KRAS and NRAS mutational gene profile of metastatic colorectal cancer patients in Jordan

Autoři: Muhammad Awidi aff001;  Nidaa Ababneh aff002;  Maha Shomaf aff003;  Feras Al Fararjeh aff004;  Laila Owaidi aff005;  Mohammad AlKhatib aff005;  Buthaina Al Tarawneh aff005;  Abdalla Awidi aff002
Působiště autorů: Beth Israel Lahey Health-Lahey Hospital and Medical Center, Burlington, Massachusetts, United States of America aff001;  Cell Therapy Center, The University of Jordan, Amman, Jordan aff002;  Department of Pathology and Microbiology and Forensic Medicine, The University of Jordan, Amman, Jordan aff003;  Department of Medicine, The University of Jordan, School of Medicine, Amman, Jordan aff004;  Hemostasis and Thrombosis Laboratory, School of Medicine, The University of Jordan, Amman, Jordan aff005;  Department of Hematology and Oncology, Jordan University Hospital, Amman, Jordan aff006
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226473



A constitutively active RAS protein in the absence of stimulation of the epidermal growth factor receptor (EGFR) is the result of mutations in KRAS and NRAS genes. Mutations in the KRAS exon 2 and outside exon 2 have been found to predict the resistance to anti-EGFR monoclonal therapy. A substantial proportion of metastatic colorectal cancer cases (mCRC) exhibit RAS mutations outside KRAS exon 2, particularly in KRAS exon 3 and 4 and NRAS exons 2 and 3. No data about RAS mutations outside KRAS exon 2 are available for Jordanian patients with mCRC. We aim to study the molecular spectrum, frequency, and distribution pattern of KRAS and NRAS mutations in Jordanian patients with mCRC.


A cohort of 190 Jordanian metastatic colorectal cancer patients were enrolled in the trial. We detected mutations in exon 2 of the KRAS and NRAS gene as well as mutations outside of exon 2 using the StripAssay technique. The KRAS StripAssay covered 29 mutations and 22 NRAS mutations.


Mutations were observed in 92 (48.42%) cases, and KRAS exon 2 mutations accounted for 76 cases (83.69%). KRAS G12D was the most common mutation, occurring in 18 cases, followed by KRAS G12A in 16 cases, and G12T in 13 cases. Mutations outside of KRAS exon 2 represented 16.3% of the mutated cases. Among those, 6 cases (6.48%) carried mutations in NRAS exon 2 and 3, and 10 cases (10.87%) in KRAS exon 3 and 4.


The frequency of NRAS and KRAS mutations outside of exon 2 appears to be higher in Jordanian patients in comparison with patients from western countries. KRAS mutations outside of exon 2 should be tested routinely to identify patients who should not be treated with anti-EGFR antibodies.

Klíčová slova:

Cancer treatment – Colorectal cancer – EGFR signaling – Glycine – Membrane receptor signaling – Mutation – Mutation detection – Mutational analysis


1. Tarawneh M, Nimri O, Arkoob K, Zaghal M (2009) Cancer incidence in Jordan 2009. Non-Communicable Diseases Directorate, Jordan Cancer Registry Ministry of Health.

2. Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7: 505–516. doi: 10.1038/nrm1962 16829981

3. Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5: 341–354. doi: 10.1038/nrc1609 15864276

4. Tsuchida N, Ohtsubo E, Ryder T (1982) Nucleotide sequence of the oncogene encoding the p21 transforming protein of Kirsten murine sarcoma virus. Science 217: 937–939. doi: 10.1126/science.6287573 6287573

5. Vigil D, Cherfils J, Rossman KL, Der CJ (2010) Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 10: 842–857. doi: 10.1038/nrc2960 21102635

6. Zenker M, Lehmann K, Schulz AL, Barth H, Hansmann D, et al. (2007) Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet 44: 131–135. doi: 10.1136/jmg.2006.046300 17056636

7. Diaz-Flores E, Shannon K (2007) Targeting oncogenic Ras. Genes Dev 21: 1989–1992. doi: 10.1101/gad.1587907 17699748

8. Schubbert S, Shannon K, Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7: 295–308. doi: 10.1038/nrc2109 17384584

9. Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3: 11–22. doi: 10.1038/nrc969 12509763

10. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, et al. (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359: 1757–1765. doi: 10.1056/NEJMoa0804385 18946061

11. Van Cutsem E, Kohne C, Hitre E, Van Cutsem E, Kohne C, et al. (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360: 1408–1417. doi: 10.1056/NEJMoa0805019 19339720

12. Forbes S, Clements J, Dawson E, Bamford S, Webb T, et al. (2006) COSMIC 2005. Br J Cancer 94: 318–322. doi: 10.1038/sj.bjc.6602928 16421597

13. Normanno N, Bianco C, De Luca A, Maiello MR, Salomon DS (2003) Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment. Endocr Relat Cancer 10: 1–21. doi: 10.1677/erc.0.0100001 12653668

14. Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, et al. (2005) Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 7: 301–311. doi: 10.1016/j.ccr.2005.03.003 15837620

15. Wong R, Cunningham D (2008) Using Predictive Biomarkers to Select Patients With Advanced Colorectal Cancer for Treatment With Epidermal Growth Factor Receptor Antibodies. Journal of Clinical Oncology 26: 5668–5670. doi: 10.1200/JCO.2008.19.5024 19001346

16. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, et al. (2010) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11: 753–762. doi: 10.1016/S1470-2045(10)70130-3 20619739

17. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, et al. (2013) Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369: 1023–1034. doi: 10.1056/NEJMoa1305275 24024839

18. Sorich M, Wiese M, Rowland A, Sorich M, Wiese M, et al. (2015) Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol 26: 13–21. doi: 10.1093/annonc/mdu378 25115304

19. Amado R, Wolf M, Peeters M, Amado R, Wolf M, et al. (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26: 1626–1634. doi: 10.1200/JCO.2007.14.7116 18316791

20. Elbjeirami WM, Sughayer MA (2012) KRAS mutations and subtyping in colorectal cancer in Jordanian patients. Oncol Lett 4: 705–710. doi: 10.3892/ol.2012.785 23205087

21. Goud KI, Matam K, Madasu AM, Ali Khan I (2019) Positive Correlation Between Somatic Mutations in RAS Gene and Colorectal Cancer in Telangana Population: Hospital-Based Study in a Cosmopolitan City. Appl Biochem Biotechnol.

22. Dinu D, Dobre M, Panaitescu E, Birla R, Iosif C, et al. (2014) Prognostic significance of KRAS gene mutations in colorectal cancer—preliminary study. J Med Life 7: 581–587. 25713627

23. Edkins S, O'Meara S, Parker A, Stevens C, Reis M, et al. (2006) Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol Ther 5: 928–932. doi: 10.4161/cbt.5.8.3251 16969076

24. Licar A, Cerkovnik P, Ocvirk J, Novakovic S (2010) KRAS mutations in Slovene patients with colorectal cancer: frequency, distribution and correlation with the response to treatment. Int J Oncol 36: 1137–1144. doi: 10.3892/ijo_00000596 20372787

25. Tong JH, Lung RW, Sin FM, Law PP, Kang W, et al. (2014) Characterization of rare transforming KRAS mutations in sporadic colorectal cancer. Cancer Biol Ther 15: 768–776. doi: 10.4161/cbt.28550 24642870

26. Higashi T, Sasai H, Suzuki F, Miyoshi J, Ohuchi T, et al. (1990) Hamster cell line suitable for transfection assay of transforming genes. Proc Natl Acad Sci U S A 87: 2409–2413. doi: 10.1073/pnas.87.7.2409 2181436

27. Smith G, Bounds R, Wolf H, Steele RJ, Carey FA, et al. (2010) Activating K-Ras mutations outwith 'hotspot' codons in sporadic colorectal tumours—implications for personalised cancer medicine. Br J Cancer 102: 693–703. doi: 10.1038/sj.bjc.6605534 20147967

28. Irahara N, Baba Y, Nosho K, Shima K, Yan L, et al. (2010) NRAS mutations are rare in colorectal cancer. Diagn Mol Pathol 19: 157–163. doi: 10.1097/PDM.0b013e3181c93fd1 20736745

29. Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, et al. (2009) KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer 101: 715–721. doi: 10.1038/sj.bjc.6605177 19603018

Článek vyšel v časopise


2019 Číslo 12