit drug-induced toxicity leading to improved patient outcomes in the most cost-effective way. Here, we review the main genetic alterations observed in familial and sporadic CRC and their associations with the metabolism, efficacy and toxicities of drugs used in this disease.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 71–96.

    Article  PubMed  Google Scholar 

  2. Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB et al. Identification of FAP locus genes from chromosome 5q21. Science 1991; 253: 661–665.

    Article  CAS  PubMed  Google Scholar 

  3. Marra G, Boland CR . Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst 1995; 87: 1114–1125.

    Article  CAS  PubMed  Google Scholar 

  4. Lengauer C, Kinzler KW, Vogelstein B . Genetic instability in colorectal cancers. Nature 1997; 386: 623–627.

    Article  CAS  PubMed  Google Scholar 

  5. Grady WM, Carethers JM . Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 2008; 135: 1079–1099.

    Article  CAS  PubMed  Google Scholar 

  6. Lim SB, Jeong SY, Lee MR, Ku JL, Shin YK, Kim WH et al. Prognostic significance of microsatellite instability in sporadic colorectal cancer. Int J Colorectal Dis 2004; 19: 533–537.

    Article  PubMed  Google Scholar 

  7. Parc Y, Gueroult S, Mourra N, Serfaty L, Flejou JF, Tiret E et al. Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut 2004; 53: 371–375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Benatti P, Gafa R, Barana D, Marino M, Scarselli A, Pedroni M et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res 2005; 11: 8332–8340.

    Article  CAS  PubMed  Google Scholar 

  9. Jover R, Zapater P, Castells A, Llor X, Andreu M, Cubiella J et al. The efficacy of adjuvant chemotherapy with 5-fluorouracil in colorectal cancer depends on the mismatch repair status. Eur J Cancer 2008; 45: 365–373.

    Article  CAS  PubMed  Google Scholar 

  10. Storojeva I, Boulay JL, Heinimann K, Ballabeni P, Terracciano L, Laffer U et al. Prognostic and predictive relevance of microsatellite instability in colorectal cancer. Oncol Rep 2005; 14: 241–249.

    CAS  PubMed  Google Scholar 

  11. Braun MS, Richman SD, Quirke P, Daly C, Adlard JW, Elliott F et al. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol 2008; 26: 2690–2698.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Wang C, van Rijnsoever M, Grieu F, Bydder S, Elsaleh H, Joseph D et al. Prognostic significance of microsatellite instability and Ki-ras mutation type in stage II colorectal cancer. Oncology 2003; 64: 259–265.

    Article  CAS  PubMed  Google Scholar 

  14. Sargent DJ, Marsoni S, Thibodeau SN, Labianca R, Hamilton SR, Torri V et al. Confirmation of deficient mismatch repair (dMMR) as a predictive marker for lack of benefit from 5-FU based chemotherapy in stage II and III colon cancer (CC): a pooled molecular reanalysis of randomized chemotherapy trials. J Clin Oncol (meeting abstracts) 2008; 26: 4008.

    Article  Google Scholar 

  15. French AJ, Sargent DJ, Burgart LJ, Foster NR, Kabat BF, Goldberg R et al. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin Cancer Res 2008; 14: 3408–3415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C . The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer 2003; 3: 695–701.

    Article  CAS  PubMed  Google Scholar 

  17. Worthley DL, Whitehall VL, Spring KJ, Leggett BA . Colorectal carcinogenesis: road maps to cancer. World J Gastroenterol 2007; 13: 3784–3791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rashid A, Issa JP . CpG island methylation in gastroenterologic neoplasia: a maturing field. Gastroenterology 2004; 127: 1578–1588.

    Article  CAS  PubMed  Google Scholar 

  19. Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD et al. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 2004; 53: 1137–1144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 2006; 38: 787–793.

    Article  CAS  PubMed  Google Scholar 

  21. Lee S, Cho NY, Choi M, Yoo EJ, Kim JH, Kang GH . Clinicopathological features of CpG island methylator phenotype-positive colorectal cancer and its adverse prognosis in relation to KRAS/BRAF mutation. Pathol Int 2008; 58: 104–113.

    Article  CAS  PubMed  Google Scholar 

  22. Yan P, Saraga EP, Bouzourene H, Bosman FT, Benhattar J . Telomerase activation in colorectal carcinogenesis. J Pathol 1999; 189: 207–212.

    Article  CAS  PubMed  Google Scholar 

  23. Kruzelock RP, Short W . Colorectal cancer therapeutics and the challenges of applied pharmacogenomics. Curr Probl Cancer 2007; 31: 315–366.

    Article  PubMed  Google Scholar 

  24. Windham TC, Parikh NU, Siwak DR, Summy JM, McConkey DJ, Kraker AJ et al. Src activation regulates anoikis in human colon tumor cell lines. Oncogene 2002; 21: 7797–7807.

    Article  CAS  PubMed  Google Scholar 

  25. Irby RB, Mao W, Coppola D, Kang J, Loubeau JM, Trudeau W et al. Activating SRC mutation in a subset of advanced human colon cancers. Nat Genet 1999; 21: 187–190.

    Article  CAS  PubMed  Google Scholar 

  26. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M et al. Genetic alterations during colorectal tumor development. N Engl J Med 1988; 319: 525–532.

    Article  CAS  PubMed  Google Scholar 

  27. Shangary S, Wang S . Targeting the MDM2-p53 interaction for cancer therapy. Clin Cancer Res 2008; 14: 5318–5324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Etienne MC, Chazal M, Laurent-Puig P, Magne N, Rosty C, Formento JL et al. Prognostic value of tumoral thymidylate synthase and p53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy: phenotypic and genotypic analyses. J Clin Oncol 2002; 20: 2832–2843.

    Article  CAS  PubMed  Google Scholar 

  29. Iacopetta B, Russo A, Bazan V, Dardanoni G, Gebbia N, Soussi T et al. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study. Ann Oncol 2006; 17: 842–847.

    Article  CAS  PubMed  Google Scholar 

  30. Russo A, Bazan V, Iacopetta B, Kerr D, Soussi T, Gebbia N . The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment. J Clin Oncol 2005; 23: 7518–7528.

    Article  CAS  PubMed  Google Scholar 

  31. Reinmuth N, Fan F, Liu W, Parikh AA, Stoeltzing O, Jung YD et al. Impact of insulin-like growth factor receptor-I function on angiogenesis, growth, and metastasis of colon cancer. Lab Invest 2002; 82: 1377–1389.

    Article  CAS  PubMed  Google Scholar 

  32. Reinmuth N, Liu W, Fan F, Jung YD, Ahmad SA, Stoeltzing O et al. Blockade of insulin-like growth factor I receptor function inhibits growth and angiogenesis of colon cancer. Clin Cancer Res 2002; 8: 3259–3269.

    CAS  PubMed  Google Scholar 

  33. Donovan EA, Kummar S . Role of insulin-like growth factor-1R system in colorectal carcinogenesis. Crit Rev Oncol Hematol 2008; 66: 91–98.

    Article  PubMed  Google Scholar 

  34. Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 2001; 1: 65–70.

    Article  CAS  PubMed  Google Scholar 

  35. Iacopetta B, Grieu F, Joseph D, Elsaleh H . A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil. Br J Cancer 2001; 85: 827–830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kawakami K, Omura K, Kanehira E, Watanabe Y . Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 1999; 19: 3249–3252.

    CAS  PubMed  Google Scholar 

  37. Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ et al. A novel single nucleotide polymorphism within the 5′ tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 2003; 63: 2898–2904.

    CAS  PubMed  Google Scholar 

  38. Mandola MV, Stoehlmacher J, Zhang W, Groshen S, Yu MC, Iqbal S et al. A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 2004; 14: 319–327.

    CAS  PubMed  Google Scholar 

  39. Gorlick R, Metzger R, Danenberg KD, Salonga D, Miles JS, Longo GS et al. Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma. J Clin Oncol 1998; 16: 1465–1469.

    Article  CAS  PubMed  Google Scholar 

  40. Bathe OF, Franceschi D, Livingstone AS, Moffat FL, Tian E, Ardalan B . Increased thymidylate synthase gene expression in liver metastases from colorectal carcinoma: implications for chemotherapeutic options and survival. Cancer J Sci Am 1999; 5: 34–40.

    CAS  PubMed  Google Scholar 

  41. Edler D, Glimelius B, Hallstrom M, Jakobsen A, Johnston PG, Magnusson I et al. Thymidylate synthase expression in colorectal cancer: a prognostic and predictive marker of benefit from adjuvant fluorouracil-based chemotherapy. J Clin Oncol 2002; 20: 1721–1728.

    Article  CAS  PubMed  Google Scholar 

  42. Soong R, Shah N, Salto-Tellez M, Tai BC, Soo RA, Han HC et al. Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy. Ann Oncol 2008; 19: 915–919.

    Article  CAS  PubMed  Google Scholar 

  43. Prall F, Ostwald C, Schiffmann L, Barten M . Do thymidylate synthase gene promoter polymorphism and the C/G single nucleotide polymorphism predict effectiveness of adjuvant 5-fluorouracil-based chemotherapy in stage III colonic adenocarcinoma? Oncol Rep 2007; 18: 203–209.

    CAS  PubMed  Google Scholar 

  44. Capitain O, Boisdron-Celle M, Poirier AL, Abadie-Lacourtoisie S, Morel A, Gamelin E . The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer. Pharmacogenomics J 2008; 8: 256–267.

    Article  CAS  PubMed  Google Scholar 

  45. Lecomte T, Ferraz JM, Zinzindohoue F, Loriot MA, Tregouet DA, Landi B et al. Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy. Clin Cancer Res 2004; 10: 5880–5888.

    Article  CAS  PubMed  Google Scholar 

  46. Popat S, Matakidou A, Houlston RS . Thymidylate synthase expression and prognosis in colorectal Cancer: a systematic review and meta-analysis. J Clin Oncol 2004; 22: 529–536.

    Article  CAS  PubMed  Google Scholar 

  47. Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 2006; 24: 5313–5327.

    Article  CAS  PubMed  Google Scholar 

  48. Tokunaga Y, Hosogi H, Hoppou T, Nakagami M, Tokuka A, Ohsumi K . Prognostic value of thymidine phosphorylase/platelet-derived endothelial cell growth factor in advanced colorectal cancer after surgery: evaluation with a new monoclonal antibody. Surgery 2002; 131: 541–547.

    Article  PubMed  Google Scholar 

  49. Tokunaga Y, Takahashi K, Saito T . Clinical role of thymidine phosphorylase and dihydropyrimidine dehydrogenase in colorectal cancer treated with postoperative fluoropyrimidine. Hepatogastroenterology 2005; 52: 1715–1721.

    CAS  PubMed  Google Scholar 

  50. Metzger R, Danenberg K, Leichman CG, Salonga D, Schwartz EL, Wadler S et al. High basal level gene expression of thymidine phosphorylase (platelet-derived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil. Clin Cancer Res 1998; 4: 2371–2376.

    CAS  PubMed  Google Scholar 

  51. Yamada H, Iinuma H, Watanabe T . Prognostic value of 5-fluorouracil metabolic enzyme genes in Dukes′ stage B and C colorectal cancer patients treated with oral 5-fluorouracil-based adjuvant chemotherapy. Oncol Rep 2008; 19: 729–735.

    CAS  PubMed  Google Scholar 

  52. Ichikawa W, Uetake H, Shirota Y, Yamada H, Takahashi T, Nihei Z et al. Both gene expression for orotate phosphoribosyltransferase and its ratio to dihydropyrimidine dehydrogenase influence outcome following fluoropyrimidine-based chemotherapy for metastatic colorectal cancer. Br J Cancer 2003; 89: 1486–1492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cockcroft VG . Incidental capture of bottle-nosed dolphins (tursiops-truncatus) in shark nets - an assessment of some possible causes. J Zool 1992; 226: 123–134.

    Article  Google Scholar 

  54. Ichikawa W, Takahashi T, Suto K, Sasaki Y, Hirayama R . Orotate phosphoribosyltransferase gene polymorphism predicts toxicity in patients treated with bolus 5-fluorouracil regimen. Clin Cancer Res 2006; 12: 3928–3934.

    Article  CAS  PubMed  Google Scholar 

  55. Ciaparrone M, Quirino M, Schinzari G, Zannoni G, Corsi DC, Vecchio FM et al. Predictive role of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer patients receiving adjuvant 5-fluorouracil. Oncology 2006; 70: 366–377.

    Article  CAS  PubMed  Google Scholar 

  56. Yoshinare K, Kubota T, Watanabe M, Wada N, Nishibori H, Hasegawa H et al. Gene expression in colorectal cancer and in vitro chemosensitivity to 5-fluorouracil: a study of 88 surgical specimens. Cancer Sci 2003; 94: 633–638.

    Article  CAS  PubMed  Google Scholar 

  57. Salonga D, Danenberg KD, Johnson M, Metzger R, Groshen S, Tsao-Wei DD et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 2000; 6: 1322–1327.

    CAS  PubMed  Google Scholar 

  58. Diasio RB . Clinical implications of dihydropyrimidine dehydrogenase on 5-FU pharmacology. Oncology (Williston Park) 2001; 15: 21–26.

    CAS  Google Scholar 

  59. Harris BE, Carpenter JT, Diasio RB . Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome. Cancer 1991; 68: 499–501.

    Article  CAS  PubMed  Google Scholar 

  60. Morel A, Boisdron-Celle M, Fey L, Soulie P, Craipeau MC, Traore S et al. Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther 2006; 5: 2895–2904.

    Article  CAS  PubMed  Google Scholar 

  61. Morel A, Boisdron-Celle M, Fey L, Laine-Cessac P, Gamelin E . Identification of a novel mutation in the dihydropyrimidine dehydrogenase gene in a patient with a lethal outcome following 5-fluorouracil administration and the determination of its frequency in a population of 500 patients with colorectal carcinoma. Clin Biochem 2007; 40: 11–17.

    Article  CAS  PubMed  Google Scholar 

  62. Lassmann S, Hennig M, Rosenberg R, Nahrig J, Schreglmann J, Krause F et al. Thymidine phosphorylase, dihydropyrimidine dehydrogenase and thymidylate synthase mRNA expression in primary colorectal tumors-correlation to tumor histopathology and clinical follow-up. Int J Colorectal Dis 2006; 21: 238–247.

    Article  PubMed  Google Scholar 

  63. Marcuello E, Altes A, Menoyo A, Rio ED, Baiget M . Methylenetetrahydrofolate reductase gene polymorphisms: genomic predictors of clinical response to fluoropyrimidine-based chemotherapy? Cancer Chemother Pharmacol 2006; 57: 835–840.

    Article  CAS  PubMed  Google Scholar 

  64. Vallbohmer D, Yang DY, Kuramochi H, Shimizu D, Danenberg KD, Lindebjerg J et al. DPD is a molecular determinant of capecitabine efficacy in colorectal cancer. Int J Oncol 2007; 31: 413–418.

    PubMed  Google Scholar 

  65. Saif MW, Elfiky A, Diasio R . Hand-foot syndrome variant in a dihydropyrimidine dehydrogenase-deficient patient treated with capecitabine. Clin Colorectal Cancer 2006; 6: 219–223.

    Article  PubMed  Google Scholar 

  66. Sharma R, Hoskins JM, Rivory LP, Zucknick M, London R, Liddle C et al. Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms and toxicity to capecitabine in advanced colorectal cancer patients. Clin Cancer Res 2008; 14: 817–825.

    Article  CAS  PubMed  Google Scholar 

  67. Meropol NJ, Gold PJ, Diasio RB, Andria M, Dhami M, Godfrey T et al. Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 2006; 24: 4069–4077.

    Article  CAS  PubMed  Google Scholar 

  68. Nishimura G, Terada I, Kobayashi T, Ninomiya I, Kitagawa H, Fushida S et al. Thymidine phosphorylase and dihydropyrimidine dehydrogenase levels in primary colorectal cancer show a relationship to clinical effects of 5′-deoxy-5-fluorouridine as adjuvant chemotherapy. Oncol Rep 2002; 9: 479–482.

    CAS  PubMed  Google Scholar 

  69. Saif MW, Black G, Roy S, Bell D, Russo S, Eloubeidi MA et al. Phase II study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: up-regulation of thymidine phosphorylase. Cancer J 2007; 13: 247–256.

    Article  CAS  PubMed  Google Scholar 

  70. Kocakova I, Svoboda M, Kubosova K, Chrenko V, Roubalova E, Krejci E et al. Preoperative radiotherapy and concomitant capecitabine treatment induce thymidylate synthase and thymidine phosphorylase mRNAs in rectal carcinoma. Neoplasma 2007; 54: 447–453.

    CAS  PubMed  Google Scholar 

  71. Puglisi F, Cardellino GG, Crivellari D, Di Loreto C, Magri MD, Minisini AM et al. Thymidine phosphorylase expression is associated with time to progression in patients receiving low-dose, docetaxel-modulated capecitabine for metastatic breast cancer. Ann Oncol 2008; 19: 1541–1546.

    Article  CAS  PubMed  Google Scholar 

  72. Layman RM, Thomas DG, Griffith KA, Smerage JB, Helvie MA, Roubidoux MA et al. Neoadjuvant docetaxel and capecitabine and the use of thymidine phosphorylase as a predictive biomarker in breast cancer. Clin Cancer Res 2007; 13: 4092–4097.

    Article  CAS  PubMed  Google Scholar 

  73. Toi M, Bando H, Horiguchi S, Takada M, Kataoka A, Ueno T et al. Modulation of thymidine phosphorylase by neoadjuvant chemotherapy in primary breast cancer. Br J Cancer 2004; 90: 2338–2343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938–2947.

    Article  CAS  PubMed  Google Scholar 

  75. Raymond E, Faivre S, Woynarowski JM, Chaney SG . Oxaliplatin: mechanism of action and antineoplastic activity. Semin Oncol 1998; 25: 4–12.

    CAS  PubMed  Google Scholar 

  76. Viguier J, Boige V, Miquel C, Pocard M, Giraudeau B, Sabourin JC et al. ERCC1 codon 118 polymorphism is a predictive factor for the tumor response to oxaliplatin/5-fluorouracil combination chemotherapy in patients with advanced colorectal cancer. Clin Cancer Res 2005; 11: 6212–6217.

    Article  CAS  PubMed  Google Scholar 

  77. Pare L, Marcuello E, Altes A, Rio ED, Sedano L, Salazar J et al. Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy. Br J Cancer 2008.

  78. Park DJ, Zhang W, Stoehlmacher J, Tsao-Wei D, Groshen S, Gil J et al. ERCC1 gene polymorphism as a predictor for clinical outcome in advanced colorectal cancer patients treated with platinum-based chemotherapy. Clin Adv Hematol Oncol 2003; 1: 162–166.

    PubMed  Google Scholar 

  79. Ruzzo A, Graziano F, Loupakis F, Rulli E, Canestrari E, Santini D et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol 2007; 25: 1247–1254.

    Article  CAS  PubMed  Google Scholar 

  80. Stoehlmacher J, Park DJ, Zhang W, Yang D, Groshen S, Zahedy S et al. A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer 2004; 91: 344–354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Shirota Y, Stoehlmacher J, Brabender J, Xiong YP, Uetake H, Danenberg KD et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 2001; 19: 4298–4304.

    Article  CAS  PubMed  Google Scholar 

  82. Longley DB, McDermott U, Johnston PG . Clinical significance of prognostic and predictive markers in colorectal cancer. Pharmacogenomics J 2002; 2: 209–216.

    Article  CAS  PubMed  Google Scholar 

  83. Le M, V, Smith D, Laurand A, Brouste V, Bellott R et al. Determination of ERCC2 Lys751Gln and GSTP1 Ile105Val gene polymorphisms in colorectal cancer patients: relationships with treatment outcome. Pharmacogenomics 2007; 8: 1693–1703.

    Article  Google Scholar 

  84. Park DJ, Stoehlmacher J, Zhang W, Tsao-Wei DD, Groshen S, Lenz HJ . A Xeroderma pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer. Cancer Res 2001; 61: 8654–8658.

    CAS  PubMed  Google Scholar 

  85. Stoehlmacher J, Ghaderi V, Iobal S, Groshen S, Tsao-Wei D, Park D et al. A polymorphism of the XRCC1 gene predicts for response to platinum based treatment in advanced colorectal cancer. Anticancer Res 2001; 21: 3075–3079.

    CAS  PubMed  Google Scholar 

  86. Prewett M, Deevi DS, Bassi R, Fan F, Ellis LM, Hicklin DJ et al. Tumors established with cell lines selected for oxaliplatin resistance respond to oxaliplatin if combined with cetuximab. Clin Cancer Res 2007; 13: 7432–7440.

    Article  CAS  PubMed  Google Scholar 

  87. Balin-Gauthier D, Delord JP, Pillaire MJ, Rochaix P, Hoffman JS, Bugat R et al. Cetuximab potentiates oxaliplatin cytotoxic effect through a defect in NER and DNA replication initiation. Br J Cancer 2008; 98: 120–128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Stoehlmacher J, Park DJ, Zhang W, Groshen S, Tsao-Wei DD, Yu MC et al. Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer. J Natl Cancer Inst 2002; 94: 936–942.

    Article  CAS  PubMed  Google Scholar 

  89. Glasgow SC, Yu J, Carvalho LP, Shannon WD, Fleshman JW, McLeod HL . Unfavourable expression of pharmacologic markers in mucinous colorectal cancer. Br J Cancer 2005; 92: 259–264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lecomte T, Landi B, Beaune P, Laurent-Puig P, Loriot MA . Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy. Clin Cancer Res 2006; 12: 3050–3056.

    Article  CAS  PubMed  Google Scholar 

  91. Gamelin L, Capitain O, Morel A, Dumont A, Traore S, Anne lB et al. Predictive factors of oxaliplatin neurotoxicity: the involvement of the oxalate outcome pathway. Clin Cancer Res 2007; 13: 6359–6368.

    Article  CAS  PubMed  Google Scholar 

  92. Cunningham D, Glimelius B . A phase III study of irinotecan (CPT-11) versus best supportive care in patients with metastatic colorectal cancer who have failed 5-fluorouracil therapy. V301 Study Group. Semin Oncol 1999; 26: 6–12.

    CAS  PubMed  Google Scholar 

  93. Saltz LB, Douillard JY, Pirotta N, Alakl M, Gruia G, Awad L et al. Irinotecan plus fluorouracil/leucovorin for metastatic colorectal cancer: a new survival standard. Oncologist 2001; 6: 81–91.

    Article  CAS  PubMed  Google Scholar 

  94. Clarke DJ, Moghrabi N, Monaghan G, Cassidy A, Boxer M, Hume R et al. Genetic defects of the UDP-glucuronosyltransferase-1 (UGT1) gene that cause familial non-haemolytic unconjugated hyperbilirubinaemias. Clin Chim Acta 1997; 266: 63–74.

    Article  CAS  PubMed  Google Scholar 

  95. Kweekel DM, Gelderblom H, Van der ST, Antonini NF, Punt CJ, Guchelaar HJ . UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group study. Br J Cancer 2008; 99: 275–282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cote JF, Kirzin S, Kramar A, Mosnier JF, Diebold MD, Soubeyran I et al. UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan. Clin Cancer Res 2007; 13: 3269–3275.

    Article  CAS  PubMed  Google Scholar 

  97. Lampe JW, Bigler J, Horner NK, Potter JD . UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations. Pharmacogenetics 1999; 9: 341–349.

    Article  CAS  PubMed  Google Scholar 

  98. Minami H, Sai K, Saeki M, Saito Y, Ozawa S, Suzuki K et al. Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28. Pharmacogenet Genomics 2007; 17: 497–504.

    Article  CAS  PubMed  Google Scholar 

  99. Iyer L, Das S, Janisch L, Wen M, Ramirez J, Karrison T et al. UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2002; 2: 43–47.

    Article  CAS  PubMed  Google Scholar 

  100. Mathijssen RH, Marsh S, Karlsson MO, Xie R, Baker SD, Verweij J et al. Irinotecan pathway genotype analysis to predict pharmacokinetics. Clin Cancer Res 2003; 9: 3246–3253.

    CAS  PubMed  Google Scholar 

  101. Sai K, Kaniwa N, Itoda M, Saito Y, Hasegawa R, Komamura K et al. Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan. Pharmacogenetics 2003; 13: 741–757.

    Article  CAS  PubMed  Google Scholar 

  102. McLeod HL, Owzar K, Kroetz D, Innocenti F, Das S, Friedman P et al. Cellular transporter pharmacogenetics in metastatic colorectal cancer: Initial analysis of C80203. J Clin Oncol (meeting abstracts) 2008; 26: 3513.

    Article  Google Scholar 

  103. Sai K, Saito Y, Fukushima-Uesaka H, Kurose K, Kaniwa N, Kamatani N et al. Impact of CYP3A4 haplotypes on irinotecan pharmacokinetics in Japanese cancer patients. Cancer Chemother Pharmacol 2008; 62: 529–537.

    Article  CAS  PubMed  Google Scholar 

  104. Vallbohmer D, Iqbal S, Yang DY, Rhodes KE, Zhang W, Gordon M et al. Molecular determinants of irinotecan efficacy. Int J Cancer 2006; 119: 2435–2442.

    Article  CAS  PubMed  Google Scholar 

  105. Hoskins JM, Marcuello E, Altes A, Marsh S, Maxwell T, Van Booven DJ et al. Irinotecan pharmacogenetics: influence of pharmacodynamic genes. Clin Cancer Res 2008; 14: 1788–1796.

    Article  CAS  PubMed  Google Scholar 

  106. Saltz LB, Meropol NJ, Loehrer Sr PJ, Needle MN, Kopit J, Mayer RJ . Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004; 22: 1201–1208.

    Article  CAS  PubMed  Google Scholar 

  107. Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 2006; 24: 4914–4921.

    Article  CAS  PubMed  Google Scholar 

  108. Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006; 66: 3992–3995.

    Article  CAS  PubMed  Google Scholar 

  109. Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008; 26: 374–379.

    Article  CAS  PubMed  Google Scholar 

  110. Van Cutsem E, Lang I, D′haens G, Moiseyenko V, Zaluski J, Folprecht G et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol (meeting abstracts) 2008; 26: 2.

    Article  Google Scholar 

  111. Bokemeyer C, Bondarenko I, Hartmann JT, De Braud FG, Volovat C, Nippgen J et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience. J Clin Oncol (meeting abstracts) 2008; 26: 4000.

    Article  Google Scholar 

  112. Karapetis CS, Khambata-Ford S, Jonker DJ, O′Callaghan CJ, Tu D, Tebbutt NC et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359: 1757–1765.

    Article  CAS  PubMed  Google Scholar 

  113. Velho S, Moutinho C, Cirnes L, Albuquerque C, Hamelin R, Schmitt F et al. BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: primary or secondary genetic events in colorectal carcinogenesis? BMC Cancer 2008; 8: 255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Finocchiaro G, Cappuzzo F, Rossi E, Toschi L, Janne PA, Roncalli M et al. Insuline like growth factor receptor-1 (IGFR-1), MET, and BRAF and primary resistance to cetuximab therapy in colorectal cancer patients. J Clin Oncol (meeting abstracts) 2008; 26: 4135.

    Article  Google Scholar 

  115. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008; 26: 5705–5712.

    Article  CAS  PubMed  Google Scholar 

  116. Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 2007; 97: 1139–1145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Loupakis F, Pollina L, Stasi I, Masi G, Funel N, Scartozzi M et al. Evaluation of PTEN expression in colorectal cancer (CRC) metastases (mets) and in primary tumors as predictors of activity of cetuximab plus irinotecan treatment. J Clin Oncol (meeting abstracts) 2008; 26: 4003.

    Article  Google Scholar 

  118. 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: 617–628.

    Article  CAS  PubMed  Google Scholar 

  119. Cappuzzo F, Finocchiaro G, Rossi E, Janne PA, Carnaghi C, Calandri C et al. EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol 2008; 19: 717–723.

    Article  CAS  PubMed  Google Scholar 

  120. Sartore-Bianchi A, Moroni M, Veronese S, Carnaghi C, Bajetta E, Luppi G et al. Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J Clin Oncol 2007; 25: 3238–3245.

    Article  CAS  PubMed  Google Scholar 

  121. Personeni N, Fieuws S, Piessevaux H, De Hertogh G, De Schutter J, Biesmans B et al. Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res 2008; 14: 5869–5876.

    Article  CAS  PubMed  Google Scholar 

  122. Italiano A, Follana P, Caroli FX, Badetti JL, Benchimol D, Garnier G et al. Cetuximab shows activity in colorectal cancer patients with tumors for which FISH analysis does not detect an increase in EGFR gene copy number. Ann Surg Oncol 2008; 15: 649–654.

    Article  PubMed  Google Scholar 

  123. Wong R, Cunningham D . Using predictive biomarkers to select patients with advanced colorectal cancer for treatment with epidermal growth factor receptor antibodies. J Clin Oncol 2008; 26: 5668–5670.

    Article  CAS  PubMed  Google Scholar 

  124. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: 1626–1634.

    Article  CAS  PubMed  Google Scholar 

  125. Doger FK, Meteoglu I, Tuncyurek P, Okyay P, Cevikel H . Does the EGFR and VEGF expression predict the prognosis in colon cancer? Eur Surg Res 2006; 38: 540–544.

    Article  CAS  PubMed  Google Scholar 

  126. Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM . Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995; 55: 3964–3968.

    CAS  PubMed  Google Scholar 

  127. Harada Y, Ogata Y, Shirouzu K . Expression of vascular endothelial growth factor and its receptor KDR (kinase domain-containing receptor)/Flk-1 (fetal liver kinase-1) as prognostic factors in human colorectal cancer. Int J Clin Oncol 2001; 6: 221–228.

    Article  CAS  PubMed  Google Scholar 

  128. Jubb AM, Hurwitz HI, Bai W, Holmgren EB, Tobin P, Guerrero AS et al. Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol 2006; 24: 217–227.

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Medicine, Royal Marsden Hospital, Sutton, UK

    A S Strimpakos

  2. Section of Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA

    K N Syrigos & M W Saif

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Strimpakos, A., Syrigos, K. & Saif, M. Pharmacogenetics and biomarkers in colorectal cancer. Pharmacogenomics J 9, 147–160 (2009). https://doi.org/10.1038/tpj.2009.8

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