Clinical Significance of Somatic Mutations in RAS/RAF/MAPK Signaling Pathway in Moroccan and North African Colorectal Cancer Patients

Document Type : Research Articles

Authors

1 Laboratory of Research and Biosafety P3, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco.

2 Laboratory of Human Pathologies Biology and Genomic Center of Human Pathologies, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco.

3 Sequencing Unit, Laboratory of Virology, Center of Virology, Infectious and Tropical Diseases, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco.

4 Sidi Mohamed Ben Abdellah University, Faculty of Medicine and Pharmacy of Fez, Morocco.

5 Department of Pathology, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco.

6 Department of Medical Oncology, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco.

7 Center of Virology, Infectious and Tropical Diseases, Mohammed V Military Teaching Hospital, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco.

8 Faculty ofMedicine and Pharmacy, Rabat, University Mohammed V, Morocco.

Abstract

Background: Mutations in RAS (KRAS, NRAS) and BRAF genes are the main biomarker predicting response to anti-EGFR monoclonal antibodies in targeted therapy in colorectal cancer (CRC). Objective: Our study aims to evaluate the frequencies of KRAS, NRAS and BRAF mutations and their possible associations with clinico-pathological features in CRC patients from Morocco. Methods: DNA was extracted from 80 FFPE samples using the QIAamp DNA FFPE-kit. RAS and BRAF mutations were assessed by pyrosequencing assays using Qiagen, KRAS Pyro®kit 24.V1, Ras-Extension Pyro®kit 24.V1 and BRAF Pyro®Kit 24.V1, respectively, and carried out in the PyroMark-Q24. Results: RAS mutations were identified in 57.5% (56.2% in KRAS, 8.8% in NRAS). In KRAS gene, exon 2 mutations accounted for 93.3% (68.9% in codon 12, 24.4% in codon 13). Within codon 12, G12D was the most prevalent mutation (37.7%), followed by G12C (13.4%), G12S (8.9%) and G12V (6.6%). Within codon 13, the most frequently observed mutation was G13D (22.3%). The mutation rates of exon 3 and 4 were 15.6% and 13.3%, respectively. In exon 3 codon 61, 2.3% patients were detected with two concurrent mutations (Q61R, Q61H), and 4.4% with three concurrent mutations (Q61R, Q61H, Q61L). In NRAS gene, the mutation rates of exon 2, 3 and 4 were 57.1%, 28.6%, and 14.3%, respectively. G13A and Q61H were the most common mutations, accounting for 42.9% and 28.5%, respectively. There were 13% patients with concurrent KRAS/NRAS mutation and 4.3% wt KRAS with NRAS mutations. No mutations were identified in BRAF gene. In both sexes, KRAS codon 12 mutations were associated with higher stage III/IV tumors. Moreover, Patients whose tumor is in the proximal colon (56.3%) are more likely to harbor KRAS mutations than those tumor located in rectum (25%). Conclusion: RAS mutations could be useful in future target anti-EGFR therapy and molecular CRC screening strategy in Morocco.

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Volume 23, Issue 11
November 2022
Pages 3725-3733
  • Receive Date: 09 March 2022
  • Revise Date: 13 July 2022
  • Accept Date: 02 November 2022
  • First Publish Date: 02 November 2022