The RAS gene family is among the most studied and best characterized of the known cancer-related genes. Of the three human ras isoforms, KRAS is the most frequently altered gene, with mutations occurring in 17%–25% of all cancers. In particular, approximately 30%–40% of colon cancers harbor a KRAS mutation. KRAS mutations in colon cancers have been associated with poorer survival and increased tumor aggressiveness. Additionally, KRAS mutations in colorectal cancer lead to resistance to select treatment strategies. In this review we examine the history of KRAS, its prognostic value in patients with colorectal cancer, and evidence supporting its predictive value in determining appropriate therapies for patients with colorectal cancer.
References
[1]
Almoguera, C.; Shibata, D.; Forrester, K.; Martin, J.; Arnheim, N.; Perucho, M. Most human carcinomas of the exocrine pancreas contain mutant C-K-Ras genes. Cell 1988, 53, 549–554.
[2]
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. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann. Oncol 2008, 19, 508–515.
[3]
Bell, S.M.; Scott, N.; Cross, D.; Sagar, P.; Lewis, F.A.; Blair, G.E.; Taylor, G.R.; Dixon, M.F.; Quirke, P. Prognostic value of p53 overexpression and c-Ki-ras gene mutations in colorectal cancer. Gastroenterology 1993, 104, 57–64.
[4]
Vogelstein, B.; Fearon, E.R.; Hamilton, S.R.; Kern, S.E.; Preisinger, A.C.; Leppert, M.; Nakamura, Y.; White, R.; Smits, A.M.; Bos, J.L. Genetic alterations during colorectal-tumor development. N. Engl. J. Med 1988, 319, 525–532.
[5]
Kranenburg, O. The KRAS oncogene: Past, present, and future. Biochim. Biophys. Acta 2005, 1756, 81–82.
[6]
Stratton, M.R.; Fisher, C.; Gusterson, B.A.; Cooper, C.S. Detection of point mutations in n-ras and k-ras genes of human embryonal rhabdomyosarcomas using oligonucleotide probes and the polymerase chain-reaction. Cancer Res 1989, 49, 6324–6327.
[7]
Baines, A.T.; Xu, D.; Der, C.J. Inhibition of Ras for cancer treatment: The search continues. Future Med. Chem 2011, 3, 1787–1808.
[8]
Bamford, S.; Dawson, E.; Forbes, S.; Clements, J.; Pettett, R.; Dogan, A.; Flanagan, A.; Teague, J.; Futreal, P.A.; Stratton, M.R.; et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br. J. Cancer 2004, 91, 355–358.
[9]
Rodenhuis, S.; Slebos, R.J.; Boot, A.J.; Evers, S.G.; Mooi, W.J.; Wagenaar, S.S.; van Bodegom, P.C.; Bos, J.L. Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res 1988, 48, 5738–5741.
[10]
Malumbres, M.; Barbacid, M. RAS oncogenes: The first 30 years. Nat. Rev. Cancer 2003, 3, 459–465.
Bos, J.L.; Fearon, E.R.; Hamilton, S.R.; Verlaan-de Vries, M.; van Boom, J.H.; van der Eb, A.J.; Vogelstein, B. Prevalence of ras gene mutations in human colorectal cancers. Nature 1987, 327, 293–297.
[13]
Forrester, K.; Almoguera, C.; Han, K.; Grizzle, W.E.; Perucho, M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 1987, 327, 298–303.
[14]
Capella, G.; Cronauer-Mitra, S.; Pienado, M.A.; Perucho, M. Frequency and spectrum of mutations at codons 12 and 13 of the c-K-ras gene in human tumors. Environ. Health Perspect 1991, 93, 125–131.
[15]
Oudejans, J.J.; Slebos, R.J.C.; Zoetmulder, F.A.N.; Mooi, W.J.; Rodenhuis, S. Differential activation of ras genes by point mutation in human colon cancer with metastases to either lung or liver. Int. J. Cancer 1991, 49, 875–879.
[16]
Burmer, G.C.; Loeb, L.A. Mutations in the KRAS2 oncogene during progressive stages of human colon carcinoma. Proc. Natl. Acad. Sci. USA 1989, 86, 2403–2407.
[17]
Finkelstein, S.D.; Sayegh, R.; Christensen, S.; Swalsky, P.A. Genotypic classification of colorectal adenocarcinoma-biologic behavior correlates with K-Ras-2 mutation type. Cancer 1993, 71, 3827–3838.
[18]
Andreyev, H.J.; Norman, A.R.; Cunningham, D.; Oates, J.R.; Clarke, P.A. Kirsten ras mutations in patients with colorectal cancer: The multicenter “RASCAL” study. J. Natl. Cancer Inst 1998, 90, 675–684.
[19]
Seeburg, P.H.; Colby, W.W.; Capon, D.J.; Goeddel, D.V.; Levinson, A.D. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature 1984, 312, 71–75.
[20]
Chipperfield, R.G.; Jones, S.S.; Lo, K.M.; Weinberg, R.A. Activation of Ha-ras p21 by substitution, deletion, and insertion mutations. Mol. Cell Biol 1985, 5, 1809–1813.
[21]
Andreyev, H.J.; Norman, A.R.; Cunningham, D.; Oates, J.; Dix, B.R.; Iacopetta, B.J.; Young, J.; Walsh, T.; Ward, R.; Hawkins, N.; et al. Kirsten ras mutations in patients with colorectal cancer: The “RASCAL II” study. Br. J. Cancer 2001, 85, 692–696.
[22]
Suchy, B.; Zietz, C.; Rabes, H.M. K-ras point mutations in human colorectal carcinomas: Relation to aneuploidy and metastasis. Int. J. Cancer 1992, 52, 30–33.
[23]
Tanaka, M.; Omura, K.; Watanabe, Y.; Oda, Y.; Nakanishi, I. Prognostic factors of colorectal-cancer - k-ras mutation, overexpression of the P53-protein, and cell proliferative activity. J. Surg. Oncol 1994, 57, 57–64.
[24]
Pricolo, V.E.; Finkelstein, S.D.; Wu, T.T.; Keller, G.; Bakker, A.; Swalsky, P.A.; Bland, K.I. Prognostic value of TP53 and K-ras-2 mutational analysis in stage III carcinoma of the colon. Am. J. Surg 1996, 171, 41–46.
[25]
Troungos, C.; Valavanis, C.; Kapranos, N.; Kittas, C. K-ras mutation in Greek patients with poorly and moderately differenciated tumours of the lower intestinal tract. Anticancer Res 1997, 17, 1399–1404.
[26]
Rochlitz, C.F.; Heide, I.; Dekant, E.; Bohmer, R.; Peter, F.J.; Neuhaus, P.; Huhn, D.; Herrmann, R. Position specificity of ki-ras oncogene mutations during the progression of colorectal-carcinoma. Oncology 1993, 50, 70–76.
[27]
Dix, B.R.; Robbins, P.; Soong, R.; Jenner, D.; House, A.K.; Iacopetta, B.J. The common molecular genetic alterations in Dukes’ B and C colorectal carcinomas are not short-term prognostic indicators of survival. Int. J. Cancer 1994, 59, 747–751.
[28]
Morrin, M.; Kelly, M.; Barrett, N.; Delaney, P. Mutations of ki-ras and p53 genes in colorectal-cancer and their prognostic-significance. Gut 1994, 35, 1627–1631.
[29]
Laurent-Puig, P.; Olschwang, S.; Delattre, O.; Remvikos, Y.; Asselain, B.; Melot, T.; Validire, P.; Muleris, M.; Girodet, J.; Salmon, R.J.; et al. Survival and acquired genetic alterations in colorectal cancer. Gastroenterology 1992, 102, 1136–1141.
[30]
Inoue, Y.; Saigusa, S.; Iwata, T.; Okugawa, Y.; Toiyama, Y.; Tanaka, K.; Uchida, K.; Mohri, Y.; Kusunoki, M. The prognostic value of KRAS mutations in patients with colorectal cancer. Oncol. Rep 2012, doi:10.3892/or.2012.1974.
[31]
Reinacher-Schick, A.; Schulmann, K.; Modest, D.; Bruns, N.; Graeven, U.; Jaworska, M.; Greil, R.; Porschen, R.; Arnold, D.; Schmiegel, W.; et al. Effect of KRAS codon13 mutations in patients with advanced colorectal cancer (advanced CRC) under oxaliplatin containing chemotherapy. Results from a translational study of the AIO colorectal study group. BMC Cancer 2012, 12, 349.
[32]
Zlobec, I.; Kovac, M.; Erzberger, P.; Molinari, F.; Bihl, M.P.; Rufle, A.; Foerster, A.; Frattini, M.; Terracciano, L.; Heinimann, K.; et al. Combined analysis of specific KRAS mutation, BRAF and microsatellite instability indentifies prognostic subgroups of sporadic and hereditary colorectal cancer. Int. J. Cancer 2010, 127, 2569–2575.
[33]
Nash, G.M.; Gimbel, M.; Shia, J.; Nathanson, D.R.; Ndubuisi, M.I.; Zeng, Z.S.; Kemeny, N.; Paty, P.B. KRAS mutation correlates with accelerated metastatic progression in patients with colorectal liver metastases. Ann. Surg. Oncol 2010, 17, 572–578.
[34]
Santini, D.; Loupakis, F.; Vincenzi, B.; Floriani, I.; Stasi, I.; Canestrari, E.; Rulli, E.; Maltese, P.E.; Andreoni, F.; Masi, G.; et al. High concordance of KRAS status between primary colorectal tumors and related metastatic sites: Implications for clinical practice. Oncologist 2008, 13, 1270–1275.
[35]
Kim, M.J.; Lee, H.S.; Kim, J.H.; Kim, Y.J.; Kwon, J.H.; Lee, J.O.; Bang, S.M.; Park, K.U.; Kim, D.W.; Kang, S.B.; et al. Different metastatic pattern according to the KRAS mutational status and site-specific discordance of KRAS status in patients with colorectal cancer. BMC Cancer 2012, 12, 347.
[36]
Louvet, C.; de Gramont, A.; Tournigand, C.; Artru, P.; Maindrault-Goebel, F.; Krulik, M. Correlation between progression free survival and response rate in patients with metastatic colorectal carcinoma. Cancer 2001, 91, 2033–2038.
[37]
Lievre, A.; Bachet, J.; Le Corre, D.; Boige, V.; Landi, B.; Emile, J.; Cote, J.; Tomasic, G.; Penna, C.; Ducreux, M.; et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006, 66, 3992–3995.
[38]
Goldstein, N.S.; 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, 1331–1346.
[39]
Salomon, D.S.; Brandt, R.; Ciardiello, F.; Normanno, N. Epidermal Growth Factor-Related Peptides and Their Receptors in Human Malignancies. Crit. Rev. Oncol./Hematol 1995, 19, 183–232.
[40]
Hemming, A.W.; Davis, N.L.; Kluftinger, A.; Robinson, B.; Quenville, N.F.; Liseman, B.; LeRiche, J. Prognostic markers of colorectal cancer: An evaluation of DNA content, epidermal growth factor receptor, and Ki-67. J. Surg. Oncol 1992, 51, 147–152.
[41]
Mayer, A.; Takimoto, M.; Fritz, E.; Schellander, G.; Kofler, K.; Ludwig, H. The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer. Cancer 1993, 71, 2454–2460.
[42]
Normanno, N.; Tejpar, S.; Morgillo, F.; de Luca, A.; van Cutsem, E.; Ciardiello, F. Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat. Rev. Clin. Oncol 2009, 6, 519–527.
[43]
Bokemeyer, C.; Bondarenko, I.; Hartmann, J.T.; de Braud, F.; Schuch, G.; Zubel, A.; Celik, I.; Schlichting, M.; Koralewski, P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: The OPUS study. Ann. Oncol 2011, 22, 1535–1546.
[44]
Van Cutsem, E.; Kohne, C.H.; Hitre, E.; Zaluski, J.; Chien, C.R.C.; Makhson, A.; D’Haens, G.; Pinter, T.; Lim, R.; Bodoky, G.; et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med 2009, 360, 1408–1417.
[45]
Van Cutsem, E.; Kohne, C.H.; Lang, I.; Folprecht, G.; Nowacki, M.P.; Cascinu, S.; Shchepotin, I.; Maurel, J.; Cunningham, D.; Tejpar, S.; et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: Updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J. Clin. Oncol 2011, 29, 2011–2019.
[46]
Bokemeyer, C.; Bondarenko, I.; Makhson, A.; Hartmann, J.T.; Aparicio, J.; de Braud, F.; Donea, S.; Ludwig, H.; et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol 2009, 27, 663–671.
[47]
Amado, R.G.; Wolf, M.; Peeters, M.; van Cutsem, E.; Siena, S.; Freeman, D.J.; Juan, T.; Sikorski, R.; Suggs, S.; Radinsky, R.; et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol 2008, 26, 1626–1634.
[48]
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. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med 2008, 359, 1757–1765.
[49]
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. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: A retrospective consortium analysis. Lancet Oncol 2010, 11, 753–762.
[50]
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. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 2010, 304, 1812–1820.
[51]
Tejpar, S.; Celik, I.; Schlichting, M.; Sartorius, U.; Bokemeyer, C.; van Cutsem, E. Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J. Clin. Oncol 2012, doi:10.1200/JCO.2012.42.2592.
[52]
Tejpar, S.; Bokemeyer, C.; Celik, I.; Schlichting, M.; Heeger, S.; van Cutsem, E. Kras mutations and outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. Ann. Oncol 2011, 22, v16–v17.
[53]
Di Nicolantonio, F.; Martini, M.; Molinari, F.; Sartore-Bianchi, A.; Arena, S.; Saletti, P.; de Dosso, S.; Mazzucchelli, L.; Frattini, M.; Siena, S.; et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J. Clin. Oncol 2008, 26, 5705–5712.
[54]
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, 1308–1324.
[55]
Vaughn, C.P.; Zobell, S.D.; Furtado, L.V.; Baker, C.L.; Samowitz, W.S. Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosom. Cancer 2011, 50, 307–312.
[56]
Bosset, J.F.; Collette, L.; Calais, G.; Mineur, L.; Maingon, P.; Radosevic-Jelic, L.; Daban, A.; Bardet, E.; Beny, A.; Ollier, J.C. Chemotherapy with preoperative radiotherapy in rectal cancer. N. Engl. J. Med 2006, 355, 1114–1123.
[57]
Bosset, J.F.; Pavy, J.J.; Hamers, H.P.; Horiot, J.C.; Fabri, M.C.; Rougier, P.; Eschwege, F.; Schraub, S. Determination of the optimal dose of 5-fluorouracil when combined with low dose D,L-leucovorin and irradiation in rectal cancer: Results of three consecutive phase II studies. Eur. J. Cancer 1993, 29A, 1406–1410.
[58]
Maas, M.; Nelemans, P.J.; Valentini, V.; Das, P.; Rodel, C.; Kuo, L.J.; Calvo, F.A.; Garcia-Aguilar, J.; Glynne-Jones, R.; Haustermans, K.; et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: A pooled analysis of individual patient data. Lancet Oncol 2010, 11, 835–844.
[59]
Bengala, C.; Bettelli, S.; Bertolini, F.; Sartori, G.; Fontana, A.; Malavasi, N.; Depenni, R.; Zironi, S.; Del Giovane, C.; Luppi, G.; et al. Prognostic role of EGFR gene copy number and KRAS mutation in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy. Br. J. Cancer 2010, 103, 1019–1024.
[60]
Duldulao, M.P.; Lee, W.; Chen, Z.; Li, W.; Nelson, R.A.; Kim, J.; Garcia-Aguilar, J. Use of KRAS codon 13 mutations predict response to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma. Ann. Surg. Oncol 2012, 19, S21–S22.
[61]
Yu, S.N.; Lu, Z.H.; Liu, C.Z.; Meng, Y.X.; Ma, Y.H.; Zhao, W.G.; Liu, J.P.; Yu, J.; Chen, J. miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer. Cancer Res 2010, 70, 6015–6025.
[62]
Ambros, V. microRNAs: Tiny regulators with great potential. Cell 2001, 107, 823–826.
[63]
Ambros, V. The function of animal microRNAs. Nature 2004, 431, 350–355.
[64]
Slaby, O.; Svoboda, M.; Fabian, P.; Smerdova, T.; Knoflickova, D.; Bednarikova, M.; Nenutil, R.; Vyzula, R. Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology 2007, 72, 397–402.
[65]
Lea, M.A. Recently identified and potential targets for colon cancer treatment. Futur. Oncol 2010, 6, 993–1002.
[66]
Wu, W.K.; Law, P.T.; Lee, C.W.; Cho, C.H.; Fan, D.; Wu, K.; Yu, J.; Sung, J.J. MicroRNA in colorectal cancer: From benchtop to bedside. Carcinogenesis 2011, 32, 247–253.
[67]
Calin, G.A.; Sevignani, C.; Dan Dumitru, C.; Hyslop, T.; Noch, E.; Yendamuri, S.; Shimizu, M.; Rattan, S.; Bullrich, F.; Negrini, M.; et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Natl. Acad. Sci. USA 2004, 101, 2999–3004.
[68]
Earle, J.S.; Luthra, R.; Romans, A.; Abraham, R.; Ensor, J.; Yao, H.; Hamilton, S.R. Association of microRNA expression with microsatellite instability status in colorectal adenocarcinoma. J. Mol. Diagn 2010, 12, 433–440.
[69]
Akao, Y.; Nakagawa, Y.; Hirata, I.; Iio, A.; Itoh, T.; Kojima, K.; Nakashima, R.; Kitade, Y.; Naoe, T. Role of anti-oncomirs miR-143 and -145 in human colorectal tumors. Cancer Gene Ther 2010, 17, 398–408.
[70]
Johnson, S.M.; Grosshans, H.; Shingara, J.; Byrom, M.; Jarvis, R.; Cheng, A.; Labourier, E.; Reinert, K.L.; Brown, D.; Slack, F.J. RAS is regulated by the let-7 MicroRNA family. Cell 2005, 120, 635–647.
[71]
Takamizawa, J.; Konishi, H.; Yanagisawa, K.; Tomida, S.; Osada, H.; Endoh, H.; Harano, T.; Yatabe, Y.; Nagino, M.; Nimura, Y.; et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 2004, 64, 3753–3756.
[72]
Jeong, S.H.; Wu, H.G.; Park, W.Y. LIN28B confers radio-resistance through the posttranscriptional control of KRAS. Exp. Mol. Med 2009, 41, 912–918.
[73]
Akao, Y.; Nakagawa, Y.; Naoe, T. let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. Biol. Pharm. Bull 2006, 29, 903–906.
[74]
King, C.E.; Cuatrecasas, M.; Castells, A.; Sepulveda, A.R.; Lee, J.S.; Rustgi, A.K. LIN28B promotes colon cancer progression and metastasis. Cancer Res 2011, 71, 4260–4268.
[75]
King, C.E.; Wang, L.; Winograd, R.; Madison, B.B.; Mongroo, P.S.; Johnstone, C.N.; Rustgi, A.K. LIN28B fosters colon cancer migration, invasion and transformation through let-7-dependent and -independent mechanisms. Oncogene 2011, 30, 4185–4193.
[76]
Graziano, F.; Canestrari, E.; Loupakis, F.; Ruzzo, A.; Galluccio, N.; Santini, D.; Rocchi, M.; Vincenzi, B.; Salvatore, L.; Cremolini, C.; et al. Genetic modulation of the Let-7 microRNA binding to KRAS 3′-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab-irinotecan. Pharmacogn. J. 10 , 458–464.
[77]
Chen, X.; Guo, X.; Zhang, H.; Xiang, Y.; Chen, J.; Yin, Y.; Cai, X.; Wang, K.; Wang, G.; Ba, Y.; et al. Role of miR-143 targeting KRAS in colorectal tumorigenesis. Oncogene 2009, 28, 1385–1392.
[78]
Pichler, M.; Winter, E.; Stotz, M.; Eberhard, K.; Samonigg, H.; Lax, S.; Hoefler, G. Down-regulation of KRAS-interacting miRNA-143 predicts poor prognosis but not response to EGFR-targeted agents in colorectal cancer. Br. J. Cancer 2012, 106, 1826–1832.
[79]
Borralho, P.M.; Kren, B.T.; Castro, R.E.; da Silva, I.B.; Steer, C.J.; Rodrigues, C.M. MicroRNA-143 reduces viability and increases sensitivity to 5-fluorouracil in HCT116 human colorectal cancer cells. FEBS J 2009, 276, 6689–6700.
[80]
Kaelin, W.G., Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 2005, 5, 689–698.
