Skip to main content

Advertisement

SpringerLink
Log in

KRAS, BRAF, EGFR and HER2 gene status in a Spanish population of colorectal cancer

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

To evaluate the KRAS, BRAF, EGFR, and HER2 gene status in colorectal cancer by novel techniques and evaluate whether anti-HER2 therapies could be offered in the treatment of these patients. There are conflicting data on the prevalence of BRAF mutations and EGFR and HER2 gene amplification in colorectal KRAS wild type patients. In our study we tried to evaluate these expressions and their relationship to future treatment assays. Clinical–pathological data and paraffin-embedded specimens were collected from 186 patients who underwent colorectal resections at General Yagüe Hospital in Burgos, Spain. KRAS and BRAF status was analyzed by real-time PCR in all patients. EGFR and HER2/NEU gene amplification was detected using fluorescent in situ hybridisation technique (FISH) in 38 KRAS and BRAF wild type patients. KRAS mutations were present in 48% of the colorectal cancer patients. BRAF mutations were present in 6.25% of the KRAS wild type patients. EGFR and HER2 gene amplification was observed in 5.3% and 26.3%, respectively, of KRAS and BRAF wild type colorectal cancer patients. HER2, but not EGFR gene amplification, was frequently observed in KRAS and BRAF wild type colorectal cancer patients. These data indicate that HER2 amplification could be one of the genes to be considered in the therapeutic management of colorectal cancer.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

BRAF:

BRAF murine sarcoma viral oncogene homolog B1

KRAS:

Human homolog of the Kirsten rat sarcoma-2 virus oncogene

EGFR:

Epidermal growth factor receptor

FISH:

Fluorescence In situ Hybridization

HER2:

Human epidermal growth factor receptor-2

mCRC:

Metastatic colorectal cancer

References

  1. Jemal A et al (2003) Cancer statistics. CA Cancer J Clin 53(1):5–26

    Article  PubMed  Google Scholar 

  2. Venook AP (2005) Epidermal growth factor receptor-targeted treatment for advanced colorectal carcinoma. Cancer 103(12):2435–2446

    Article  CAS  PubMed  Google Scholar 

  3. Moore MJ et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25(15):1960–1966

    Article  CAS  PubMed  Google Scholar 

  4. Van Cutsem E et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25(13):1658–1664

    Article  PubMed  Google Scholar 

  5. Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5(5):341–354

    Article  CAS  PubMed  Google Scholar 

  6. Mendelsohn J, Baselga J (2006) Epidermal growth factor receptor targeting in cancer. Semin Oncol 33(4):369–385

    Article  CAS  PubMed  Google Scholar 

  7. Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3(1):11–22

    Article  CAS  PubMed  Google Scholar 

  8. Malumbres M, Barbacid M (2003) RAS oncogenes: the first 30 years. Nat Rev Cancer 3(6):459–465

    Article  CAS  PubMed  Google Scholar 

  9. Schubbert S, Shannon K, Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7(4):295–308

    Article  CAS  PubMed  Google Scholar 

  10. Andreyev HJ et al (2001) Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer 85(5):692–696

    Article  CAS  PubMed  Google Scholar 

  11. Bazan V et al (2002) Specific codon 13 K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with mucinous histotype. Ann Oncol 13(9):1438–1446

    Article  CAS  PubMed  Google Scholar 

  12. Benvenuti S et al (2007) Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67(6):2643–2648

    Article  CAS  PubMed  Google Scholar 

  13. De Roock W et al (2008) KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 19(3):508–515

    Article  PubMed  Google Scholar 

  14. Di Fiore F et al (2007) Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer 96(8):1166–1169

    Article  CAS  PubMed  Google Scholar 

  15. Lievre A et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66(8):3992–3995

    Article  CAS  PubMed  Google Scholar 

  16. Adams R, Maughan T (2007) Predicting response to epidermal growth factor receptor-targeted therapy in colorectal cancer. Expert Rev Anticancer Ther 7(4):503–518

    Article  CAS  PubMed  Google Scholar 

  17. Nahta R et al (2006) Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol 3(5):269–280

    Article  CAS  PubMed  Google Scholar 

  18. Lu Y et al (2007) Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance escaping treatment by the anti-EGFR monoclonal antibody cetuximab. Cancer Res 67(17):8240–8247

    Article  CAS  PubMed  Google Scholar 

  19. Cunningham D et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351(4):337–345

    Article  CAS  PubMed  Google Scholar 

  20. Chung KY et al (2005) Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23(9):1803–1810

    Article  CAS  PubMed  Google Scholar 

  21. Moroni M et al (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6(5):279–286

    Article  CAS  PubMed  Google Scholar 

  22. Dowsett M et al (2009) Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA Trial. J Clin Oncol 27(18):2962–2969

    Article  CAS  PubMed  Google Scholar 

  23. Paez JG et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676):1497–1500

    Article  CAS  PubMed  Google Scholar 

  24. Newton CR et al (1989) Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res 17(7):2503–2516

    Article  CAS  PubMed  Google Scholar 

  25. Thelwell N et al (2000) Mode of action and application of Scorpion primers to mutation detection. Nucleic Acids Res 28(19):3752–3761

    Article  CAS  PubMed  Google Scholar 

  26. Whitcombe D et al (1999) Detection of PCR products using self-probing amplicons and fluorescence. Nat Biotechnol 17(8):804–807

    Article  CAS  PubMed  Google Scholar 

  27. Benlloch S et al (2006) Detection of BRAF V600E mutation in colorectal cancer: comparison of automatic sequencing and real-time chemistry methodology. J Mol Diagn 8(5):540–543

    Article  CAS  PubMed  Google Scholar 

  28. Amado RG et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26(10):1626–1634

    Article  CAS  PubMed  Google Scholar 

  29. Di Nicolantonio F et al (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26(35):5705–5712

    Article  CAS  PubMed  Google Scholar 

  30. Kavanagh DO et al (2009) Is overexpression of HER-2 a predictor of prognosis in colorectal cancer? BMC Cancer 9:1

    Article  PubMed  Google Scholar 

  31. Ooi A et al (2004) Protein overexpression and gene amplification of HER-2 and EGFR in colorectal cancers: an immunohistochemical and fluorescent in situ hybridization study. Mod Pathol 17(8):895–904

    Article  CAS  PubMed  Google Scholar 

  32. Schuell B et al (2006) HER 2/neu protein expression in colorectal cancer. BMC Cancer 6:123

    Article  CAS  PubMed  Google Scholar 

  33. Moroni M et al (2008) EGFR FISH in colorectal cancer: what is the current reality? Lancet Oncol 9(5):402–403

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Celia Barrrio for her technical help with the FISH analysis and Susana Santamaría for her technical help. MHV is especially thankful to CVP, IHH and AHV, for their support. This work was supported by a grant FIS CA08/00070 and Caja de Burgos.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Unidad de Investigación, Hospital General Yagüe, Avenida del Cid 96, 09005, Burgos, Spain

    Marta Herreros-Villanueva & Maria Jesus Coma del Corral

  2. Servicio de Anatomía Patológica, Hospital General Yagüe, Burgos, Spain

    Maximiliano Rodrigo & Manuel Claver

  3. Departamento de Bioquímica, Universidad de Burgos, Burgos, Spain

    Pilar Muñiz

  4. Servicio de Oncología, Hospital General Yagüe, Burgos, Spain

    Enrique Lastra & Carlos García-Girón

Authors
  1. Marta Herreros-Villanueva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maximiliano Rodrigo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manuel Claver
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pilar Muñiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Enrique Lastra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carlos García-Girón
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maria Jesus Coma del Corral
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marta Herreros-Villanueva.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Herreros-Villanueva, M., Rodrigo, M., Claver, M. et al. KRAS, BRAF, EGFR and HER2 gene status in a Spanish population of colorectal cancer. Mol Biol Rep 38, 1315–1320 (2011). https://doi.org/10.1007/s11033-010-0232-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-010-0232-x

Keywords

Search

Navigation