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Abstract: colorectal cancer remains one of the most common types of cancer and leading causes of cancer death worldwide. Although we have made steady progress in chemotherapy and targeted therapy, evidence suggests that the majority of patients undergoing drug therapy experience severe, debilitating, and even lethal adverse drug events which considerably outweigh the benefits. The identification of suitable biomarkers will allow clinicians to deliver the most appropriate drugs to specific patients and spare them ineffective and expensive treatments. Prognostic and predictive biomarkers have been the subjects of many published papers, but few have been widely incorporated into clinical practice. Here, we want to review recent biomarker data related to colorectal cancer, which may have been ready for clinical use.

[1]Afzal, S., Jensen, S.A., Vainer, B., Vogel, U., Matsen, J.P., Sørensen, J.B., Andersen, P.K., Poulsen, H.E., 2009. MTHFR polymorphisms and 5-FU-based adjuvant chemotherapy in colorectal cancer. Ann. Oncol., 20(10):1660-1666.

[2]Akiyama, Y., Fujita, K., Nagashima, F., Yamamoto, W., Endo, H., Sunakawa, Y., Yamashita, K., Ishida, H., Mizuno, K., Araki, K., et al., 2008. Genetic testing for UGT1A1*28 and *6 in Japanese patients who receive irinotecan chemotherapy. Ann. Oncol., 19(12):2089-2090.

[3]Andreetta, C., Puppin, C., Minisini, A., Valent, F., Pegolo, E., Damante, G., di Loreto, C., Pizzolitto, S., Pandolfi, M., Fasola, G., et al., 2009. Thymidine phosphorylase expression and benefit from capecitabine in patients with advanced breast cancer. Ann. Oncol., 20(2):265-271.

[4]Best, L., Simmonds, P., Baughan, C., Buchanan, R., Davis, C., Fentiman, I., George, S., Gosney, M., Northover, J., Williams, C., 2000. Palliative chemotherapy for advanced or metastatic colorectal cancer. Cochrane Database Syst. Rev., (2):CD001545.

[5]Beutler, E., Gelbart, T., Demina, A., 1998. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? PNAS, 95(14):8170-8174.

[6]Bokemeyer, C., Bondarenko, I., Makhson, A., Hartmann, J.T., Aparicio, J., de Braud, F., Donea, S., Ludwig, H., Schuch, G., Stroh, C., et al., 2009. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol., 27(5):663-671.

[7]Boland, C.R., Thibodeau, S.N., Hamilton, S.R., Sidransky, D., Eshleman, J.R., Burt, R.W., Meltzer, S.J., Rodriguez-Bigas, M.A., Fodde, R., Ranzani, G.N., et al., 1998. A national cancer institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res., 58(22):5248-5257.

[8]Cassidy, J., Tabernero, J., Twelves, C., Brunet, R., Butts, C., Conroy, T., Debraud, F., Figer, A., Grossmann, J., Sawada, N., et al., 2004. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J. Clin. Oncol., 22(11):2084-2091.

[9]Chibaudel, B., Tournigand, C., André, T., Larsen, A.K., de Gramont, A., 2010. Targeted therapies as adjuvant treatment for early-stage colorectal cancer: first impressions and clinical questions. Clin. Colorectal Cancer, 9(5):269-273.

[10]Cohen, V., Panet-Raymond, V., Sabbaghian, N., Morin, I., Batist, G., Rozen, R., 2003. Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Clin. Cancer Res., 9(5):1611-1615.

[11]Colucci, G., Gebbia, V., Paoletti, G., Giuliani, F., Caruso, M., Gebbia, N., Cartenì, G., Agostara, B., Pezzella, G., Manzione, L., et al., 2005. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell′Italia Meridionale. J. Clin. Oncol., 23(22):4866-4875.

[12]Coursier, S., Martelet, S., Guillermet, A., Emptoz, J., Villier, C., Bontemps, H., 2010. Severe toxicity following capecitabine administration because of dihydropyrimidine deshydrogenase (DPD) deficiency. Gastroenterol. Clin. Biol., 34(3):218-223.

[13]de Roock, W., Piessevaux, H., de Schutter, J., Janssens, M., de Hertogh, G., Personeni, N., Biesmans, B., van Laethem, J.L., Peeters, M., Humblet, Y., et al., 2008. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann. Oncol., 19(3):508-515.

[14]de Roock, W., Jonker, D.J., di Nicolantonio, F., Sartore-Bianchi, A., Tu, D., Siena, S., Lamba, S., Arena, S., Frattini, M., Piessevaux, H., et al., 2010a. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA, 304(16):1812-1820.

[15]de Roock, W., Claes, B., Bernasconi, D., de Schutter, J., Biesmans, B., Fountzilas, G., Kalogeras, K.T., Kotoula, V., Papamichael, D., Laurent-Puig, P., et al., 2010b. Effects of KRAS, BRAF, NRAS, and PIK3A, mutations on the efficacy of cetuximab plus chemotherapy in chemotehrapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol., 11(8):753-762.

[16]Diep, C.B., Thorstensen, L., Meling, G.I., Skovlund, E., Rognum, T.O., Lothe, R.A., 2003. Genetic tumor markers with prognostic impact in Dukes’ stages B and C colorectal cancer patients. J. Clin. Oncol., 21(5):820-829.

[17]Eschrich, S., Yang, I., Bloom, G., Kwong, K.Y., Boulware, D., Cantor, A., Coppola, D., Kruhøffer, M., Aaltonen, L., Orntoft, T.F., et al., 2005. Molecular staging for survival prediction of colorectal cancer patients. J. Clin. Oncol., 23(15):3526-3535.

[18]Formica, V., Palmirotta, R., del Monte, G., Savonarola, A., Ludovici, G., de Marchis, M.L., Grenga, I., Schirru, M., Guadagni, F., Roselli, M., 2011. Predictive value of VEGF gene polymorphisms for metastatic colorectal cancer patients receiving first-line treatment including fluorouracil, irinotecan, and bevacizumab. Int. J. Colorectal Dis., 26(2):143-151.

[19]French, A.J., Sargent, D.J., Burgart, L.J., Foster, N.R., Kabat, B.F., Goldberg, R., Shepherd, L., Windschitl, H.E., Thibodeau, S.N., 2008. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin. Cancer Res., 14(11):3408-3415.

[20]Fuchs, C.S., Marshall, J., Mitchell, E., Wierzbicki, R., Ganju, V., Jeffery, M., Schulz, J., Richards, D., Soufi-Mahjoubi, R., Wang, B., et al., 2007. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C study. J. Clin. Oncol., 25(30):4779-4786.

[21]Gao, J., Lu, M., Yu, J.W., Li, Y.Y., Shen, L., 2011. Thymidine Phosphorylase/β-tubulin III expressions predict the response in Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel. BMC Cancer, 11:177.

[22]Garman, K.S., Acharya, C.R., Edelman, E., Grade, M., Gaedcke, J., Sud, S., Barry, W., Diehl, A.M., Provenzale, D., Ginsburg, G.S., et al., 2008. A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities. PNAS, 105(49):19432-19437.

[23]Gill, S., Loprinzi, C.L., Sargent, D.J., Thomé, S.D., Alberts, S.R., Haller, D.G., Benedetti, J., Francini, G., Shepherd, L.E., Francois, S.J., et al., 2004. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J. Clin. Oncol., 22(10):1797-1806.

[24]Gray, R., Barnwell, J., McConkey, C., Hills, R.K., Williams, N.S., Kerr, D.J., 2007. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet, 370(9604):2020-2029.

[25]Gray, R.G., Quirke, P., Handley, K., Lopatin, M., Magill, L., Baehner, F.L., Beaumont, C., Clark-Langone, K.M., Yoshizawa, C.N., Lee, M., et al., 2011. Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J. Clin. Oncol., 29(35):4611-4619.

[26]Hoskins, J.M., Goldberg, R.M., Qu, P., Ibrahim, J.G., McLeod, H.L., 2007. UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J. Natl. Cancer Inst., 99(17):1290-1295.

[27]Hotta, T., Taniguchi, K., Kobayashi, Y., Johata, K., Sahara, M., Naka, T., Watanabe, T., Ochiai, M., Tanimura, H., Tsubota, Y.T., 2004. Increased expression of thymidine phosphorylase in tumor tissue in proportion to TP-expression in primary normal tissue. Oncol. Rep., 12(3):539-541.

[28]Huang, M.Y., Huang, M.L., Chen, M.J., Lu, C.Y., Chen, C.F., Tsai, P.C., Chuang, S.C., Hou, M.F., Lin, S.R., Wang, J.Y., 2011. Multiple genetic polymorphisms in the prediction of clinical outcome of metastatic colorectal cancer patients treated with first-line FOLFOX-4 chemotherapy. Pharmacogenet. Genomics, 21(1):18-25.

[29]Hurwitz, H., Fehrenbacher, L., Novotny, W., Cartwright, T., Hainsworth, J., Heim, W., Berlin, J., Baron, A., Griffing, S., Holmgren, E., et al., 2004. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med., 350:2335-2342.

[30]Hurwitz, H.I., Yi, J., Ince, W., Novotny, W.F., Rosen, O., 2009. The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of KRAS mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist, 14(1):22-28.

[31]Iacopetta, B., Russo, A., Bazan, V., Dardanoni, G., Gebbia, N., Soussi, T., Kerr, D., Elsaleh, H., Soong, R., Kandioler, D., et al., 2006. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study. Ann. Oncol., 17(5):842-847.

[32]Inada, M., Sato, M., Morita, S., Kitagawa, K., Kawada, K., Mitsuma, A., Sawaki, M., Fujita, K., Ando, Y., 2010. Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the ERCC1 and GSTP1 genes. Int. J. Clin. Pharmacol. Ther., 48(11):729-734.

[33]Innocenti, F., Undevia, S.D., Iyer, L., Chen, P.X., Das, S., Kocherginsky, M., Karrison, T., Janisch, L., Ramírez, J., Rudin, C.M., et al., 2004. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J. Clin. Oncol., 22(8):1382-1388.

[34]Innocenti, F., Kroetz, D.L., Schuetz, E., Dolan, M.E., Ramírez, J., Relling, M., Chen, P., Das, S., Rosner, G.L., Ratain, M.J., 2009. Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. J. Clin. Oncol., 27(16):2604-2614.

[35]Jada, S.R., Lim, R., Wong, C.I., Shu, X., Lee, S.C., Zhou, Q., Goh, B.C., Chowbay, B., 2007. Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan induced neutropenia in Asian cancer patients. Cancer Sci., 98(9):1461-1467.

[36]Jakobsen, A., Nielsen, J.N., Gyldenkerne, N., Lindeberg, J., 2005. Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J. Clin. Oncol., 23(7):1365-1369.

[37]Jorissen, R.N., Gibbs, P., Christie, M., Prakash, S., Lipton, L., Desai, J., Kerr, D., Aaltonen, L.A., Arango, D., Kruhøffer, M., et al., 2009. Metastasis-associated gene expression changes predict poor outcomes in patients with Dukes stage B and C colorectal cancer. Clin. Cancer Res., 15(24):7642-7651.

[38]Kalow, W., Tang, B., Endrenyi, L., 1998. Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research. Pharmacogenetics, 8(4):283-289.

[39]Kaniwa, N., Kurose, K., Jinno, H., Tanaka-Kagawa, T., Saito, Y., Saeki, M., Sawada, J., Tohkin, M., Hasegawa, R., 2005. Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C>T (P229L) found in an African-American. Drug Metab. Dispos., 33(3):458-465.

[40]Karapetis, C.S., Khambata-Ford, S., Jonker, D.J., O'Callaghan, C.J., Tu, D., Tebbutt, N.C., Simes, R.J., Chalchal, H., Shapiro, J.D., Robitaille, S., et al., 2008. KRAS mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med., 359(17):1757-1765.

[41]Kawakami, K., Omura, K., Kanehira, E., Watanabe, Y., 1999. Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res., 19(4B):3249-3252.

[42]Khambata-Ford, S., Garrett, C.R., Meropol, N.J., Basik, M., Harbison, C.T., Wu, S., Wong, T.W., Huang, X., Takimoto, C.H., Godwin, A.K., et al., 2007. Expression of epiregulin and amphiregulin and KRAS mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J. Clin. Oncol., 25(22):3230-3237.

[43]Köhne, C.H., Lenz, H.J., 2009. Chemotherapy with targeted agents for the treatment of metastatic colorectal cancer. Oncologist, 14(5):478-488.

[44]Lamas, M.J., Duran, G., Balboa, E., Bernardez, B., Touris, M., Vidal, Y., Gallardo, E., Lopez, R., Carracedo, A., Barros, F., 2011. Use of a comprehensive panel of biomarkers to predict response to a fluorouracil-oxaliplatin regimen in patients with metastatic colorectal cancer. Pharmacogenomics, 12(3):433-442.

[45]Lecomte, T., Landi, B., Beaune, P., Laurent-Puig, P., Loriot, M.A., 2006. Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy. Clin. Cancer Res., 12(10):3050-3056.

[46]Lièvre, A., Bachet, J.B., le Corre, D., Boige, V., Landi, B., Emile, J.F., Côté, J.F., Tomasic, G., Penna, C., Ducreux, M., et al., 2006. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res., 66(8):3992-3995.

[47]Marsh, S., McLeod, H., 2001. Thymidylate synthase pharmacogenetics in colorectal cancer. Clin. Colorectal. Cancer, 1(3):175-178.

[48]Mattison, L.K., Soong, R., Diasio, R.B., 2002. Implications of dihydropyrimidine dehydrogenase on 5-fluorouracil pharmacogenetics and pharmacogenomics. Pharmacogenomics, 3(4):485-492.

[49]Mayer, A., Takimoto, M., Fritz, E., Schellander, G., Kofler, K., Ludwig, H., 1993. The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer. Cancer, 71(8):2454-2460.

[50]Mcleod, H.L., Sargent, D.J., Marsh, S., Green, E.M., King, C.R., Fuchs, C.S., Ramanathan, R.K., Williamson, S.K., Findlay, B.P., Thibodeau, S.N., et al., 2010. Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741. J. Clin. Oncol., 28(20):3227-3233.

[51]Milano, G., Etienne, M.C., Pierrefite, V., Barberi-Heyob, M., Deporte-Fety, R., Renée, N., 1999. Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity. Br. J. Cancer, 79:627-630.

[52]Moreno, V., Gemignani, F., Landi, S., Gioia-Patricola, L., Chabrier, A., Blanco, I., González, S., Guino, E., Capellà, G., Canzian, F., 2006. Polymorphisms in genes of nucleotide and base excision repair: risk and prognosis of colorectal cancer. Clin. Cancer Res., 12(7Pt1):2101-2108.

[53]Moroni, M., Veronese, S., Benvenuti, S., Marrapese, G., Sartore-Bianchi, A., di Nicolantonio, F., Gambacorta, M., Siena, S., Bardelli, A., 2005. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol., 6(5):279-286.

[54]Moroni, M., Sartore-Bianchi, A., Veronese, S., Siena, S., 2008. EGFR FISH in colorectal cancer: what is the current reality? Lancet Oncol., 9(5):402-403.

[55]O′Connell, M.J., Lavery, I., Yothers, G., Paik, S., Clark-Langone, K.M., Lopatin, M., Watson, D., Baehner, F.L., Shak, S., Baker, J., et al., 2010. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J. Clin. Oncol., 28:3937-3944.

[56]Palomaki, G.E., Bradley, L.A., Douglas, M.P., Kolor, K., Dotson, W.D., 2009. Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review. Genet. Med., 11(1):21-34.

[57]Petrioli, R., Bargagli, G., Lazzi, S., Pascucci, A., Francini, E., Bellan, C., Conca, R., Martellucci, I., Fiaschi, A.I., Lorenzi, B., et al., 2010. Thymidine phosphorylase expression in metastatic sites is predictive for response in patients with colorectal cancer treated with continuous oral capecitabine and biweekly oxaliplatin. Anticancer Drugs, 21(3):313-319.

[58]Popat, S., Hubner, R., Houlston, R.S., 2005. Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol., 23(3):609-618.

[59]Raida, M., Schwabe, W., Hausler, P., van Kuilenburg, A.B., van Gennip, A.H., Behnke, D., Höffken, K., 2001. Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5′-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)-related toxicity compared with controls. Clin. Cancer Res., 7(9):2832-2839.

[60]Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K.W., Vogelstein, B., Velculescu, V.E., 2002. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature, 418(6901):934.

[61]Ribic, C.M., Sargent, D.J., Moore, M.J., Thibodeau, S.N., French, A.J., Goldberg, R.M., Hamilton, S.R., Laurent-Puig, P., Gryfe, R., Shepherd, L.E., et al., 2003. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N. Engl. J. Med., 349(3):247-257.

[62]Roth, A.D., Tejpar, S., Delorenzi, M., Yan, P., Fiocca, R., Klingbiel, D., Dietrich, D., Biesmans, B., Bodoky, G., Barone, C., et al., 2010. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J. Clin. Oncol., 28(3):466-474.

[63]Sartore-Bianchi, A., Moroni, M., Veronese, S., Carnaghi, C., Bajetta, E., Luppi, G., Sobrero, A., Barone, C., Cascinu, S., Colucci, G., et al., 2007. Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J. Clin. Oncol., 25(22):3238-3245.

[64]Scaltriti, M., Baselga, J., 2006. The epidermal growth factor receptor pathway: a model for targeted therapy. Clin. Cancer Res., 12(18):5268-5272.

[65]Scartozzi, M., Galizia, E., Chiorrini, S., Giampieri, R., Berardi, R., Pierantoni, C., Cascinu, S., 2009. Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann. Oncol., 20(2):227-230.

[66]Schneider, B.P., Wang, M., Radovich, M., Sledge, G.W., Badve, S., Thor, A., Flockhart, D.A., Hancock, B., Davidson, N., Gralow, J., et al., 2008. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J. Clin. Oncol., 26(28):4672-4678.

[67]Schultheis, A.M., Lurje, G., Rhodes, K.E., Zhang, W., Yang, D., Garcia, A.A., Morgan, R., Gandara, D., Scudder, S., Oza, A., et al., 2008. Polymorphisms and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab. Clin. Cancer Res., 14(22):7554-7563.

[68]Seck, K., Riemer, S., Kates, R., Ullrich, T., Lutz, V., Harbeck, N., Schmitt, M., Kiechle, M., Diasio, R., Gross, E., 2005. Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in a cohort of Caucasian individuals. Clin. Cancer Res., 11(16):5886-5892.

[69]Segaert, S., Chiritescu, G., Lemmens, L., Dumon, K., van Cutsem, E., Tejpar, S., 2009. Skin toxicities of targeted therapies. Eur. J. Cancer, 45(Suppl. 1):295-308.

[70]Siegel, R., Ward, E., Brawley, O., Jemal, A., 2011. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J. Clin., 61(4):212-236.

[71]Siena, S., Sartore-Bianchi, A., di Nicolantonio, F., Balfour, J., Bardelli, A., 2009. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J. Natl. Cancer Inst., 101(19):1308-1324.

[72]Sinicrope, F.A., Foster, N.R., Thibodeau, S.N., Marsoni, S., Monges, G., Labianca, R., Yothers, G., Allegra, C., Moore, M.J., Gallinger, S., et al., 2011. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J. Natl. Cancer Inst., 103(11):863-875.

[73]Spano, J.P., Fagard, R., Soria, J.C., Rixe, O., Khayat, D., Milano, G., 2005. Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspectives. Ann. Oncol., 16(2):189-194.

[74]Stockmann, C., Doedens, A., Weidemann, A., Zhang, N., Takeda, N., Greenberg, J.I., Cheresh, D.A., Johnson, R.S., 2008. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature, 456:814-818.

[75]Sugatani, J., Yamakawa, K., Yoshinari, K., Machida, T., Takagi, H., Mori, M., Kakizaki, S., Sueyoshi, T., Negishi, M., Miwa, M., 2002. Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia. Biochem. Biophys. Res. Commun., 292(2):492-497.

[76]Suh, K.W., Kim, J.H., Kim, D.Y., Kim, Y.B., Lee, C., Choi, S., 2006. Which gene is a dominant predictor of response during FOLFOX chemotherapy for the treatment of metastatic colorectal cancer, the MTHFR or XRCC1 gene? Ann. Surg. Oncol., 13(11):1379-1385.

[77]van Kuilenburg, A.B., Meinsma, R., Zoetekouw, L., van Gennip, A.H., 2002. Increased risk of grade IV neutropenia after administration of 5-fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: high prevalence of the IVS14+1G>A mutation. Int. J. Cancer, 101(3):253-258.

[78]Villafranca, E., Okruzhnov, Y., Dominguez, M.A., García-Foncillas, J., Azinovic, I., Martínez, E., Illarramendi, J.J., Arias, F., Martínez Monge, R., Salgado, E., et al., 2001. Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J. Clin. Oncol., 19(6):1779-1786.

[79]Walther, A., Johnstone, E., Swanton, C., Midgley, R., Tomlinson, I., Kerr, D., 2009. Genetic prognostic and predictive markers in colorectal cancer. Nat. Rev. Cancer, 9(7):489-499.

[80]Wang, T.L., Diaz, L.A.Jr., Romans, K., Bardelli, A., Saha, S., Galizia, G., Choti, M., Donehower, R., Parmigiani, G., Shih, I.M., et al., 2004. Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. PNAS, 101(9):3089-3094.

[81]Wang, Y., Jatkoe, T., Zhang, Y., Mutch, M.G., Talantov, D., Jiang, J., McLeod, H.L., Atkins, D., 2004. Gene expression profiles and molecular markers to predict recurrence of Dukes’ B colon cancer. J. Clin. Oncol., 22(9):1564-1571.

[82]Watson, R.G., McLeod, H.L., 2011. Pharmacogenomic contribution to drug response. Cancer J., 17(2):80-88.

[83]Weaver, D.A., Crawford, E.L., Warner, K.A., Elkhairi, F., Khuder, S.A., Willey, J.C., 2005. ABCC5, ERCC2, XPA and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines. Mol. Cancer, 4(1):18.

[84]Wei, X., McLeod, H.L., McMurrough, J., Gonzalez, F.J., Fernandez-Salguero, P., 1996. Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J. Clin. Invest., 98(3):610-615.

[85]Weisberg, I., Tran, P., Christensen, B., Sibani, S., Rozen, R., 1998. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol. Genet. Metab., 64(3):169-172.

[86]Weitz, J., Koch, M., Debus, J., Höhler, T., Galle, P.R., Büchler, M.W., 2005. Colorectal cancer. Lancet, 365(9454):153-165.

[87]Yin, M., Yan, J., Martinez-Balibrea, E., Graziano, F., Lenz, H.J., Kim, H.J., Robert, J., Im, S.A., Wang, W.S., Etienne-Grimaldi, M.C., et al., 2011. ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta-analysis. Clin. Cancer Res., 17(6):1632-1640.

[88]Zhang, W., Press, O.A., Haiman, C.A., Yang, D.Y., Gordon, M.A., Fazzone, W., El-Khoueiry, A., Iqbal, S., Sherrod, A.E., Lurje, G., et al., 2007. Association of methylenetetrahydrofolate reductase gene polymorphisms and sex-specific survival in patients with metastatic colon cancer. J. Clin. Oncol., 25(24):3726-3731.