Role of Notch gene receptors as prognostic biomarkers in colorectal cancer

The incidence of colorectal cancer (CRC) is increasing across the world, especially in younger age groups and the Indian subcontinent. Dysregulation in Notch pathway genes and their Single Nucleotide Polymorphism (SNPs) can potentially lead to aberrant signaling and contribute to CRC development. We investigated SNPs of Notch1 (rs3124591), Notch2 (rs10910779), Notch3 (rs1043994), and Notch4 (rs367398) in CRC (n = 103) and Controls (n = 103) along with their protein expression in the cases. The SNPs were detected by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism method followed by Sanger sequencing. The protein expression was determined by the western blot technique. SPSS was used to analyze the correlations of the molecular findings with clinicopathological features and survival. The frequency of CT genotype in Notch1 was significantly lower in CRC patients compared to healthy controls (40.77% vs 62.14%; p = 0.009) and was associated with increased depth of invasion (p = 0.03). Notch3 polymorphism A > G showed significant association with the advanced TNM stage (p = 0.013). Interestingly, AG and GG genotype in Notch3 was significantly associated with increased protein expression (p = 0.047). The patients carrying the 'G' allele in Notch3 had an increased risk of having CRC (OR = 1.697, CI 95%: 1.001-2.873, p = 0.049) and a lower survival rate (p > 0.05). Notch4 polymorphism showed an association with tumor grade (p = 0.03). The genotypes CT and TT had lower survival rates than the CC genotype (p = 0.08). Notch receptor polymorphism, especially Notch3, is associated with increased protein expression and a higher risk of having CRC. Furthermore, poor survival in patients with Notch3 and Notch4 polymorphism suggests their potential as prognostic biomarker in CRC.