Skip to main content

ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1498295
This article is part of the Research Topic Cell Cycle Modulators: Regulating the Basic Unit of Life for Disease Treatment and Tissue Regeneration View all 4 articles

Exploring Somatic Mutations in BRAF, KRAS, and NRAS as Therapeutic Targets in Saudi Colorectal Cancer Patients through Massive Parallel Sequencing and Variant Classification

Provisionally accepted
Thamer A. Aljuhani Thamer A. Aljuhani 1,2Shaik N. Ahmad Shaik N. Ahmad 1,2*Rahaf T. Alqawas Rahaf T. Alqawas 3*Rana Y. Bokhary Rana Y. Bokhary 4*Mahmoud Almutadares Mahmoud Almutadares 1Hadiah B. Al Mahdi Hadiah B. Al Mahdi 5Nuha Al-Rayes Nuha Al-Rayes 6*Ashraf A. El-Harouni Ashraf A. El-Harouni 1Ramu Elango Ramu Elango 1,2Zuhier A. Awan Zuhier A. Awan 7*Babajan Banaganapalli Babajan Banaganapalli 1,2*
  • 1 Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
  • 2 Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Makkah, Saudi Arabia
  • 3 Molecular Diagnostic Laboratory at King Abdulaziz University Hospital, Jeddah, Saudi Arabia
  • 4 Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Makkah, Saudi Arabia
  • 5 Research and Development Unit, Alborg Diagnostics, Jeddah, Saudi Arabia
  • 6 Department of Medical Laboratory Technology, College of Applied Medical Sciences, King Abdulaziz University, Jeddah, Makkah, Saudi Arabia
  • 7 Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Makkah, Saudi Arabia

The final, formatted version of the article will be published soon.

    Background Colorectal cancer (CRC) is the leading cancer among Saudis, and mutations in BRAF, KRAS, and NRAS genes are therapeutically significant due to their association with pathways critical for cell cycle regulation. This study evaluates the prevalence and frequency of somatic mutations in these actionable genes in Saudi CRC patients and assesses their pathogenicity with bioinformatics methods. Methodology The study employed the TruSight Tumor 15 next-generation sequencing (NGS) panel on 86 colorectal cancer (CRC) samples to detect somatic mutations in BRAF, KRAS, and NRAS genes. Bioinformatic analyses of NGS sequences included variant annotation with ANNOVAR, pathogenicity prediction, variant reclassification with CancerVar, and extensive structural analysis. Additionally, molecular docking assessed the binding of Encorafenib to wild-type and mutant BRAF proteins, providing insights into the therapeutic relevance of pathogenic variants. Results Out of 86 tumor samples, 40 (46.5%) harbored somatic mutations within actionable genes (BRAF: 2.3%, KRAS: 43%, NRAS: 2.3%). Fourteen missense variants were identified (BRAF: n = 1, KRAS: n = 11, NRAS: n = 2). Variants with strong clinical significance included BRAF V600E (2.32%) and KRAS G12D (18.60%). Variants with potential clinical significance included several KRAS and an NRAS mutation, while variants of unknown significance included KRAS E49K and NRAS R102Q. One variant was novel: NRAS R102Q, and two were rare: KRAS E49K and G138E. We further extended the CancerVar prediction capability by adding new pathogenicity prediction tools. Molecular docking demonstrated that Encorafenib inhibits the V600E variant BRAF protein less effectively compared to its wild-type counterpart.

    Keywords: somatic mutations, BRAF V600E, TruSight Tumor 15 Panel, Targeted drug therapy, colorectal cancer

    Received: 18 Sep 2024; Accepted: 31 Oct 2024.

    Copyright: © 2024 Aljuhani, Ahmad, Alqawas, Bokhary, Almutadares, Al Mahdi, Al-Rayes, El-Harouni, Elango, Awan and Banaganapalli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Shaik N. Ahmad, Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
    Rahaf T. Alqawas, Molecular Diagnostic Laboratory at King Abdulaziz University Hospital, Jeddah, Saudi Arabia
    Rana Y. Bokhary, Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589, Makkah, Saudi Arabia
    Nuha Al-Rayes, Department of Medical Laboratory Technology, College of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589, Makkah, Saudi Arabia
    Zuhier A. Awan, Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589, Makkah, Saudi Arabia
    Babajan Banaganapalli, Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia

    Disclaimer: 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.