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Prognostic biomarkers in colorectal cancer: where do we stand?

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Abstract

Colorectal cancer remains a major cause of cancer-related death worldwide. One way to reduce its staggering mortality rate and socio-economic burden is to predict outcome based on the aggressiveness of the tumor biology in order to treat patients accordingly to their risk profile. As such, it comes as no surprise that prognostic biomarker discovery is a hot topic in colorectal cancer research. The last two decades have literally produced tons of new data and an avalanche of potential clinically applicable biomarkers. This review explores and summarizes data concerning the prognostic strength and clinical utility of current and future tissue biomarkers in the diagnosis and treatment of colorectal cancer.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    PubMed  Google Scholar 

  2. Center MM, Jemal A, Smith RA, Ward E (2009) Worldwide variations in colorectal cancer. CA Cancer J Clin 59:366–378

    PubMed  Google Scholar 

  3. Edge SB, Compton CC (2010) The American Joint Committee on Cancer: the 7th edition of the AJCC Cancer Staging Manual and the future of TNM. Ann Surg Oncol 17:1471–1474

    PubMed  Google Scholar 

  4. Compton CC (1999) Pathology report in colon cancer: what is prognostically important? Digest Dis 17:67–79

    CAS  Google Scholar 

  5. O'Connell JB, Maggard MA, Ko CY (2004) Colon cancer survival rates with the new American Joint Committee on cancer sixth edition staging. J Natl Cancer Inst 96:1420–1425

    PubMed  Google Scholar 

  6. Wiggers T, Arends JW, Volovics A (1988) Regression-analysis of prognostic factors in colorectal-cancer after curative resections. Dis Colon Rectum 31:33–41

    CAS  PubMed  Google Scholar 

  7. Chapuis PH, Dent OF, Fisher R et al (1985) A multivariate-analysis of clinical and pathological variables in prognosis after resection of large bowel-cancer. Br J Surg 72:698–702

    CAS  PubMed  Google Scholar 

  8. Takahashi T, Kato T, Kodaira S et al (1996) Prognostic factors of colorectal cancer—results of multivariate analysis of curative resection cases with or without adjuvant chemotherapy. Am J Clin Oncol-Canc 19:408–415

    CAS  Google Scholar 

  9. Shepherd NA, Baxter KJ, Love SB (1997) The prognostic importance of peritoneal involvement in colonic cancer: a prospective evaluation. Gastroenterology 112:1096–1102

    CAS  PubMed  Google Scholar 

  10. Steward C, Hillery S, Platell C, Puppa G (2011) Assessment of serosal invasion and criteria for the classification of pathological (p) T4 staging in colorectal carcinoma: confusions, controversies and criticisms. Cancers 3:164–181

    Google Scholar 

  11. Washington MK, Berlin J, Branton PA et al (2008) Protocol for the examination of specimens from patients with primary carcinomas of the colon and rectum. Arch Pathol Lab Med 132:1182–1193

    PubMed  Google Scholar 

  12. Lennon AM, Mulcahy HE, Hyland JMP et al (2003) Peritoneal involvement in stage II colon cancer. Am J Clin Pathol 119:108–113

    CAS  PubMed  Google Scholar 

  13. Douard R, Cugnenc PH, Wind P, Benichou J (2004) Peritoneal involvement and free tumor cells in peritoneal cavity of patients with colon cancer. Am J Clin Pathol 121:154–155

    PubMed  Google Scholar 

  14. Wolmark N, Fisher B, Wieand HS (1986) The prognostic value of the modifications of the Dukes-C class of colorectal-cancer—an analysis of the Nsabp Clinical-Trials. Ann Surg 203:115–122

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Greene FL, Stewart AK, Norton HJ (2002) A new TNM staging strategy for node-positive (stage III) colon cancer—an analysis of 50,042 patients. Ann Surg 236:416–421

    PubMed Central  PubMed  Google Scholar 

  16. Swanson RS, Compton CC, Stewart AK, Bland KI (2003) The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 10:65–71

    PubMed  Google Scholar 

  17. Chen SL, Bilchik AJ (2006) More extensive nodal dissection improves survival for stages I to III of colon cancer—a population-based study. Ann Surg 244:602–610

    PubMed Central  PubMed  Google Scholar 

  18. Tepper JE, O'Connell MJ, Niedzwiecki D et al (2001) Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 19:157–163

    CAS  PubMed  Google Scholar 

  19. Chang GJ, Rodriguez-Bigas MA, Skibber JM, Moyer VA (2007) Lymph node evaluation and survival after curative resection of colon cancer: systematic review. J Natl Cancer Inst 99:433–441

    PubMed  Google Scholar 

  20. Johnson PM, Porter GA, Ricciardi R, Baxter NN (2006) Increasing negative lymph node count is independently associated with improved long-term survival in stage IIIB and IIIC colon cancer. J Clin Oncol 24:3570–3575

    PubMed  Google Scholar 

  21. Le Voyer TE, Sigurdson ER, Hanlon AL et al (2003) Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of Intergroup Trial INT-0089. J Clin Oncol 21:2912–2919

    PubMed  Google Scholar 

  22. Baxter NN, Ricciardi R, Simunovic M, Urbach DR, Virnig BA (2010) An evaluation of the relationship between lymph node number and staging in pT3 colon cancer using population-based data. Dis Colon Rectum 53:65–70

    PubMed  Google Scholar 

  23. Berger AC, Sigurdson ER, LeVoyer T et al (2005) Colon cancer survival is associated with decreasing ratio of metastatic to examined lymph nodes. J Clin Oncol 23:8706–8712

    PubMed  Google Scholar 

  24. Ceelen W, Van Nieuwenhove Y, Pattyn P (2010) Prognostic value of the lymph node ratio in stage III colorectal cancer: a systematic review. Ann Surg Oncol 17:2847–2855

    CAS  PubMed  Google Scholar 

  25. Govindarajan A, Gonen M, Weiser MR et al (2011) Challenging the feasibility and clinical significance of current guidelines on lymph node examination in rectal cancer in the era of neoadjuvant therapy. J Clin Oncol 29:4568–4573

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Goldstein NS, Turner JR (2000) Pericolonic tumor deposits in patients with T3N + M0 colon adenocarcinomas—markers of reduced disease free survival and intra-abdominal metastases and their implications for TNM classification. Cancer 88:2228–2238

    CAS  PubMed  Google Scholar 

  27. Lo DS, Polleft A, Siu LL, Gallinger S, Burkes RL (2008) Prognostic significance of mesenteric tumor nodules in patients with stage III colorectal cancer. Cancer 112:50–54

    PubMed  Google Scholar 

  28. Belt EJT, van Stijn MFM, Bril H et al (2010) Lymph node negative colorectal cancers with isolated tumor deposits should be classified and treated as stage III. Ann Surg Oncol 17:3203–3211

    PubMed Central  PubMed  Google Scholar 

  29. Nagtegaal ID, Tot T, Jayne DG et al (2011) Lymph nodes, tumor deposits, and TNM: are we getting better? J Clin Oncol 29:2487–2492

    PubMed  Google Scholar 

  30. Paramo JC, Summerall J, Wilson C et al (2001) Intraoperative sentinel lymph node mapping in patients with colon cancer. Am J Surg 182:40–43

    CAS  PubMed  Google Scholar 

  31. Bernini A, Spencer M, Frizelle S et al (2000) Evidence for colorectal cancer micrometastases using reverse transcriptase–polymerase chain reaction analysis of MUC2 in lymph nodes. Cancer Detection Prevention 24:72–79

    CAS  PubMed  Google Scholar 

  32. Bilchik AJ, Nora DT, Sabin LH et al (2003) Effect of lymphatic mapping on the new tumor-node-metastasis classification for colorectal cancer. J Clin Oncol 21:668–672

    PubMed  Google Scholar 

  33. Rahbari NN, Bork U, Motschall E et al (2012) Molecular detection of tumor cells in regional lymph nodes is associated with disease recurrence and poor survival in node-negative colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 30:60–70

    PubMed  Google Scholar 

  34. Mulcahy HE, Skelly MM, Husain A, O’Donoghue DP (1996) Long-term outcome following curative surgery for malignant large bowel obstruction. Br J Surg 83:46–50

    CAS  PubMed  Google Scholar 

  35. Betge J, Pollheimer MJ, Lindtner RA et al (2012) Intramural and extramural vascular invasion in colorectal cancer prognostic significance and quality of pathology reporting. Cancer 118:628–638

    PubMed  Google Scholar 

  36. Takebayashi Y, Akiyama S, Yamada K, Akiba S, Aikou T (1996) Angiogenesis as an unfavorable prognostic factor in human colorectal carcinoma. Cancer 78:226–231

    CAS  PubMed  Google Scholar 

  37. Takahashi Y, Tucker SL, Kitadai Y et al (1997) Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg 132:541–546

    CAS  PubMed  Google Scholar 

  38. Hermanek P, Guggenmoosholzmann I, Gall FP (1989) Prognostic factors in rectal-carcinoma—a contribution to the further development of tumor classification. Dis Colon Rectum 32:593–599

    CAS  PubMed  Google Scholar 

  39. Blenkinsopp WK, Stewartbrown S, Blesovsky L, Kearney G, Fielding LP (1981) Histopathology reporting in large bowel-cancer. J Clin Pathol 34:509–513

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Betge J, Langner C (2011) Vascular invasion, perineural invasion, and tumour budding: predictors of outcome in colorectal cancer. Acta Gastro-Enterologica Belgica 74:516–529

    PubMed  Google Scholar 

  41. Mitrovic B, Schaeffer DF, Riddell RH, Kirsch R (2012) Tumor budding in colorectal carcinoma: time to take notice. Mod Pathol 25:1315–1325

    CAS  PubMed  Google Scholar 

  42. Prall F (2007) Tumour budding in colorectal carcinoma. Histopathology 50:151–162

    CAS  PubMed  Google Scholar 

  43. Zlobec I, Lugli A (2010) Epithelial mesenchymal transition and tumor budding in aggressive colorectal cancer: tumor budding as oncotarget. Oncotarget 1:651–661

    PubMed Central  PubMed  Google Scholar 

  44. Halvorsen TB, Seim E (1989) Association between invasiveness, inflammatory reaction, desmoplasia and survival in colorectal-cancer. J Clin Pathol 42:162–166

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Shepherd NA, Saraga EP, Love SB, Jass JR (1989) Prognostic factors in colonic-cancer. Histopathology 14:613–620

    CAS  PubMed  Google Scholar 

  46. Morikawa T, Kuchiba A, Qian ZR et al (2012) Prognostic significance and molecular associations of tumor growth pattern in colorectal cancer. Ann Surg Oncol 19:1944–1953

    PubMed Central  PubMed  Google Scholar 

  47. Naito Y, Saito K, Shiiba K et al (1998) CD8(+) T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:3491–3494

    CAS  PubMed  Google Scholar 

  48. Chiba T, Ohtani H, Mizoi T et al (2004) Intraepithelial CD8(+) T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis. Br J Cancer 91:1711–1717

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Diederichsen ACP, Hjelmborg JV, Christensen PB, Zeuthen J, Fenger C (2003) Prognostic value of the CD4(+)/CD8(+) ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol Immun 52:423–428

    CAS  Google Scholar 

  50. Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964

    CAS  PubMed  Google Scholar 

  51. Guidoboni M, Gafa R, Viel A et al (2001) Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis. Am J Pathol 159:297–304

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Laghi L, Bianchi P, Miranda E et al (2009) CD3 + cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study. Lancet Oncol 10:877–884

    CAS  PubMed  Google Scholar 

  53. Pages F, Berger A, Camus M et al (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666

    CAS  PubMed  Google Scholar 

  54. Pages F, Kirilovsky A, Mlecnik B et al (2009) In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 27:5944–5951

    CAS  PubMed  Google Scholar 

  55. Prall F, Duhrkop T, Weirich V et al (2004) Prognostic role of CD8 + tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Hum Pathol 35:808–816

    CAS  PubMed  Google Scholar 

  56. Gosens MJEM, Klaassen RA, Tan-Go I et al (2007) Circumferential margin involvement is the crucial prognostic factor after multimodality treatment in patients with locally advanced rectal carcinoma. Clin Cancer Res 13:6617–6623

    CAS  PubMed  Google Scholar 

  57. Nagtegaal ID, Marijnen CAA, Kranenbarg EK, van de Velde CJH, van Krieken JHJM (2002) Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma—not one millimeter but two millimeters is the limit. Am J Surg Pathol 26:350–357

    PubMed  Google Scholar 

  58. Bernstein TE, Endreseth BH, Romundstad P, Wibe A (2009) Circumferential resection margin as a prognostic factor in rectal cancer. Br J Surg 96:1348–1357

    CAS  PubMed  Google Scholar 

  59. Nagtegaal ID, Quirke P (2008) What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol 26:303–312

    PubMed  Google Scholar 

  60. den Dulk M, Putter H, Collette L et al (2009) The abdominoperineal resection itself is associated with an adverse outcome: the European experience based on a pooled analysis of five European randomised clinical trials on rectal cancer. Eur J Cancer 45:1175–1183

    Google Scholar 

  61. den Dulk M, Krijnen P, Marijnen CAM et al (2008) Improved overall survival for patients with rectal cancer since 1990: the effects of TME surgery and pre-operative radiotherapy. Eur J Cancer 44:1710–1716

    Google Scholar 

  62. Peeters KCMJ, Marijnen CAM, Nagtegaal ID et al (2007) The TME trial after a median follow-up of 6 years—increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 246:693–701

    PubMed  Google Scholar 

  63. Hohenberger W, Weber K, Matzel K, Papadopoulos T, Merkel S (2009) Standardized surgery for colonic cancer: complete mesocolic excision and central ligation—technical notes and outcome. Colorectal Dis 11:354–364

    CAS  PubMed  Google Scholar 

  64. Kapiteijn E, Marijnen CAM, Nagtegaal ID et al (2001) Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638–646

    CAS  PubMed  Google Scholar 

  65. Ryan R, Gibbons D, Hyland JMP et al (2005) Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology 47:141–146

    CAS  PubMed  Google Scholar 

  66. Dworak O, Keilholz L, Hoffmann A (1997) Pathological features of rectal cancer after preoperative radiochemotherapy. Intl J Colorectal Dis 12:19–23

    CAS  Google Scholar 

  67. Mandard AM, Dalibard F, Mandard JC et al (1994) Pathological assessment of tumor-regression after preoperative chemoradiotherapy of esophageal-carcinoma. Cancer 73:2680–2686

    CAS  PubMed  Google Scholar 

  68. Hyngstrom JR, Hu CY, Xing Y et al (2012) Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: analysis from the National Cancer Data Base. Ann Surg Oncol 19:2814–2821

    PubMed Central  PubMed  Google Scholar 

  69. Thirunavukarasu P, Sathaiah M, Singla S et al (2010) Medullary carcinoma of the large intestine: a population based analysis. Intl J Oncol 37:901–907

    Google Scholar 

  70. Winn B, Tavares R, Fanion J et al (2009) Differentiating the undifferentiated: immunohistochemical profile of medullary carcinoma of the colon with an emphasis on intestinal differentiation. Hum Pathol 40:398–404

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Vogelstein B, Fearon ER, Hamilton SR et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532

    CAS  PubMed  Google Scholar 

  72. Lengauer C, Kinzler KW, Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396:643–649

    CAS  PubMed  Google Scholar 

  73. Vogelstein B, Fearon ER, Kern SE et al (1989) Allelotype of colorectal carcinomas. Science 244:207–211

    CAS  PubMed  Google Scholar 

  74. Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561

    CAS  PubMed  Google Scholar 

  75. Aaltonen LA, Peltomaki P, Leach FS et al (1993) Clues to the pathogenesis of familial colorectal-cancer. Science 260:812–816

    CAS  PubMed  Google Scholar 

  76. Peltomaki P (2003) Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 21:1174–1179

    CAS  PubMed  Google Scholar 

  77. Cunningham JM, Christensen ER, Tester DJ et al (1998) Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 58:3455–3460

    CAS  PubMed  Google Scholar 

  78. Kane MF, Loda M, Gaida GM et al (1997) 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 57:808–811

    CAS  PubMed  Google Scholar 

  79. Lynch HT, Smyrk T, Watson P et al (1991) Hereditary colorectal-cancer. Semin Oncol 18:337–366

    CAS  PubMed  Google Scholar 

  80. Hendriks YMC, de Jong AE, Morreau H et al (2006) Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians. CA Cancer J Clin 56:213–225

    PubMed  Google Scholar 

  81. Umar A, Boland CR, Terdiman JP et al (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Alexander J, Watanabe T, Wu TT, Rashid A, Li SA, Hamilton SR (2001) Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 158:527–535

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Gafa R, Maestri I, Matteuzzi M et al (2000) Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability—pathobiologic features, hMLH1 and hMSH2 expression, and clinical outcome. Cancer 89:2025–2037

    CAS  PubMed  Google Scholar 

  84. Greenson JK, Bonner JD, Ben Yzhak O et al (2003) Phenotype of microsatellite unstable colorectal carcinomas—well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol 27:563–570

    PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Malesci A, Laghi L, Bianchi P et al (2007) Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res 13:3831–3839

    CAS  PubMed  Google Scholar 

  87. Smyrk TC, Watson P, Kaul K, Lynch HT (2001) Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer 91:2417–2422

    CAS  PubMed  Google Scholar 

  88. Ward R, Meagher A, Tomlinson I et al (2001) Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut 48:821–829

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Gryfe R, Kim H, Hsieh ETK et al (2000) Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342:69–77

    CAS  PubMed  Google Scholar 

  90. Ribic CM, Sargent DJ, Moore MJ et al (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247–257

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Halling KC, French AJ, McDonnell SK et al (1999) Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst 91:1295–1303

    CAS  PubMed  Google Scholar 

  92. Deschoolmeester V, Baay M, Van Marck E et al (2010) Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. Bmc Immunol 11

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

    CAS  PubMed  Google Scholar 

  94. Sargent DJ, Marsoni S, Thibodeau SN et al (2008) 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 26

  95. Jover R, Zapater P, Castells A et al (2009) The efficacy of adjuvant chemotherapy with 5-fluorouracil in colorectal cancer depends on the mismatch repair status. Eur J Cancer 45:365–373

    CAS  PubMed  Google Scholar 

  96. Al Sohaily S, Biankin A, Leong R, Kohonen-Corish M, Warusavitarne J (2012) Molecular pathways in colorectal cancer. J Gastroenterol Hepatol 27:1423–1431

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  98. Gnanasampanthan G, Elsaleh H, McCaul K, Iacopetta B (2001) Ki-ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes' C colorectal cancer. J Pathol 195:543–548

    CAS  PubMed  Google Scholar 

  99. De Roock W, Janssens M, Biesmans B et al (2008) DUSP4 expression level in colorectal primaries predicts overall survival benefit in Kras wild-type and Kras mutant colorectal cancer after treatment with cetuximab for metastatic disease. EJC Suppl 6:33

    Google Scholar 

  100. Khambata-Ford S, Garrett CR, Meropol NJ et al (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230–3237

    CAS  PubMed  Google Scholar 

  101. Bokemeyer C, Bondarenko I, Makhson A et al (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671

    CAS  PubMed  Google Scholar 

  102. Van Cutsem E, Kohne CH, Hitre E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417

    PubMed  Google Scholar 

  103. Amado RG, Wolf M, Peeters M et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634

    CAS  PubMed  Google Scholar 

  104. Andreyev HJN, Norman AR, Cunningham D, Oates JR, Clarke PA (1998) Kirsten ras mutations in patients with colorectal cancer: the multicenter "RASCAL" study. J Natl Cancer Instit 90:675–684

    CAS  Google Scholar 

  105. Andreyev HJN, Norman AR, Cunningham D et al (2001) Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study. Br J Cancer 85:692–696

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Ahnen DJ, Feigl P, Quan G et al (1998) Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group Study. Cancer Res 58:1149–1158

    CAS  PubMed  Google Scholar 

  107. Ogino S, Meyerhardt JA, Irahara N et al (2009) KRAS mutation in stage III colon cancer and clinical outcome following Intergroup Trial CALGB 89803. Clin Cancer Res 15:7322–7329

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Roth AD, Tejpar S, Delorenzi M 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 28:466–474

    CAS  PubMed  Google Scholar 

  109. Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE (2002) Tumorigenesis—RAF/RAS oncogenes and mismatch-repair status. Nature 418:934

    CAS  PubMed  Google Scholar 

  110. Ikenoue T, Hikiba Y, Kanai F et al (2003) Functional analysis of mutations within the kinase activation segment of B-Raf in human colorectal tumors. Cancer Res 63:8132–8137

    CAS  PubMed  Google Scholar 

  111. French AJ, Sargent DJ, Burgart LJ et al (2008) Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin Cancer Res 14:3408–3415

    CAS  PubMed Central  PubMed  Google Scholar 

  112. 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 101:1308–1324

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Ogino S, Nosho K, Kirkner GJ et al (2009) CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 58:90–96

    PubMed Central  PubMed  Google Scholar 

  114. Irahara N, Baba Y, Nosho K et al (2010) NRAS mutations are rare in colorectal cancer. Diagnostic Mol Pathol 19:157–163

    CAS  Google Scholar 

  115. Demunter A, Stas M, Degreef H, Wolf-Peeters C, van den Oord JJ (2001) Analysis of N- and K-ras mutations in the distinctive tumor progression phases of melanoma. J Invest Dermatol 117:1483–1489

    CAS  PubMed  Google Scholar 

  116. Haigis KM, Kendall KR, Wang YF et al (2008) Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nature Gen 40:600–608

    CAS  Google Scholar 

  117. Yun JY, Rago C, Cheong I et al (2009) Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325:1555–1559

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310

    CAS  PubMed  Google Scholar 

  119. Rodrigues NR, Rowan A, Smith MEF et al (1990) P53 mutations in colorectal-cancer. Proc Natl Acad Sci U S A 87:7555–7559

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Iacopetta B, Russo A, Bazan V et al (2006) Functional categories of TP53 mutation in colorectal cancer: results of an international collaborative study. Ann Oncol 17:842–847

    CAS  PubMed  Google Scholar 

  121. Russo A, Bazan V, Iacopetta B, Kerr D, Soussi T, Gebbia N (2005) 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 23:7518–7528

    CAS  PubMed  Google Scholar 

  122. Fearon ER, Cho KR, Nigro JM et al (1990) Identification of a chromosome-18Q gene that is altered in colorectal cancers. Science 247:49–56

    CAS  PubMed  Google Scholar 

  123. Jen J, Kim HG, Piantadosi S et al (1994) Allelic loss of chromosome 18Q and prognosis in colorectal-cancer. N Engl J Med 331:213–221

    CAS  PubMed  Google Scholar 

  124. Martinez-Lopez E, Abad A, Font A et al (1998) Allelic loss on chromosome 18q as a prognostic marker in stage II colorectal cancer. Gastroenterology 114:1180–1187

    CAS  PubMed  Google Scholar 

  125. Ogunbiyi OA, Goodfellow PJ, Herfarth K et al (1998) Confirmation that chromosome 18q allelic loss in colon cancer is a prognostic indicator. J Clin Oncol 16:427–433

    CAS  PubMed  Google Scholar 

  126. Popat S, Houlston RS (2005) A systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status and colorectal cancer prognosis. Eur J Cancer 41:2060–2070

    CAS  PubMed  Google Scholar 

  127. Popat S, Zhao DB, Chen ZM et al (2007) Relationship between chromosome 18q status and colorectal cancer prognosis: a prospective, blinded analysis of 280 patients. Anticancer Res 27:627–633

    PubMed  Google Scholar 

  128. Melo FDSE, Wang X, Jansen M et al (2013) Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nature Med 19:614–618

    Google Scholar 

  129. Perez-Villamil B, Romera-Lopez A, Hernandez-Prieto S et al (2012) Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior. BMC Cancer 12:260

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Sadanandam A, Lyssiotis CA, Homicsko K et al (2013) Colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 19:619–625

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Budinska E, Popovici V, Tejpar S et al (2013) Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J Pathol 231:63–76

    CAS  PubMed Central  PubMed  Google Scholar 

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  1. Department of Pathology, University Hospitals Leuven, Herenstraat 49, 3000, Leuven, Belgium

    Xavier Sagaert

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  1. Xavier Sagaert
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Correspondence to Xavier Sagaert.

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Sagaert, X. Prognostic biomarkers in colorectal cancer: where do we stand?. Virchows Arch 464, 379–391 (2014). https://doi.org/10.1007/s00428-013-1532-z

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  • DOI: https://doi.org/10.1007/s00428-013-1532-z

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