Abstract
Nowadays, the results of clinical translational researches reflecting in the management of colorectal cancer patients are limited with usa of antibody therapy and detection of KRAS mutation determining the response to antibody treatment. However, in the near future, the new molecular markers are expected to enter into clinical usa with the results of these studies. In this review, the genetic and epigenetic risk factors which play a role in the development of colorectal cancer, molecular diagnostic and prognostic markers, molecular- targeted treatments and promising molecules that are critical in determining the response to the therapy will be examined.
Keywords: Colorectal cancer, genetic, molecular markers
References
Murphy JE, Ryan DP. American Society of Clinical Oncology 2010 colorectal update. Expert Rev Anticancer Ther 2010;10:1371- 1373. doi:10.1586/era.10.123 http://dx.doi.org/10.1586/era.10.123
Garufi C, Torsello A, Tumolo S, Ettorre GM, Zeuli M, Campanella C, Vennarecci G, Mottolese M, Sperduti I, Cognetti F. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer 2010;103:1542-1547.
Van Meter ME, Kim ES. Bevacizumab: current updates in treatment. Curr Opin Oncol 2010;22:586-591.
Dahabreh IJ, Terasawa T, Castaldi PJ, Trikalinos TA. Systematic review: Anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med 2011;154:37-49.
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL. Genetic alterations during colorectal- tumor development. N Engl J Med 1988;319:525-532.
Goldstein NS. Serrated pathway and APC (conventional)-type colorectal polyps: molecularmorphologic correlations, genetic pathways, and implications for classification. Am J Clin Pathol 2006;125:146-153.
Jass JR. Hyperplastic polyps and colorectal cancer: is there a link? Clin Gastroenterol Hepatol 2004;2:1-8.
Noffsinger AE. Serrated polyps and colorectal cancer: new pathway to malignancy. Annu Rev Pathol 2009;4:343-364.
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70.
Little MP, Vineis P, Li G. A stochastic carcinogenesis model incorporating multiple types of genomic instability fitted to colon cancer data. J Theor Biol 2008;254:229-238.
Grady WM, Carethers JM. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 2008;135:1079-1099.
Walther A, Houlston R, Tomlinson I. Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis. Gut 2008;57:941-950.
Popat S, Houlston RS. A systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status and colorectal cancer prognosis. Eur J Cancer 2005;41:2060-2070.
Walther A, Johnstone E, Swanton C, Midgley R, Tomlinson I, Kerr D. Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer 2009;9:489-499.
Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005;23:609-618.
Grady WM. Genomic instability and colon cancer. Cancer Metastasis Rev 2004;23:11-27.
Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM, Kolodner R. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 1997;57:808-811.
Domingo E, Laiho P, Ollikainen M, Pinto M, Wang L, French AJ, Westra J, Frebourg T, Espín E, Armengol M, Hamelin R, Yamamoto H, Hofstra RM, Seruca R, Lindblom A, Peltomäki P, Thibodeau SN, Aaltonen LA, Schwartz S Jr. BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet 2004;41:664-668.
Wang L, Cunningham JM, Winters JL, Guenther JC, French AJ, Boardman LA, Burgart LJ, McDonnell SK, Schaid DJ, Thibodeau SN. BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res 2003;63:5209-5212.
Barault L, Charon-Barra C, Jooste V, de la Vega MF, Martin L, Roignot P, Rat P, Bouvier AM, Laurent-Puig P, Faivre J, Chapusot C, Piard F. Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. Cancer Res 2008;68:8541-8546.
Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, Koh H, Simms L, Barker M, Leggett B, Levine J, Kim M, French AJ, Thibodeau SN, Jass J, Haile R, Laird PW. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 2006;38:787-793.
Chung DC. The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis. Gastroenterology 2000;119:854-865.
Miyaki M, Iijima T, Kimura J, Yasuno M, Mori T, Hayashi Y, Koike M, Shitara N, Iwama T, Kuroki T. Frequent mutation of beta-catenin and APC genes in primary colorectal tumors from patients with hereditary nonpolyposis colorectal cancer. Cancer Res 1999;59:4506-4509.
Samowitz WS, Powers MD, Spirio LN, Nollet F, van Roy F, Slattery ML. Betacatenin mutations are more frequent in small colorectal adenomas than in larger adenomas and invasive carcinomas. Cancer Res 1999;59:1442-1444.
Chittenden TW, Howe EA, Culhane AC, Sultana R, Taylor JM, Holmes C, Quackenbush J. Functional classification analysis of somatically mutated genes in human breast and colorectal cancers. Genomics 2008;91:508-511.
Grady WM, Myeroff LL, Swinler SE, Rajput A, Thiagalingam S, Lutterbaugh JD, Neumann A, Brattain MG, Chang J, Kim SJ, Kinzler KW, Vogelstein B, Willson JK, Markowitz S. Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. Cancer Res 1999;59:320-324.
Grady WM, Rajput A, Myeroff L, Liu DF, Kwon K, Willis J, Markowitz S. 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;58:3101-3104.
Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 1995;268:1336- 1338.
Tanaka T, Watanabe T, Kazama Y, Tanaka J, Kanazawa T, Kazama S, Nagawa H. Loss of Smad4 protein expression and 18qLOH as molecular markers indicating lymph node metastasis in colorectal cancer--a study matched for tumor depth and pathology. J Surg Oncol 2008;97:69-73.
Alhopuro P, Alazzouzi H, Sammalkorpi H, Dávalos V, Salovaara R, Hemminki A, Järvinen H, Mecklin JP, Schwartz S Jr, Aaltonen LA, Arango D. SMAD4 levels and response to 5-fluorouracil in colorectal cancer. Clin Cancer Res 2005; 1;11:6311-6316. doi:10.1053/j. gastro.2005.06.066 http://dx.doi. org/10.1053/j.gastro.2005.06.066 doi:10.1158/1078-0432.CCR-05- 0244 http://dx.doi.org/10.1158/1078- 0432.CCR-05-0244
Boulay JL, Mild G, Lowy A, Reuter J, Lagrange M, Terracciano L, Laffer U, Herrmann R, Rochlitz C. SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer. Br J Cancer 2002;87:630-634.
Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer, 2003;3:11-22.
Artale S, Sartore-Bianchi A, Veronese SM, Gambi V, Sarnataro CS, Gambacorta M, Lauricella C, Siena S. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J Clin Oncol 2008; 26:4217-4219 doi:10.1200/ JCO.2008.18.7286 http://dx.doi. org/10.1200/JCO.2008.18.7286 doi:10.1200/ JCO.2008.20.2358 http://dx.doi. org/10.1200/JCO.2008.20.2358
Zauber P, Sabbath-Solitare M, Marotta SP, Bishop DT. Molecular changes in the Ki-ras and APC genes in primary colorectal carcinoma and synchronous metastases compared with the findings in accompanying adenomas. Mol Pathol 2003;56:137-140.
Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status, Nature 2002;418:934.
Lubomierski N, Plotz G, Wormek M, Engels K, Kriener S, Trojan J, Jungling B, Zeuzem S, Raedle J. BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors. Cancer 2005;104:952-961.
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.
Danielsen SA, Lind GE, Bjørnslett M, Meling GI, Rognum TO, Heim S, Lothe RA. Novel mutations of the suppressor gene PTEN in colorectal carcinomas stratified by microsatellite instabilityand TP53 mutation- status. Hum Mutat. 2008;29:252-262.
Razis E, Briasoulis E, Vrettou E, Skarlos DV, Papamichael D, Kostopoulos I, Samantas E, Xanthakis I, Bobos M, Galanidi E, Bai M, Gikonti I, Koukouma A, Kafiri G, Papakostas P, Kalogeras KT, Kosmidis P, Fountzilas G. Potential value of PTEN in predicting cetuximab response in colorectal cancer: an exploratory study. BMC Cancer 2008; 8:234. doi:10.1186/1471-2407-8- 234 http://dx.doi.org/10.1186/1471- 2407-8-234
Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 2009;69:1851- 1857.
Baudhuin LM, Burgart LJ, Leontovich O, Thibodeau SN. Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome. Fam Cancer 2005;4:255-265.
Shia J. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry. J Mol Diagn 2008;10:293-300.
Dundar M, Caglayan AO, Saatci C, Karaca H, Baskol M, Tahiri S, Ozkul Y. How the I1307K adenomatous polyposis coli gene variant contributes in the assessment of risk of colorectal cancer, but not stomach cancer, in a Turkish population. Cancer Genet Cytogenet 2007;177:95-97.
Cacina C, Yaylim-Eraltan I, Arikan S, Saglam EK, Zeybek U, Isbir T. Association between CDKN1A Ser31Arg and C20T gene polymorphisms and colorectal cancer risk and prognosis. In Vivo, 2010; 24:179-83.
Arıkan S, Cacina C, Guler E, Culcu S, Tuna G, Yaylım-Eraltan I. The effects of NOS3 Glu298Asp variant on colorectal cancer risk and progression in Turkish population. Mol Biol Rep. 2011.
Canbay E, Cakmakoglu B, Zeybek U, Sozen S, Cacina C, Gulluoglu M, Balik E, Bulut T, Yamaner S, Bugra D. Association of APE1 and hOGG1 polymorphisms with colorectal cancer risk in a Turkish population. Curr Med Res Opin 2011;27:1295-1302.
Canbay E, Ozturk O, Bugra D, Yamaner S, Kahraman OT, Seyhan MF, Gulluoglu M, Balik E, Bulut T. Kolorektal kanser riski ile PTEN ve HER2 polimorfizmi arasındaki ilişki. Sözlü bildiri. 13. Ulusal Kolon ve Rektum Cerrahisi Kongresi, 2011
Smith RA, Cokkinides V, Brooks D, Saslow D, Shah M, Brawley OW. Cancer screening in the United States: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin 2010;60:99-119.
Ahlquist DA. Molecular detection of colorectal neoplasia. Gastroenterology 2010;138:2127-39.
Osborn NK, Ahlquist DA. Stool screening for colorectal cancer: molecular approaches. Gastroenterology 2005;128:192-
Itzkowitz SH, Jandorf L, Brand R, Rabeneck L, Schroy PC 3rd, Sontag S, Johnson D, Skoletsky J, Durkee K, Markowitz S, Shuber A. Improved fecal DNA test for colorectal cancer screening. Clin Gastroenterol Hepatol 2007; 5:111-117. doi:10.1016/j. cgh.2006.10.006 http://dx.doi. org/10.1016/j.cgh.2006.10.006
Itzkowitz S, Brand R, Jandorf L, Durkee K, Millholland J, Rabeneck L, Schroy PC 3rd, Sontag S, Johnson D, Markowitz S, Paszat L, Berger BM . A simplified, noninvasive stool DNA test for colorectal cancer detection. Am J Gastroenterol 2008;103:2862-2870.
Bertagnolli MM, Redston M, Compton CC, Niedzwiecki D, Mayer RJ, Goldberg RM, Colacchio TA, Saltz LB, Warren RS. Microsatellite instability and loss of heterozygosity at chromosomal location 18q: prospective evaluation of biomarkers for stages II and III colon cancer--A Study of CALGB 9581 and 89803. J Clin Oncol 2011; 10;29:3153-3162. doi:10.1200/ JCO.2010.33.0092 http://dx.doi. org/10.1200/JCO.2010.33.0092 doi:10.1200/JCO.2010.32.5357 http:// dx.doi.org/10.1200/JCO.2010.32.5357
Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, Dietrich D, Biesmans B, Bodoky G, Barone C, Aranda E, Nordlinger B, Cisar L, Labianca R, Cunningham D, Van Cutsem E, Bosman F. 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 2010;28:466-474.
Fuchs C, Ogino S, Meyerhardt JA. KRAS mutation, cancer recurrence, and patient survival in stage III colon cancer: findings from CALGB 89803. J Clin Oncol 2009;27:4037.
Ogino S, Nosho K, Kirkner GJ, Shima K, Irahara N, Kure S, Chan AT, Engelman JA, Kraft P, Cantley LC, Giovannucci EL, Fuchs CS. PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol 2009;27:1477-1484.
Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, Taylor G, Barrett JH, Quirke P. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 2009;27:5931-5937.
Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med 2009;361:98-99.
Zlobec I, Kovac M, Erzberger P, Molinari F, Bihl MP, Rufle A, Foerster A, Frattini M, Terracciano L, Heinimann K, Lugli A. Combined analysis of specific KRAS mutation, BRAF and microsatellite instability identifies prognostic subgroups of sporadic and hereditary colorectal cancer. Int J Cancer 2010;127:2569-2575.
Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, Taylor G, Barrett JH, Quirke P. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 2009;27:5931-5937.
Bardelli A, Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol 2010;28:1254-1261.
Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med 2005;352:476-487.
Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009;27:663-671.
Van Cutsem E, Siena S, Humblet Y, Canon JL, Maurel J, Bajetta E, Neyns B, Kotasek D, Santoro A, Scheithauer W, Spadafora S, Amado RG, Hogan N, Peeters M. Open-label phase II trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy refractory metastatic colorectal cancer. J Clin Oncol 2007;25:1658-1664.
European Medicines Agency. Committee for Medicinal Products for Human Use May 2008 Plenary Meeting monthly report. 2008.
Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, McAllister PK, Morton RF, Schilsky RL. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 2009;27:2091-2096.
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Colon Cancer V.2.2011
Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008;26:5705-5712.
Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, Floriani I, Bencardino K, Galluccio N, Catalano V, Tonini G, Magnani M, Fontanini G, Basolo F, Falcone A, Graziano F. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer 2009;101:715-721.
Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med 2009;361:98-99.
Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, Rougier P, Lievre A, Landi B, Boige V, Ducreux M, Ychou M, Bibeau F, Bouché O, Reid J, Stone S, Penault-Llorca F. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 2009;27:5924-5930.
Jhawer M, Goel S, Wilson AJ, Montagna C, Ling YH, Byun DS, Nasser S, Arango D, Shin J, Klampfer L, Augenlicht LH, Perez-Soler R, Mariadason JM. PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 2008;68:1953- 1961.
Prenen H, De Schutter J, Jacobs B, De Roock W, Biesmans B, Claes B, Lambrechts D, Van Cutsem E, Tejpar S. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res 2009;15:3184-3188.
Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, Molinari M, De Dosso S, Saletti P, Martini M, Cipani T, Marrapese G, Mazzucchelli L, Lamba S, Veronese S, Frattini M, Bardelli A. Multideterminants analysis of molecular alterations for predicting clinical benefit to EGFRtargeted monoclonal antibodies in colorectal cancer. PLoS One 2009;4:e-7287.
Shia J, Klimstra DS, Li AR, Qin J, Saltz L, Teruya-Feldstein J, Akram M, Chung KY, Yao D, Paty PB, Gerald W, Chen B. Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study. Mod Pathol 2005;18:1350-1356.
Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, Tu D, Redston M, Gallinger S. Tumor microsatellite instability status as a predictor of benefit from fluorouracilbased adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349:247-257.
Kim GP, Colangelo LH, Wieand HS, Paik S, Kirsch IR, Wolmark N, Allegra CJ. Prognostic and predictive roles of highdegree microsatellite instability in colon cancer: a National Cancer Institutee National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol 2007;25:767-772.
Liang JT, Huang KC, Lai HS, Lee PH, Cheng YM, Hsu HC, Cheng AL, Hsu CH, Yeh KH, Wang SM, Tang C, Chang KJ. High-frequency microsatellite instability predicts better chemosensitivity to high-dose 5-fluorouracil plus leucovorin chemotherapy for stage IV sporadic colorectal cancer after palliative bowel resection. Int J Cancer 2002;101:519-525.
Saltz LB, Niedzwiecki D, Hollis D, Goldberg RM, Hantel A, Thomas JP, Fields AL, Mayer RJ. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol 2007;25:3456- 3461.
Watanabe T, Wu TT, Catalano PJ, Ueki T, Satriano R, Haller DG, Benson AB 3rd, Hamilton SR. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 2001;344:1196- 1206.
Braun MS, Richman SD, Quirke P, Daly C, Adlard JW, Elliott F, Barrett JH, Selby P, Meade AM, Stephens RJ, Parmar MK, Seymour MT. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol 2008;26:2690-2698.
Ezzeldin HH, Diasio RB. Predicting fluorouracil toxicity: can we finally do it? J Clin Oncol 2008;26:2080-2082.
Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U, Bokemeyer C, Eichelbaum M. Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 2008;26:2131-2138.
Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL. UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst 2007;99:1290e5.
Palomaki GE, Bradley LA, Douglas MP, Kolor K, Dotson WD. Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidencebased review. Genet Med 2009;11:21-34.
Zambon A, Ménard D, Suijkerbuijk BM, Niculescu-Duvaz I, Whittaker S, Niculescu- Duvaz D, Nourry A, Davies L, Manne HA, Lopes F, Preece N, Hedley D, Ogilvie LM, Kirk R, Marais R, Springer CJ. Novel hinge binder improves activity and pharmacokinetic properties of BRAF inhibitors. J Med Chem 2010;53:5639-5655.
Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008;27:5497-5510.
