Colorectal cancer (CRC) is recognised globally as the third most common cancer with a prevalence of 10% [1]. In Uganda, as in many Sub-Saharan African countries, there is a steady increase in CRC and many patients present with advanced-stage CRC which is associated with a poor overall survival [2]. It is a multifactorial disease caused by a combination of genetic and environmental factors, like most cancers. The contributing genetic factors include somatic and germline mutations, as well as epigenetic changes and chromosomal abnormalities. In colorectal cancer development, EGFR receptor-dependent signalling pathway is one of the most significant signalling pathways [3-5]. In 60%-80% of colorectal cancers, increased levels of EGF activity is seen, and in colorectal cancer this receptor is an important therapeutic target [6]. In the treatment of metastatic colorectal cancer (mCRC), panitumumab and cetuximab have been introduced as two targeted therapeutic drugs since 2004. These drugs obstruct the downstream pathway by binding to the tyrosine kinase receptor as they are monoclonal anti-EGFR antibodies. The most recent approach to the treatment of metastatic colorectal cancer is targeted therapy. In this type of treatment, in cancer cells, therapeutic molecules are developed to stop carcinogenic signalling pathways [7, 8].

Following the activation of the EGFR receptor, the signalling pathways PI3K-PTEN-AKT and RAS-RAF-MEK-ERK are activated. The most prominent genes in these signalling pathways that undergo somatic mutations are the RAS, BRAF and PIK3CA genes. Independent of EGFR activation, mutations in these genes cause activation of PI3K-PTEN-AKT and RAS-RAF-MEK-ERK signalling pathways. Therefore, with mutations in one of these genes, targeted therapies that target EGFR are less effective in colorectal cancers [9-11].

In mCRC precision therapy, the first significant advance was the identification of KRAS gene mutation as a predictive marker of targeted anti-EGFR treatment [12]. Key regulators and cellular processes are small GTPases from Ras superfamily and are driven by genetic mutations in the RAS gene family (NRAS, KRAS and HRAS) [13]. In the West, with a strong correlation between primary tumours and metastatic tumours, NRAS mutations are found in 1-3% of CRC patients, while KRAS mutations are found in 40%-50% of CRC patients [14]. Mutations in codons 117 and 146 (exon 4), as well as condons 59 and 61 (exon 3), are associated with a reduced response to anti-EGFR monoclonal antibodies. The most common mutation hotspots (80%) are found on condons 12 and 13 in exon 2 of the KRAS gene and are related to response to targeted therapy [15]. Some studies have shown that KRAS is an independent prognostic marker with distinct clinicopathological features, in addition to being a predictor of response to targeted treatment [16, 17].

A lack of response to anti-EGFR antibodies in CRC patients with wild-type KRAS, suggests that in the downstream of EGFR signalling pathway additional mutations could be responsible, resulting in a poor response to these drugs. In addition to RAS genes, mutations in BRAF or PIK3CA genes may also result in a lack of response to anti-EGFR drugs. In the West, BRAF V600E is a frequent mutation affecting 8%-15% of colorectal tumours, and is related to a poor prognosis [18]. PIK3CA mutations frequently occur simultaneously with KRAS whilst mutations in KRAS and BRAF are mutually exclusive [19,20].

We investigated the genetic profile of the NRAS, KRAS, BRAF and PIK3CA genes in Uganda CRC patients due to their utility in disease prognosis and diagnosis and in predicting response to targeted therapy. Therefore, pyrosequencing was used to determine the mutational profile in exons 2, 3 and 4 of NRAS and KRAS, codons 600 of BRAF and exons 9 and 20 of PIK3CA. The associations between the clinicopathological characteristics and the gene mutations of CRC patients were then evaluated.

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