https://doi.org/10.4081/jbr.2026.15119
High frequency of NRAS mutations and RAS co-mutations in colorectal cancer from the Kurdistan region of Iraq: molecular and survival analysis
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Accepted: 15 July 2026
Published: 8 September 2026
Mutations in RAS and PI3K pathway genes play a critical role in Colorectal Cancer (CRC) pathogenesis and therapy response, yet data from underrepresented populations remain limited. Molecular analysis was performed on 48 CRC cases from the Kurdistan region of Iraq to detect mutations in KRAS and NRAS (codons 12, 13, 59, 61, 117, and 146; exons 2–4), BRAF (codon 600; exon 15), PIK3CA (codons 542, 545, and 1047; exons 9 and 20), and AKT1 (codon 17; exon 4), and to correlate findings with histopathological characteristics and survival outcomes. NRAS mutations were the most frequently detected alterations (52.08%), followed by KRAS (47.92%) and PIK3CA (16.67%). A high frequency of co-mutations, particularly involving KRAS and NRAS, was observed, substantially exceeding frequencies reported in international cohorts; possible contributing factors including intratumoral heterogeneity and assay sensitivity are discussed. Tumor-associated inflammatory response and lymph node status demonstrated significant associations with patient survival. These findings from a small patient cohort suggest the need for further investigation of regional CRC molecular profiles using larger cohorts and orthogonal validation methods.
Downloads
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30. DOI: https://doi.org/10.3322/caac.21442
2. Wild CP, Weiderpass E, Stewart BW. Cancer research for cancer prevention [Internet]. 1st ed. Lyon (FR): International Agency for Research on Cancer; 2020 [cited 2026]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK606505/
3. World Health Organization. Global Cancer Observatory (GLOBOCAN) [Internet]. Lyon (FR): International Agency for Research on Cancer; 2022 [cited 2026]. Available from: https://gco.iarc.fr/today/
4. Arnold M, Sierra MS, Laversanne M, et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017;66:683–91. DOI: https://doi.org/10.1136/gutjnl-2015-310912
5. Dolatkhah R, Somi MH, Kermani IA, et al. Increased colorectal cancer incidence in Iran: a systematic review and meta-analysis. BMC Public Health 2015;15:997. DOI: https://doi.org/10.1186/s12889-015-2342-9
6. Li N, Lu B, Luo C, et al. Incidence, mortality, survival, risk factor and screening of colorectal cancer: a comparison among China, Europe, and North America. Cancer Lett 2021;522:255–68. DOI: https://doi.org/10.1016/j.canlet.2021.09.034
7. Loomans-Kropp HA, Umar A. Increasing incidence of colorectal cancer in young adults. J Cancer Epidemiol 2019;2019:9841295. DOI: https://doi.org/10.1155/2019/9841295
8. Brinzan CS, Aschie M, Cozaru GC, et al. KRAS, NRAS, BRAF, PIK3CA, and AKT1 signatures in colorectal cancer patients in south-eastern Romania. Medicine (Baltimore) 2022;101:e30979. DOI: https://doi.org/10.1097/MD.0000000000030979
9. O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004;96:1420–5. DOI: https://doi.org/10.1093/jnci/djh275
10. Zhang C, Yin S, Tan Y, et al. Patient selection for adjuvant chemotherapy in high-risk stage II colon cancer: a systematic review and meta-analysis. Am J Clin Oncol 2020;43:279–87. DOI: https://doi.org/10.1097/COC.0000000000000663
11. Schirripa M, Cremolini C, Loupakis F, et al. Role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer. Int J Cancer 2015;136:83–90. DOI: https://doi.org/10.1002/ijc.28955
12. Isnaldi E, Garuti A, Cirmena G, et al. Clinico-pathological associations and concomitant mutations of the RAS/RAF pathway in metastatic colorectal cancer. J Transl Med 2019;17:1–10. DOI: https://doi.org/10.1186/s12967-019-1879-2
13. Hsu HC, Thiam TK, Lu YJ, et al. Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients. Oncotarget 2016;7:22257–69. DOI: https://doi.org/10.18632/oncotarget.8076
14. Cervantes A, Adam R, Roselló S, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2022;34:10–32. DOI: https://doi.org/10.1016/j.annonc.2022.10.003
15. Sartore-Bianchi A, Martini M, Molinari F, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 2009;69:1851–7. DOI: https://doi.org/10.1158/0008-5472.CAN-08-2466
16. Duhok Health Directorate. Duhok Health Directory Registration [Internet]. Duhok (IQ): Duhok Health Directorate; [cited 2025]. Available from: https://duhokhealth.org/
17. Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumors of the digestive system. Histopathology 2020;76:182–8. DOI: https://doi.org/10.1111/his.13975
18. Jessup JM, Goldberg RM, Asare EA, et al. Colon and rectum. In: Amin MB, Edge SB, Greene FL, editors. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017. p.251–74.
19. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7–33. DOI: https://doi.org/10.3322/caac.21708
20. Vuik FE, Nieuwenburg SA, Bardou M, et al. Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years. Gut 2019;68:1820–6. DOI: https://doi.org/10.1136/gutjnl-2018-317592
21. Lauby-Secretan B, Vilahur N, Bianchini F, et al. The IARC perspective on colorectal cancer screening. N Engl J Med 2018;378:1734–40. DOI: https://doi.org/10.1056/NEJMsr1714643
22. Mosli MH, Al-Ahwal MS. Colorectal cancer in the Kingdom of Saudi Arabia: need for screening. Asian Pac J Cancer Prev 2012;13:3809–13. DOI: https://doi.org/10.7314/APJCP.2012.13.8.3809
23. Erdem L, Akbal E, Koçak E, et al. A new risk-scoring system for colorectal cancer and polyp screening by Turkish colorectal cancer and polyp study group. Turk J Gastroenterol 2022;33:286–94. DOI: https://doi.org/10.5152/tjg.2022.21072
24. Bae JM, Kim JH, Kang GH. Molecular subtypes of colorectal cancer and their clinicopathologic features, with emphasis on the serrated neoplasia pathway. Arch Pathol Lab Med 2016;140:406–12. DOI: https://doi.org/10.5858/arpa.2015-0310-RA
25. Ge P, Wang W, Li L, et al. Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of colorectal cancer. Biomed Pharmacother 2019;118:109228. DOI: https://doi.org/10.1016/j.biopha.2019.109228
26. Tao L, Huang G, Song H, et al. Cancer-associated fibroblasts: an essential role in the tumor microenvironment. Oncol Lett 2017;14:2611–20. DOI: https://doi.org/10.3892/ol.2017.6497
27. Richards CH, Roxburgh CSD, Anderson JH, et al. Prognostic value of tumor necrosis and host inflammatory responses in colorectal cancer. Br J Surg 2012;99:287–94. DOI: https://doi.org/10.1002/bjs.7755
28. Väyrynen SA, Väyrynen JP, Klintrup K, et al. Clinical impact and network of determinants of tumour necrosis in colorectal cancer. Br J Cancer 2016;114:1334–42. DOI: https://doi.org/10.1038/bjc.2016.128
29. Irahara N, Baba Y, Nosho K, et al. NRAS mutations are rare in colorectal cancer. Diagn Mol Pathol 2010;19:157–63. DOI: https://doi.org/10.1097/PDM.0b013e3181c93fd1
30. Lech G, Słotwiński R, Słodkowski M, Krasnodębski IW. Colorectal cancer tumour markers and biomarkers: recent therapeutic advances. World J Gastroenterol 2016;22:1745–55. DOI: https://doi.org/10.3748/wjg.v22.i5.1745
31. Huang Q, Wang L, Jiang W, et al. Establishment and evaluation of high-resolution melting analysis for screening KRAS mutations in colorectal cancer. Oncol Rep 2015;34:3126–34.
32. Bettoni F, Masotti C, Habr-Gama A, et al. Intratumoral genetic heterogeneity in rectal cancer. Cancer Med 2016;5:1604–13.
33. Al-Shamsi HO, Jones J, Fahmawi Y, et al. Molecular spectrum of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC somatic gene mutations in Arab patients with colorectal cancer: determination of frequency and distribution pattern. J Gastrointest Oncol 2016;7:882–902. DOI: https://doi.org/10.21037/jgo.2016.11.02
34. Namiq KF, Ali KM, Gubari MIM, Muhamad DA. Prevalence and predictive value of RAS mutations in metastatic colorectal cancer at Hiwa Cancer Hospital, in Sulaimani Iraq. PJMHS 2020;14:1485–90.
35. Hamasharif HG. Molecular identification of KRAS, BRAF, and PIK3CA mutations in colorectal cancer patients from the Kurdistan region of Iraq. Mol Biol Res Commun 2025;14:259–69.
36. Cercek A, Braghiroli MI, Chou JF, et al. Clinical features and outcomes of patients with colorectal cancers harboring NRAS mutations. Clin Cancer Res 2017;23:4753–60. DOI: https://doi.org/10.1158/1078-0432.CCR-17-0400
37. Rimbert J, Tachon G, Junca A, et al. Association between clinicopathological characteristics and RAS mutation in colorectal cancer. Mod Pathol 2018;31:517–26. DOI: https://doi.org/10.1038/modpathol.2017.119
38. Akman T, Oztop I, Baskin Y, et al. The association of clinicopathological features and survival in colorectal cancer patients with KRAS mutation status. J Cancer Res Ther 2016;12:96–102. DOI: https://doi.org/10.4103/0973-1482.148684
39. Sorich MJ, Wiese MD, Rowland A, et al. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol 2015;26:13–21. DOI: https://doi.org/10.1093/annonc/mdu378
40. Liu T, Jiang S, Teng X, et al. A comparison of panitumumab and cetuximab in the treatment of KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Immunopharmacol Immunotoxicol 2023;45:1–9. DOI: https://doi.org/10.1080/08923973.2022.2112222
Ethics Approval
CRediT authorship contribution
Jiyan Ali Haji conceptualized and designed the study, supervised the molecular analyses, performed data interpretation, and prepared the original draft, being primarily responsible for manuscript writing. Dijwar Ali Haji was involved in the molecular practical work and, together with Mayda Ilias Yalda, performed the pathological examinations and contributed to clinicopathological correlation. Ghazwan Fawzi Ahmed participated in data interpretation and contributed to manuscript writing. All authors reviewed, revised, and approved the final version of the manuscript.
Supporting Agencies
Data Availability Statement
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
How to Cite
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.