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Distinct gene expression profiles of proximal and distal colorectal cancer: implications for cytotoxic and targeted therapy

The Pharmacogenomics Journal volume 15, pages 354–362 (2015)Cite this article

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Abstract

Colorectal cancer (CRC) is a heterogeneous disease with genetic profiles and clinical outcomes dependent on the anatomic location of the primary tumor. How location has an impact on the molecular makeup of a tumor and how prognostic and predictive biomarkers differ between proximal versus distal colon cancers is not well established. We investigated the associations between tumor location, KRAS and BRAF mutation status, and the messenger RNA (mRNA) expression of proteins involved in major signaling pathways, including tumor growth (epidermal growth factor receptor (EGFR)), angiogenesis (vascular endothelial growth factor receptor 2 (VEGFR2)), DNA repair (excision repair cross complement group 1 (ERCC1)) and fluoropyrimidine metabolism (thymidylate synthase (TS)). Formalin-fixed paraffin-embedded tumor specimens from 431 advanced CRC patients were analyzed. The presence of seven different KRAS base substitutions and the BRAF V600E mutation was determined. ERCC1, TS, EGFR and VEGFR2 mRNA expression levels were detected by reverse transcriptase-PCR. BRAF mutations were significantly more common in the proximal colon (P<0.001), whereas KRAS mutations occurred at similar frequencies throughout the colorectum. Rectal cancers had significantly higher ERCC1 and VEGFR2 mRNA levels compared with distal and proximal colon tumors (P=0.001), and increased TS levels compared with distal colon cancers (P=0.02). Mutant KRAS status was associated with lower ERCC1, TS, EGFR and VEGFR2 gene expression in multivariate analysis. In a subgroup analysis, this association remained significant for all genes in the proximal colon and for VEGFR2 expression in rectal cancers. The mRNA expression patterns of predictive and prognostic biomarkers, as well as associations with KRAS and BRAF mutation status depend on primary tumor location. Prospective studies are warranted to confirm these findings and determine the underlying mechanisms.

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References

  1. 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  Google Scholar 

  2. Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A et al. 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.

    Article  CAS  Google Scholar 

  3. 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  Google Scholar 

  4. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu 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.

    Article  CAS  Google Scholar 

  5. Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol 2012; 30: 1755–1762.

    Article  CAS  Google Scholar 

  6. Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 2011; 377: 2103–2114.

    Article  CAS  Google Scholar 

  7. Primrose J, Falk S, Finch-Jones M, Valle J, O'Reilly D, Siriwardena A et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol 2014; 15: 601–611.

    Article  CAS  Google Scholar 

  8. Chung KY, Shia J, Kemeny NE, Shah M, Schwartz GK, Tse A et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005; 23: 1803–1810.

    Article  CAS  Google Scholar 

  9. 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  Google Scholar 

  10. Vallbohmer D, Zhang W, Gordon M, Yang DY, Yun J, Press OA et al. Molecular determinants of cetuximab efficacy. J Clin Oncol 2005; 23: 3536–3544.

    Article  Google Scholar 

  11. Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 2012; 48: 1466–1475.

    Article  CAS  Google Scholar 

  12. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G 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.

    Article  CAS  Google Scholar 

  13. Zhang W, Azuma M, Lurje G, Gordon MA, Yang D, Pohl A et al. Molecular predictors of combination targeted therapies (cetuximab, bevacizumab) in irinotecan-refractory colorectal cancer (BOND-2 study). Anticancer Res 2010; 30: 4209–4217.

    CAS  PubMed  Google Scholar 

  14. Schimanski CC, Zimmermann T, Schmidtmann I, Gockel I, Lang H, Galle PR et al. K-ras mutation status correlates with the expression of VEGFR1, VEGFR2, and PDGFRalpha in colorectal cancer. Int J Colorectal Dis 2010; 25: 181–186.

    Article  Google Scholar 

  15. 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 

  16. Uchida K, Danenberg PV, Danenberg KD, Grem JL . Thymidylate synthase, dihydropyrimidine dehydrogenase, ERCC1, and thymidine phosphorylase gene expression in primary and metastatic gastrointestinal adenocarcinoma tissue in patients treated on a phase I trial of oxaliplatin and capecitabine. BMC Cancer 2008; 8: 386.

    Article  Google Scholar 

  17. Kim SH, Kwon HC, Oh SY, Lee DM, Lee S, Lee JH et al. Prognostic value of ERCC1, thymidylate synthase, and glutathione S-transferase pi for 5-FU/oxaliplatin chemotherapy in advanced colorectal cancer. Am J Clin Oncol 2009; 32: 38–43.

    Article  CAS  Google Scholar 

  18. 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  Google Scholar 

  19. Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487: 330–337.

    Article  Google Scholar 

  20. Triff K, Konganti K, Gaddis S, Zhou B, Ivanov I, Chapkin RS . Genome-wide analysis of the rat colon reveals proximal-distal differences in histone modifications and proto-oncogene expression. Physiol Genomics 2013; 45: 1229–1243.

    Article  CAS  Google Scholar 

  21. Benedix F, Kube R, Meyer F, Schmidt U, Gastinger I, Lippert H . Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum 2010; 53: 57–64.

    Article  Google Scholar 

  22. Sinicrope FA, Mahoney MR, Smyrk TC, Thibodeau SN, Warren RS, Bertagnolli MM et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol 2013; 31: 3664–3672.

    Article  CAS  Google Scholar 

  23. Glebov OK, Rodriguez LM, Nakahara K, Jenkins J, Cliatt J, Humbyrd CJ et al. Distinguishing right from left colon by the pattern of gene expression. Cancer Epidemiol Biomarkers Prev 2003; 12: 755–762.

    CAS  PubMed  Google Scholar 

  24. Sadler TW, Thomas W . Langman’s Medical Embryology, 11th edn. 2010.

  25. Forster S, Sattler HP, Hack M, Romanakis K, Rohde V, Seitz G et al. Microsatellite instability in sporadic carcinomas of the proximal colon: association with diploid DNA content, negative protein expression of p53, and distinct histomorphologic features. Surgery 1998; 123: 13–18.

    Article  CAS  Google Scholar 

  26. Kim H, Jen J, Vogelstein B, Hamilton SR . Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994; 145: 148–156.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. De Roock W, Biesmans B, De Schutter J, Tejpar S . Clinical biomarkers in oncology: focus on colorectal cancer. Mol Diagn Ther 2009; 13: 103–114.

    Article  CAS  Google Scholar 

  28. Minoo P, Zlobec I, Peterson M, Terracciano L, Lugli A . Characterization of rectal, proximal and distal colon cancers based on clinicopathological, molecular and protein profiles. Int J Oncol 2010; 37: 707–718.

    Article  CAS  Google Scholar 

  29. Bufill JA . Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med 1990; 113: 779–788.

    Article  CAS  Google Scholar 

  30. Distler P, Holt PR . Are right- and left-sided colon neoplasms distinct tumors? Dig Dis 1997; 15: 302–311.

    Article  CAS  Google Scholar 

  31. Nawa T, Kato J, Kawamoto H, Okada H, Yamamoto H, Kohno H et al. Differences between right- and left-sided colon cancer in patient characteristics, cancer morphology and histology. J Gastroenterol Hepatol 2008; 23: 418–423.

    Article  Google Scholar 

  32. Weiss JM, Pfau PR, O'Connor ES, King J, LoConte N, Kennedy G et al. Mortality by stage for right- versus left-sided colon cancer: analysis of surveillance, epidemiology, and end results—Medicare data. J Clin Oncol 2011; 29: 4401–4409.

    Article  Google Scholar 

  33. Bonner RF, Emmert-Buck M, Cole K, Pohida T, Chuaqui R, Goldstein S et al. Laser capture microdissection: molecular analysis of tissue. Science 1997; 278: 3.

    Article  Google Scholar 

  34. Chomczynski P, Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156–159.

    Article  CAS  Google Scholar 

  35. Gibson UE, Heid CA, Williams PM . A novel method for real time quantitative RT-PCR. Genome Res 1996; 6: 995–1001.

    Article  CAS  Google Scholar 

  36. Rosty C, Young JP, Walsh MD, Clendenning M, Walters RJ, Pearson S et al. Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features. Mod Pathol 2013; 26: 825–834.

    Article  CAS  Google Scholar 

  37. Yamauchi M, Morikawa T, Kuchiba A, Imamura Y, Qian ZR, Nishihara R et al. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut 2012; 61: 847–854.

    Article  CAS  Google Scholar 

  38. Samowitz WS, Curtin K, Schaffer D, Robertson M, Leppert M, Slattery ML . Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study. Cancer Epidemiol Biomarkers Prev 2000; 9: 1193–1197.

    CAS  PubMed  Google Scholar 

  39. Benedix F, Meyer F, Kube R, Kropf S, Kuester D, Lippert H et al. Influence of anatomical subsite on the incidence of microsatellite instability, and KRAS and BRAF mutation rates in patients with colon carcinoma. Pathol Res Pract 2012; 208: 592–597.

    Article  CAS  Google Scholar 

  40. Lleonart ME, Garcia-Foncillas J, Sanchez-Prieto R, Martin P, Moreno A, Salas C et al. Microsatellite instability and p53 mutations in sporadic right and left colon carcinoma: different clinical and molecular implications. Cancer 1998; 83: 889–895.

    Article  Google Scholar 

  41. Samowitz WS, Slattery ML, Kerber RA . Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancer. Gastroenterology 1995; 109: 1765–1771.

    Article  CAS  Google Scholar 

  42. Lochhead P, Kuchiba A, Imamura Y, Liao X, Yamauchi M, Nishihara R et al. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst 2013; 105: 1151–1156.

    Article  CAS  Google Scholar 

  43. Tran B, Kopetz S, Tie J, Gibbs P, Jiang ZQ, Lieu CH et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer 2011; 117: 4623–4632.

    Article  CAS  Google Scholar 

  44. Lenz HJ, Danenberg KD, Leichman CG, Florentine B, Johnston PG, Groshen S et al. p53 and thymidylate synthase expression in untreated stage II colon cancer: associations with recurrence, survival, and site. Clin Cancer Res 1998; 4: 1227–1234.

    CAS  PubMed  Google Scholar 

  45. Sulzyc-Bielicka V, Domagala P, Majdanik E, Chosia M, Bielicki D, Kladny J et al. Nuclear thymidylate synthase expression in sporadic colorectal cancer depends on the site of the tumor. Virchows Arch 2009; 454: 695–702.

    Article  CAS  Google Scholar 

  46. Wong NA, Brett L, Stewart M, Leitch A, Longley DB, Dunlop MG et al. Nuclear thymidylate synthase expression, p53 expression and 5FU response in colorectal carcinoma. Br J Cancer 2001; 85: 1937–1943.

    Article  CAS  Google Scholar 

  47. Lin YL, Liau JY, Yu SC, Ou DL, Lin LI, Tseng LH et al. KRAS mutation is a predictor of oxaliplatin sensitivity in colon cancer cells. PLoS ONE 2012; 7: e50701.

    Article  CAS  Google Scholar 

  48. Hawkins N, Norrie M, Cheong K, Mokany E, Ku SL, Meagher A et al. CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology 2002; 122: 1376–1387.

    Article  CAS  Google Scholar 

  49. van Rijnsoever M, Grieu F, Elsaleh H, Joseph D, Iacopetta B . Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands. Gut 2002; 51: 797–802.

    Article  CAS  Google Scholar 

  50. Toyota M, Ohe-Toyota M, Ahuja N, Issa JP . Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc Natl Acad Sci USA 2000; 97: 710–715.

    Article  CAS  Google Scholar 

  51. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010; 28: 4697–4705.

    Article  CAS  Google Scholar 

  52. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F 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.

    Article  CAS  Google Scholar 

  53. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360: 1408–1417.

    Article  CAS  Google Scholar 

  54. Rosty C, Chazal M, Etienne MC, Letoublon C, Bourgeon A, Delpero JR et al. Determination of microsatellite instability, p53 and K-RAS mutations in hepatic metastases from patients with colorectal cancer: relationship with response to 5-fluorouracil and survival. Int J Cancer 2001; 95: 162–167.

    Article  CAS  Google Scholar 

  55. 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  Google Scholar 

  56. Etienne-Grimaldi MC, Formento JL, Francoual M, Francois E, Formento P, Renee N et al. K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin Cancer Res 2008; 14: 4830–4835.

    Article  CAS  Google Scholar 

  57. Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM et al. 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.

    Article  CAS  Google Scholar 

  58. Jover R, Nguyen TP, Perez-Carbonell L, Zapater P, Paya A, Alenda C et al. 5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer. Gastroenterology 2011; 140: 1174–1181.

    Article  CAS  Google Scholar 

  59. Van Rijnsoever M, Elsaleh H, Joseph D, McCaul K, Iacopetta B . CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer. Clin Cancer Res 2003; 9: 2898–2903.

    CAS  PubMed  Google Scholar 

  60. Popat S, Hubner R, Houlston RS . Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005; 23: 609–618.

    Article  CAS  Google Scholar 

  61. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003; 349: 247–257.

    Article  CAS  Google Scholar 

  62. Shen L, Catalano PJ, Benson AB 3rd, O'Dwyer P, Hamilton SR, Issa JP . Association between DNA methylation and shortened survival in patients with advanced colorectal cancer treated with 5-fluorouracil based chemotherapy. Clin Cancer Res 2007; 13: 6093–6098.

    Article  CAS  Google Scholar 

  63. Des Guetz G, Uzzan B, Nicolas P, Schischmanoff O, Perret GY, Morere JF . Microsatellite instability does not predict the efficacy of chemotherapy in metastatic colorectal cancer. A systematic review and meta-analysis. Anticancer Res 2009; 29: 1615–1620.

    CAS  PubMed  Google Scholar 

  64. Elsaleh H, Joseph D, Grieu F, Zeps N, Spry N, Iacopetta B . Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 2000; 355: 1745–1750.

    Article  CAS  Google Scholar 

  65. Ricciardiello L, Ceccarelli C, Angiolini G, Pariali M, Chieco P, Paterini P et al. High thymidylate synthase expression in colorectal cancer with microsatellite instability: implications for chemotherapeutic strategies. Clin Cancer Res 2005; 11: 4234–4240.

    Article  CAS  Google Scholar 

  66. Jensen SA, Vainer B, Kruhoffer M, Sorensen JB . Microsatellite instability in colorectal cancer and association with thymidylate synthase and dihydropyrimidine dehydrogenase expression. BMC Cancer 2009; 9: 25.

    Article  Google Scholar 

  67. Odin E, Wettergren Y, Nilsson S, Carlsson G, Gustavsson B . Colorectal carcinomas with microsatellite instability display increased thymidylate synthase gene expression levels. Clin Colorectal Cancer 2007; 6: 720–727.

    Article  CAS  Google Scholar 

  68. Popat S, Wort R, Houlston RS . Inter-relationship between microsatellite instability, thymidylate synthase expression, and p53 status in colorectal cancer: implications for chemoresistance. BMC Cancer 2006; 6: 150.

    Article  Google Scholar 

  69. Sinicrope FA, Rego RL, Halling KC, Foster NR, Sargent DJ, La Plant B et al. Thymidylate synthase expression in colon carcinomas with microsatellite instability. Clin Cancer Res 2006; 12: 2738–2744.

    Article  CAS  Google Scholar 

  70. Merkelbach-Bruse S, Hans V, Mathiak M, Sanguedolce R, Alessandro R, Ruschoff J et al. Associations between polymorphisms in the thymidylate synthase gene, the expression of thymidylate synthase mRNA and the microsatellite instability phenotype of colorectal cancer. Oncol Rep 2004; 11: 839–843.

    CAS  PubMed  Google Scholar 

  71. V H, Modest DP, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U et al. Gender and tumor location as predictors for efficacy: Influence on endpoints in first-line treatment with FOLFIRI in combination with cetuximab or bevacizumab in the AIO KRK 0306 (FIRE3) trial. J Clin Oncol 2014; 32: Abstract 3600.

    Article  Google Scholar 

  72. Ruzzo A, Graziano F, Canestrari E, Magnani M . Molecular predictors of efficacy to anti-EGFR agents in colorectal cancer patients. Curr Cancer Drug Targets 2010; 10: 68–79.

    Article  CAS  Google Scholar 

  73. Larsen AK, Ouaret D, El Ouadrani K, Petitprez A . Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis. Pharmacol Ther 2011; 131: 80–90.

    Article  CAS  Google Scholar 

  74. Grimminger PP, Danenberg P, Dellas K, Arnold D, Rodel C, Machiels JP et al. Biomarkers for cetuximab-based neoadjuvant radiochemotherapy in locally advanced rectal cancer. Clin Cancer Res 2011; 17: 3469–3477.

    Article  CAS  Google Scholar 

  75. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2012; 2: 227–235.

    Article  CAS  Google Scholar 

  76. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012; 483: 100–103.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was funded by P30CA014089-27S1 and supported by the Dhont Foundation, Wunderglo Foundation.

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Authors and Affiliations

  1. Department of General, Visceral and Tumor Surgery, University of Cologne, Cologne, Germany

    M K H Maus & P P Grimminger

  2. Response Genetics, Inc., Los Angeles, CA, USA

    M K H Maus, C L Stephens, S H Astrow, J H Hsiang & G Zeger

  3. Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    D L Hanna, D Yang, F Loupakis, T Wakatsuki, A Barzi & H-J Lenz

  4. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Instituto Toscano, Tumori, Italy

    F Loupakis

  5. Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    G Zeger

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Preliminary results presented at the American Society of Clinical Oncology Annual Meeting, 30 May–3 June 2013, Chicago, IL, USA

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Maus, M., Hanna, D., Stephens, C. et al. Distinct gene expression profiles of proximal and distal colorectal cancer: implications for cytotoxic and targeted therapy. Pharmacogenomics J 15, 354–362 (2015). https://doi.org/10.1038/tpj.2014.73

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