BackgroundA 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.MethodsA 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.ResultsMutations 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.ConclusionThe 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.

Atorvastatin is commonly used among type 2 diabetic (DM2) patients at the University of Jordan Hospital to prevent cardiovascular complication. However, we noticed that there is a wide inter-individual variation in the efficacy and toxicity of atorvastatin. This study aimed to find out the effects of major genetic variants in 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), Apolipoprotein E (APOE), and Solute Carrier Organic Anion (SLCO1B1) genes on atorvastatin response among DM2 patients. A sample of 139 DM2 patients on 20 mg of atorvastatin was included in this study. The lipid and glycemic profile and the levels of hepatic enzymes alanine aminotransferase (ALT) and aspartate transaminase were recorded before and after 3 months of atorvastatin treatment. Additionally, the genetic variants HMGCR rs17244841,APOE rs7412 and rs429357, and SLCO1B1 rs2306283 and rs11045818 were genotyped using an Applied Biosystems DNA sequencing method (ABI3730×1). We found that atorvastatin reduced total cholesterol and low-density lipoprotein (LDL) more significantly (p-value < 0.05) in patients with wild genotype than variant alleles APOE rs7412C > T and SLCO1B1 rs2306283A > G. Furthermore, the ALT level was elevated significantly (p-value < 0.05) by 27% in patients with heterozygous SLCO1B1 rs11045818 G/A genotype, while it was not elevated among wild genotype carriers. Additionally, atorvastatin reduced total cholesterol more significantly (p-value < 0.05) in patients with SLCO1B1 rs2306283A and rs11045818G haplotypes and increased ALT levels by 27% (p-value < 0.05) in patients with SLCO1B1 rs2306283G and rs11045818A haplotypes. In conclusion, it was found in this study that APOE rs7412, SLCO1B1 rs2306283, and rs11045818 genotypes can be considered as potential genetic biomarkers of atorvastatin response among DM2 patients of Jordanian Arabic origin. Further clinical studies with larger sample numbers are needed to confirm these findings.