DOI QR코드

DOI QR Code

Mutation Analysis of KRAS and BRAF Genes in Metastatic Colorectal Cancer: a First Large Scale Study from Iran

  • koochak, Aghigh (Gastrointestinal and Liver Diseases Research Center, Firoozgar Hospital) ;
  • Rakhshani, Nasser (Gastrointestinal and Liver Diseases Research Center, Firoozgar Hospital) ;
  • Niya, Mohammad Hadi Karbalaie (Department Of Virology, Iran University Of Medical Sciences) ;
  • Tameshkel, Fahimeh Safarnezhad (Gastrointestinal and Liver Diseases Research Center, Firoozgar Hospital) ;
  • Sohrabi, Masoud Reza (Gastrointestinal and Liver Diseases Research Center, Firoozgar Hospital) ;
  • Babaee, Mohammad Reza (Gastrointestinal and Liver Diseases Research Center, Firoozgar Hospital) ;
  • Rezvani, Hamid (Department of Oncology, Shahid Beheshti University of Medical Sciences) ;
  • Bahar, Babak (Gastrointestinal and Liver Diseases Research Center, Firoozgar Hospital) ;
  • Imanzade, Farid (Department of Pediatrics, Shahid Beheshti University of Medical Sciences) ;
  • Zamani, Farhad (Gastrointestinal and Liver Diseases Research Center, Firoozgar Hospital) ;
  • Khonsari, Mohammad Reza (Gastrointestinal and Liver Diseases Research Center, Firoozgar Hospital) ;
  • Ajdarkosh, Hossein (Gastrointestinal and Liver Diseases Research Center, Firoozgar Hospital) ;
  • Hemmasi, Gholamreza (Gastrointestinal and Liver Diseases Research Center, Firoozgar Hospital)
  • Published : 2016.03.07

Abstract

Background: The investigation of mutation patterns in oncogenes potentially can make available a reliable mechanism for management and treatment decisions for patients with colorectal cancer (CRC). This study concerns the rate of KRAS and BRAF genes mutations in Iranian metastatic colorectal cancer (mCRC) patients, as well as associations of genotypes with clinicopathological features. Materials and Methods: A total of 1,000 mCRC specimens collected from 2008 to 2012 that referred to the Mehr Hospital and Partolab center, Tehran, Iran enrolled in this cross sectional study. Using HRM, Dxs Therascreen and Pyrosequencing methods, we analyzed the mutational status of KRAS and BRAF genes in these. Results: KRAS mutations were present in 33.6% cases (n=336). Of KRAS mutation positive cases, 85.1% were in codon 12 and 14.9% were in codon 13. The most frequent mutation at KRAS codon 12 was Gly12Asp; BRAF mutations were not found in any mCRC patients (n=242). In addition, we observed a strong correlation of KRAS mutations with some clinicopathological characteristics. Conclusions: KRAS mutations are frequent in mCRCs while presence of BRAF mutations in these patients is rare. Moreover, associations of KRAS genotypes with non-mucinous adenocarcinoma and depth of invasion (pT3) were remarkable.

Keywords

References

  1. Ahlquist T, Bottillo I, Danielsen SA, et al (2008). RAS signaling in colorectal carcinomas through alteration of RAS, RAF, NF1, and/or RASSF1A. Neoplasia, 10, 680-6, 2 p following 686. https://doi.org/10.1593/neo.08312
  2. Allegra CJ, Jessup JM, Somerfield MR, et al (2009). American society of clinical oncology provisional clinical opinion:testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol, 27, 2091-6. https://doi.org/10.1200/JCO.2009.21.9170
  3. 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, 1626-34. https://doi.org/10.1200/JCO.2007.14.7116
  4. Andreyev HJ, Norman AR, Cunningham D, et al (2001). Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II' study. Br J Cancer, 85, 692-6. https://doi.org/10.1054/bjoc.2001.1964
  5. Andreyev HJ, Norman AR, Cunningham D, et al (1998). Kirsten ras mutations in patients with colorectal cancer:the multicenter “RASCAL” study. J Natl Cancer Inst, 90, 675-84. https://doi.org/10.1093/jnci/90.9.675
  6. Bamford S, Dawson E, Forbes S, et al (2004). The COSMIC (catalogue of somatic mutations in cancer) database and website. Br J Cancer, 91, 355-8. https://doi.org/10.1038/sj.bjc.6601894
  7. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, 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, 2643-8. https://doi.org/10.1158/0008-5472.CAN-06-4158
  8. Borras E, Jurado I, Hernan I, et al (2011). Clinical pharmacogenomic testing of KRAS, BRAF and EGFR mutations by high resolution melting analysis and ultra-deep pyrosequencing. BMC Cancer, 11, 406. https://doi.org/10.1186/1471-2407-11-406
  9. Bos JL, Fearon ER, Hamilton SR, et al (1987). Prevalence of ras gene mutations in human colorectal cancers. Nature, 327, 293-7. https://doi.org/10.1038/327293a0
  10. Campbell SL, Khosravi-Far R, Rossman KL, et al (1998). Increasing complexity of Ras signaling. Oncogene, 17, 1395-413. https://doi.org/10.1038/sj.onc.1202174
  11. Chen D, Wang YY, Chuai ZR, et al (2014). High-resolution melting analysis for accurate detection of BRAF mutations:a systematic review and meta-analysis. Sci Rep, 4, 4168.
  12. Ciardiello F, Tejpar S, Normanno N, et al (2011). Uptake of KRAS mutation testing in patients with metastatic colorectal cancer in Europe, Latin America and Asia. Target Oncol, 6, 133-45. https://doi.org/10.1007/s11523-011-0181-x
  13. De Roock W, De Vriendt V, Normanno N, et al (2011). KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol, 12, 594-603. https://doi.org/10.1016/S1470-2045(10)70209-6
  14. Deng G, Bell I, Crawley S, et al (2004). BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res, 10, 191-5. https://doi.org/10.1158/1078-0432.CCR-1118-3
  15. Dolatkhah R, Somi MH, Bonyadi MJ, et al (2015). Colorectal cancer in iran: molecular epidemiology and screening strategies. J Cancer Epidemiol, 2015, 643020.
  16. Farina-Sarasqueta A, van Lijnschoten G, Moerland E, et al (2010). The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann Oncol, 21, 2396-402. https://doi.org/10.1093/annonc/mdq258
  17. Fransen K, Klintenas M, Osterstrom A, et al (2004). Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis, 25, 527-33.
  18. 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, 3408-15. https://doi.org/10.1158/1078-0432.CCR-07-1489
  19. Guedes JG, Veiga I, Rocha P, et al (2013). High resolution melting analysis of KRAS, BRAF and PIK3CA in KRAS exon 2 wild-type metastatic colorectal cancer. BMC Cancer, 13, 169. https://doi.org/10.1186/1471-2407-13-169
  20. Herreros-Villanueva M, Rodrigo M, Claver M, et al (2011). KRAS, BRAF, EGFR and HER2 gene status in a Spanish population of colorectal cancer. Mol Biol Rep, 38, 1315-20. https://doi.org/10.1007/s11033-010-0232-x
  21. Hsieh LL, Er TK, Chen CC, et al (2012). Characteristics and prevalence of KRAS, BRAF, and PIK3CA mutations in colorectal cancer by high-resolution melting analysis in Taiwanese population. Clin Chim Acta, 413, 1605-11. https://doi.org/10.1016/j.cca.2012.04.029
  22. Imamura Y, Morikawa T, Liao X, et al (2012). Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF wild-type colorectal cancers. Clin Cancer Res, 18, 4753-63. https://doi.org/10.1158/1078-0432.CCR-11-3210
  23. Janakiraman M, Vakiani E, Zeng Z, et al (2010). Genomic and biological characterization of exon 4 KRAS mutations in human cancer. Cancer Res, 70, 5901-11. https://doi.org/10.1158/0008-5472.CAN-10-0192
  24. Jemal A, Bray F, Center MM, et al. (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  25. Kadowaki S, Kakuta M, Takahashi S, et al (2015). Prognostic value of KRAS and BRAF mutations in curatively resected colorectal cancer. World J Gastroenterol, 21, 1275-83. https://doi.org/10.3748/wjg.v21.i4.1275
  26. Kwon MJ, Lee SE, Kang SY, et al (2011). Frequency of KRAS, BRAF, and PIK3CA mutations in advanced colorectal cancers: Comparison of peptide nucleic acid-mediated PCR clamping and direct sequencing in formalin-fixed, paraffinembedded tissue. Pathol Res Pract, 207, 762-8. https://doi.org/10.1016/j.prp.2011.10.002
  27. Li HT, Lu YY, An YX, et al (2011). KRAS, BRAF and PIK3CA mutations in human colorectal cancer: relationship with metastatic colorectal cancer. Oncol Rep, 25, 1691-7.
  28. Mahdavinia M, Bishehsari F, Ansari R, et al (2005). Family history of colorectal cancer in Iran. BMC Cancer, 5, 112. https://doi.org/10.1186/1471-2407-5-112
  29. Malekzadeh R, Bishehsari F, Mahdavinia M, et al (2009). Epidemiology and molecular genetics of colorectal cancer in iran: a review. Arch Iran Med, 12, 161-9.
  30. Naghibalhossaini F, Hosseini HM, Mokarram P, et al (2011). High frequency of genes' promoter methylation, but lack of BRAF V600E mutation among Iranian colorectal cancer patients. Pathol Oncol Res, 17, 819-25. https://doi.org/10.1007/s12253-011-9388-5
  31. Negru S, Papadopoulou E, Apessos A, et al (2014). KRAS, NRAS and BRAF mutations in Greek and Romanian patients with colorectal cancer: a cohort study. BMJ Open, 4, 4652.
  32. Rajagopalan H, Bardelli A, Lengauer C, et al (2002). Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature, 418, 934. https://doi.org/10.1038/418934a
  33. Rizzo S, Bronte G, Fanale D, et al (2010). Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy? Cancer Treat Rev, 36, 56-61. https://doi.org/10.1016/S0305-7372(10)70021-9
  34. 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, 466-74. https://doi.org/10.1200/JCO.2009.23.3452
  35. Saridaki Z, Tzardi M, Papadaki C, et al (2011). Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in >/= 2 line cetuximab-based therapy of colorectal cancer patients. PLoS One, 6, 15980. https://doi.org/10.1371/journal.pone.0015980
  36. Schubbert S, Shannon K, Bollag G (2007). Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer, 7, 295-308. https://doi.org/10.1038/nrc2109
  37. Simi L, Pratesi N, Vignoli M, et al (2008). High-resolution melting analysis for rapid detection of KRAS, BRAF, and PIK3CA gene mutations in colorectal cancer. Am J Clin Pathol, 130, 247-53. https://doi.org/10.1309/LWDY1AXHXUULNVHQ
  38. Spindler KL, Lindebjerg J, Lahn M, et al (2009). Protein kinase C-beta II (PKC-beta II) expression in patients with colorectal cancer. Int J Colorectal Dis, 24, 641-5. https://doi.org/10.1007/s00384-009-0680-8
  39. Vaughn CP, Zobell SD, Furtado LV, et al (2011). Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosomes Cancer, 50, 307-12. https://doi.org/10.1002/gcc.20854
  40. Ye JX, Liu Y, Qin Y, et al (2015). KRAS and BRAF gene mutations and DNA mismatch repair status in Chinese colorectal carcinoma patients. World J Gastroenterol, 21, 1595-605. https://doi.org/10.3748/wjg.v21.i5.1595
  41. Yokota T, Ura T, Shibata N, et al (2011). BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer, 104, 856-62. https://doi.org/10.1038/bjc.2011.19

Cited by

  1. Association between clinicopathological characteristics and RAS mutation in colorectal cancer pp.1530-0285, 2017, https://doi.org/10.1038/modpathol.2017.119