Skip to main content

Advertisement

Log in

Gene Signatures in Stage II Colon Cancer: A Clinical Review

  • Adjuvant Therapy for Colon Cancers (AB Benson and A de Gramont, Section Editors)
  • Published:
Current Colorectal Cancer Reports

Abstract

Understanding the biology of cancer is the key to understanding its behavior. Stage II colon cancers represent a unique treatment challenge for medical oncologists because they contain a very heterogeneous group of tumors with a wide range of recurrence risks after resection. Defining these differences in biology can help to explain differences in disease behavior. To this end, gene signatures have been developed to define various prognostic groups beyond the clinicopathologic features alone. Adjuvant chemotherapy for stage II colon cancers as a group has not shown survival advantage in clinical trials. Future research to develop gene signatures to predict a group that will benefit from adjuvant chemotherapy will be helpful in the clinical decision-making process. The purpose of this review is to present the prognostic gene signatures currently available for use, those in development, and their utility in stratifying recurrence risk in stage II colon cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Siegel R, Naishadham D, Jemal A, et al. Cancer statistics, 2012. Cancer J Clin. 2012;62:10–29.

    Article  Google Scholar 

  2. Edge SE, Byrd DR, Carducci MA. AJCC Cancer Staging Manual 7th ed. 14th ed. New York, NY: Springer; 2010. p. 143–64.

    Google Scholar 

  3. • Gunderson LL, Jessup JM, Sargent DJ. Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol. 2010;28:264–71. This article updates the survival pattern of patients with colon cancer, which is the basis of changes made to the substaging in the AJCC colon cancer staging 7th edition.

    Article  PubMed  Google Scholar 

  4. Green FL, Page DL, Fleming ID, et al. AJCC cancer staging manual. 6th ed. New York, NY: Springer-Verlay; 2002 (Chapter 12, pages 113-122).

    Google Scholar 

  5. O’Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with new American joint committee on cancer sixth edition staging. J Natl Cancer Inst. 2004;96(19):1420.

    Article  PubMed  Google Scholar 

  6. The QUASAR Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: A randomised study. Lancet. 2007;370:2020–9.

    Article  Google Scholar 

  7. André T, Boni C, Navarro M. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27(19):3109.

    Article  PubMed  Google Scholar 

  8. Kuebler JP, Wieand S, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: Results from NSABP C-07. J Clin Oncol. 2007;25(16):2198.

    Article  PubMed  CAS  Google Scholar 

  9. • Wilkinson NW, Yothers G, Lopa S. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: Pooled analysis of NSABP C-01 through C-05. A baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010;17(4):959–66. This article is a meta-analysis of NSABP C-01 through C-06 showing benefit in outcomes when 5-FU is given in addition to surgery to provide anticipated survival outcome with which to compare modern adjuvant trials.

    Article  PubMed  Google Scholar 

  10. NCCN guidelines Version 3.2012. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp

  11. • O’Conner ES, Greenblatt DY, LoConte NK. Adjuvant chemotherapy for stage II colon cancer with poor prognostic features. J Clin Oncol. 2011;29(25):3381–8. This article provides information that older patients with stage II colon cancer and at least one clinicopathologic risk factor do not benefit from adjuvant chemotherapy.

    Article  Google Scholar 

  12. Benson AB, Schrag D, Somerfield MR, et al. American society of clinical oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol. 2004;22(16):3408–19.

    Article  PubMed  Google Scholar 

  13. Adjuvant! Online: www.adjuvantonline.com

  14. Numeracy: www.mayoclinic.com/calcs

  15. • Sargent DJ, Marsoni S, Monges G. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28(30):3216–26. This article shows that stage II colon cancer patients do not benefit from adjuvant 5-FU-based therapy.

    Google Scholar 

  16. Waldman SA, Hyslop T, Schulz S, et al. Association of GUCY2C expression in lymph nodes with time to recurrence and disease-free survival in pN0 colorectal cancer. JAMA. 2009;301(7):745–52.

    Article  PubMed  CAS  Google Scholar 

  17. •• Sargent DJ, Resnick MB, Meyers MO. Evaluation of Guanylyl Cyclase C lymph node status for colon cancer staging and prognosis. Ann Surg Oncol. 2011;18(12):3261–70. This article shows the importance of detecting guanylyl cyclase C as a marker for metastatic disease in the lymph nodes in stage II patients without histologic evidence of positive nodes.

    Article  PubMed  Google Scholar 

  18. Gal R, Sadikov E, Sulkes J, et al. Deleted in colorectal cancer protein expression as a possible predictor of response to adjuvant chemotherapy in colorectal cancer patients. Dis Colon Rectum. 2004;47(7):1216.

    Article  PubMed  Google Scholar 

  19. Sargent DJ, Sobrero A, Grothey A, et al. Evidence for cure by adjuvant therapy in colon cancer: Observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2009;27(6):872–7.

    Article  PubMed  Google Scholar 

  20. Dotor E, Cuatrecases M, Martínez-Iniesta M, et al. Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment. J Clin Oncol. 2006;24(10):1603–11.

    Article  PubMed  CAS  Google Scholar 

  21. Ahnen DJ, Feigl P, Quan G. Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: A Southwest Oncology Group study. Cancer Res. 1998;58:1149–58.

    PubMed  CAS  Google Scholar 

  22. Elsaleh H, Powell B, Soontrapornchai P. p53 gene mutation, microsatellite instability and adjuvant chemotherapy: Impact on survival of 388 patients with Dukes’ C colon carcinoma. Oncology. 2000;58:52–9.

    Article  PubMed  CAS  Google Scholar 

  23. Westra JL, Schaapveld M, Hollema H. Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients. J Clin Oncol. 2005;23:5635–43.

    Article  PubMed  CAS  Google Scholar 

  24. • Roth AD, Tejpar S, Yan P. Stage-specific prognostic value of molecular markers in colon cancer: Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial. J Clin Oncol. 2009;27(4002):169s. This abstract provides information that molecular markers in stage II and III colon cancer have stage- specific prognostic information and may represent different diseases rather than sequential steps in the evolution of colon cancer.

    Google Scholar 

  25. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.

    Article  PubMed  CAS  Google Scholar 

  26. Storojeva I, Boulay JL, Heinimann K. Prognostic and predictive relevance of microsatellite instability in colorectal cancer. Oncol Rep. 2005;14:241–9.

    PubMed  CAS  Google Scholar 

  27. Carethers JM, Smith EJ, Behling CA, et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology. 2004;126:394–401.

    Article  PubMed  CAS  Google Scholar 

  28. González-García I, Moreno V, Navarro M. Standardized approach for microsatellite instability detection in colorectal carcinomas. J Natl Cancer Inst. 2000;92:544–9.

    Article  PubMed  Google Scholar 

  29. Bertucci F, Salas S, Eysteries S, et al. Gene expression profiling of colon cancer by DNA microarrays and correlation with histoclinical parameters. Oncogene. 2004;23:1377–91.

    Article  PubMed  CAS  Google Scholar 

  30. Wang Y, Jatkoe T, Zhang Y. Gene expression profiles and molecular markers to predict recurrence of Dukes’ B colon cancer. J Clin Oncol. 2004;22:1564–71.

    Article  PubMed  CAS  Google Scholar 

  31. Barrier A, Boelle PY, Roser F. Stage II colon cancer prognosis prediction by tumor gene expression profiling. J Clin Oncol. 2006;24:4685–91.

    Article  PubMed  CAS  Google Scholar 

  32. Eschrich S, Yang I, Bloom G. Molecular staging for survival prediction of colorectal cancer patients. J Clin Oncol. 2005;23:3526–35.

    Article  PubMed  CAS  Google Scholar 

  33. •• O’Connell MJ, Lavery I, Yothers G. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol. 2010;28(25):3937–44. This article details the process of gene selection and validation to develop the 12-gene OncotypeDX Recurrence Score from formalin-fixed paraffin embedded tissue.

    Article  PubMed  Google Scholar 

  34. Dukes CE. The classification of cancer of the rectum. J Pathol Bact. 1932;35:323–32.

    Article  Google Scholar 

  35. Dukes CE, Bussey HJ. The spread of rectal cancer and its effect on prognosis. Br J Cancer. 1958;12:309–20.

    Article  PubMed  CAS  Google Scholar 

  36. •• Gray RG, Quirke P, Handley K. Validation study of a quantitative multigene reverse transcriptase–polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol. 2011;29(35):4611–9. This article describes the external validation of the 12-gene OncotypeDX Recurrence Score in the QUASAR and CALGB 9581 trials.

    Article  PubMed  Google Scholar 

  37. Barratt PL, Seymour MT, Stenning SP, et al. DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: A molecular study. Lancet. 2002;360:1381–91.

    Article  PubMed  CAS  Google Scholar 

  38. de Bruin M, van Capel T, Van der Born K, et al. Role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in fluoropyrimidine sensitivity. Br J Cancer. 2003;88:957–64.

    Article  PubMed  Google Scholar 

  39. van Triest B, Pinedo HM, Blaauwgeers JL, et al. Prognostic role of thymidine synthase, thymidine phosphorylase/platelet-derived endothelial cell growth factor and proliferation markers in colorectal cancer. Clin Cancer Res. 2000;6:1063–72.

    PubMed  Google Scholar 

  40. van Kuilenburg AB. Screening for dihyrodropyrimidine dehydrogenase deficiency: To do or not to do, that’s the question. Cancer Invest. 2006;24:215–7.

    Article  PubMed  Google Scholar 

  41. Peters GJ, Smorenburg CH, Van Groeningen CJ. Prospective clinical trials using a pharmacogenetic/pharmacogenomic approach. J Chemother. 2004;16(4):25–30.

    PubMed  CAS  Google Scholar 

  42. Salonga D, Danenberg KD, Johnson M, 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;6:1322–7.

    PubMed  CAS  Google Scholar 

  43. Ichikawa W, Uetake H, Shirota Y, et al. Combination of dihydropyrimidine dehydrogenase and thymidylate synthase gene expression in primary tumors as predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy for metastatic colorectal cancer. Clin Cancer Res. 2003;9:786–91.

    PubMed  CAS  Google Scholar 

  44. •• O’Connell MJ, Lee M, Lopatin M, et al.: Validation of the 12-gene colon cancer recurrence score (RS) in NSABP C-07 as a predictor of recurrence in stage II and III colon cancer patients treated with 5-FU/LV (FU) and 5-FU/LV + oxaliplatin (FU + Ox). Being presented at American Society of Clinical Oncology June 1-5th 2012. Poster Discussion Session. Abstract #3512. This abstract provides results of validation study of OncotypeDX Recurrence Score (RS) on NSABP C-07 patients showing that the RS is prognostic of outcomes in patients treated with 5-FU and degree of benefit from oxaliplatin is a function of risk.

  45. •• Salazar R, Roepman P, Capella G. Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol. 2011;29(1):17–24. This article describes the process of development of the 18-gene ColoPrint assay using Agilent 44K oligonucleotide assay from fresh frozen tissue.

    Article  PubMed  Google Scholar 

  46. •• Tabernero J, Moreno V, Rosenberg R. Clinical and technical validation of genomic classifier (ColoPrint) for predicting outcomes in stage II colon cancer. J Clin Oncol. 2012;30(4):abstr 384. This abstract provides the validation study for the 18-gene ColoPrint.

  47. •• Kennedy RD, Bylesjo M, Kerr P. Development and independent validation of a prognostic assay for stage II colon cancer using formalin-fixed paraffin-embedded tissue. J Clin Oncol. 2011;29(35):4620–8. This article provides the development and validation of the ColDx which is a 634-gene microarray analysis of formalin fixed paraffin embedded tissue.

    Article  PubMed  Google Scholar 

  48. Nosho K, Yamamoto H, Taniguchi H, et al. Interplay of insulin-like growth factor-II, insulin-like growth factor-I, insulin-like growth factor-I receptor, COX-2, and matrix metalloproteinase-7, play key roles in the early stage of colorectal carcinogenesis. Clin Cancer Res. 2004;10:7950–7.

    Article  PubMed  CAS  Google Scholar 

  49. Tsushima H, Kawata S, Tamura S, et al. High levels of transforming growth factor beta 1 in patients with colorectal cancer: Association with disease progression. Gastroenterology. 1996;110:375–82.

    Article  PubMed  CAS  Google Scholar 

  50. Volp K, Brezniceanu ML, Bosser S, et al. Increased expression of high mobility group box 1 (HMGB1) is associated with an elevated level of the antiapoptotic c-IAP2 protein in human colon carcinomas. Gut. 2006;55:234–42.

    Article  PubMed  CAS  Google Scholar 

  51. Giacomini CP, Leung SY, Chen X, et al. A gene expression signature of genetic instability in colon cancer. Cancer Res. 2005;65:9200–5.

    Article  PubMed  CAS  Google Scholar 

  52. de Gramont A, Hubbard J, Shi Q, et al. Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: Simulations based on the 20,800 patient ACCENT data set. J Clin Oncol. 2012;28(3):460–5.

    Article  Google Scholar 

  53. van’t Veer LJ, Dai H, van de Vijver MJ. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530–6.

    Article  Google Scholar 

  54. Glas AM, Floore A, Delahaye LJ, et al. Converting a breast cancer microarray signature into a high-throughput diagnostic test. BMC Genomics. 2006;7:278.

    Article  PubMed  Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Saima Sharif.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sharif, S., O’Connell, M.J. Gene Signatures in Stage II Colon Cancer: A Clinical Review. Curr Colorectal Cancer Rep 8, 225–231 (2012). https://doi.org/10.1007/s11888-012-0132-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11888-012-0132-7

Keywords

Navigation