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Mutations of KRAS and PIK3CA as independent predictors of distant metastases in colorectal cancer

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Abstract

The objective was to evaluate DNA mutations of KRAS, BRAF, and PIK3CA and their clinicopathological correlations with colorectal cancer (CRC) and to identify their contribution to distant metastases in CRC. A total of 148 tumor samples were obtained from patients with CRC in the Shandong Tumor Hospital and Institute between January 2008 and December 2009. DNA was extracted for polymerase chain reaction amplification and pyrosequencing to evaluate mutations of KRAS, BRAF, and PIK3CA, and clinicopathological correlations of these mutations with CRC [including age, gender, tumor location, pathological type, tumor–node–metastasis (TNM) classification, and distant metastatic status] were analyzed. KRAS, BRAF, and PIK3CA mutation rates were identified in 46 (31.1 %), 11 (7.4 %), and 14 (9.5 %) of the total 148 CRC tumor samples, respectively. Neither mutation had significant correlation with age, gender, size and location of the tumor, and pathological type. KRAS, BRAF, and PIK3CA mutations were found in 14 (66.7 %), 3 (14.3 %), and 8 (38.1 %) of the 21 distant metastatic colorectal tumor samples, respectively. The relative risks of distant metastasis for KRAS, BRAF, and PIK3CA mutations were 30.4 versus 6.8 % (P = 0.001), 27.3 versus 13.1 % (P = 0.191), and 57.1 versus 9.7 % (P < 0.001) (5-year risks), respectively. Patients with either KRAS or PIK3CA mutations are more susceptible to distant metastasis. Thus, these two mutations might be used as independent predictors of distant metastatic CRC.

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References

  1. Weitz J, Koch M, Debus J, Hohler T, Galle PR, Buchler MW. Colorectal cancer. Lancet. 2005;365:153–65.

    Article  PubMed  Google Scholar 

  2. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–45.

    Article  CAS  PubMed  Google Scholar 

  3. Cutsem EV, Peeters M, Siena S, et al. 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. 2007;25:1658–64.

    Article  PubMed  Google Scholar 

  4. McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006;46:249–79.

    Article  CAS  PubMed  Google Scholar 

  5. Scaltriti M, Baselga J. The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res. 2006;12:5268–72.

    Article  CAS  PubMed  Google Scholar 

  6. Samowitz WS, Curtin K, Schaffer D, et al. Relationship of K-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study. Cancer Epidemiol Biomark Prev. 2000;9:1193–7.

    CAS  Google Scholar 

  7. Brink M, de Goeij AF, Weijenberg MP, et al. K-ras oncogene mutations in sporadic colorectal cancer in the Netherlands Cohort Study. Carcinogenesis. 2003;24:703–10.

    Article  CAS  PubMed  Google Scholar 

  8. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    Article  CAS  PubMed  Google Scholar 

  9. Ogino S, Nosho K, Kirkner GJ, et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut. 2009;58:90–6.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Samuels Y, Diaz LA Jr, Schmidt-Kittler O, et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell. 2005;7:561–73.

    Article  CAS  PubMed  Google Scholar 

  11. Rodriguez-Viciana P, Warne PH, Dhand R, et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994;370:527–32.

    Article  CAS  PubMed  Google Scholar 

  12. Gupta S, Ramjaun AR, Haiko P, et al. Binding of ras to phosphoinositide 3-kinase p110α is required for ras-driven tumorigenesis in mice. Cell. 2007;129:957–68.

    Article  CAS  PubMed  Google Scholar 

  13. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.

    Article  CAS  PubMed  Google Scholar 

  14. Velho S, Oliveira C, Ferreira A, et al. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005;41:1649–54.

    Article  CAS  PubMed  Google Scholar 

  15. Barault L, Veyrie N, Jooste V, et al. Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. Int J Cancer. 2008;122:2255–9.

    Article  CAS  PubMed  Google Scholar 

  16. Kato S, Iida S, Higuchi T, et al. PIK3CA mutation is predictive of poor survival in patients with colorectal cancer. Int J Cancer. 2007;121:1771–8.

    Article  CAS  PubMed  Google Scholar 

  17. Ogino S, Nosho K, Kirkner GJ, et al. PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol. 2009;27:1477–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Nosho K, Kawasaki T, Ohnishi M, et al. PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. Neoplasia. 2008;10:534–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Stephan B, Karl LS, Rainer E, et al. Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res. 2010;16(3):790–9.

    Article  Google Scholar 

  20. Vakiani E, Janakiraman M, Shen R, et al. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol. 2012;30(24):2956–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Ogino S, Kawasaki T, Brahmandam M, et al. Sensitive sequencing method for KRAS mutation detection by pyrosequencing. J Mol Diagn. 2005;7(3):413–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Thomas RK, Baker AC, Debiasi RM, et al. High-throughput oncogene mutation profiling in human cancer. Nat Genet. 2007;39:347–51.

    Article  CAS  PubMed  Google Scholar 

  23. Simi L, Pratesi N, Vignoli M, et al. High-resolution melting analysis for rapid detection of KRAS, BRAF, and PIK3CA gene mutations in colorectal cancer. Am J Clin Pathol. 2008;130:247–53.

    Article  CAS  PubMed  Google Scholar 

  24. Tie J, Lipton L, Desai J, et al. KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. Clin Cancer Res. 2011;17(5):1122–30.

    Article  CAS  PubMed  Google Scholar 

  25. Richman SD, Seymour M, Chambers P, 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(35):5931–7.

    Article  CAS  PubMed  Google Scholar 

  26. Ree AH, Kristensen AT, Saelen MG, et al. Tumor phosphatidylinositol-3-kinase signaling and development of metastatic disease in locally advanced rectal cancer. PLoS One. 2012;7(11):50806.

    Article  Google Scholar 

  27. Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC23, EORTC 40993, SAKK 60200 trial. J Clin Oncol. 2010;28(3):466–74.

    Article  CAS  PubMed  Google Scholar 

  28. Liao X, Morikawa T, Lochhead P, et al. Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review. Clin Cancer Res. 2012;18(8):2257–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors thank Mr. Xin Yi for excellent technical help concerning the PCR. This work was supported by Youth Fund of Shandong Academy of Medical Science Research Grant (2011-23).

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Authors and Affiliations

  1. Department of Radiation Oncology, Shandong Tumor Hospital and Institute, Jinan, 250117, China

    Kunli Zhu, Hongjiang Yan, Renben Wang, Hui Zhu, Xiangjiao Meng, Xiaoqing Xu, Xue Dou & Dong Chen

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  1. Kunli Zhu
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  2. Hongjiang Yan
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  3. Renben Wang
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  4. Hui Zhu
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  5. Xiangjiao Meng
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  8. Dong Chen
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Correspondence to Renben Wang.

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Zhu, K., Yan, H., Wang, R. et al. Mutations of KRAS and PIK3CA as independent predictors of distant metastases in colorectal cancer. Med Oncol 31, 16 (2014). https://doi.org/10.1007/s12032-014-0016-6

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  • DOI: https://doi.org/10.1007/s12032-014-0016-6

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