Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel protein involved in trans-epithelial transport of salt and the regulation of intracellular ion concentrations. The present study aims to investigate the relationship between CFTR non-synonymous SNPs (nsSNPs) and cancer. The study also seeks to elucidate the structural and functional consequences of the deleterious CFTR variants on the protein. The CFTR nsSNPs were retrieved from the Ensembl genome browser, and the deleterious nsSNPs were filtered out using PredictSNP2, CADD, FunSeq2 and GWAVA. The most pathogenic nsSNPs were shortlisted for further analysis. By employing I-TASSER, ProjectHOPE, I-Mutant, MUpro, DynaMut and MutPred, the influence of SNPs on the function and structure of the protein was assessed. Secondary and tertiary structures were predicted through PSIPRED and AlphaFold. Normal Mode Analysis (NMA) were performed through IMOD software, while the RMSD values of the mutated structures were determined through myPresto. Genotyping analyses were conducted through Tetra-primer ARMS-PCR (Amplification Refractory Mutation System). Fourteen nsSNPs of CFTR were identified as deleterious, significantly decreasing protein stability and potentially contributing to carcinogenesis. The pathogenic variants were mapped onto the ATP-binding cassette domain, indicating a strong association with altered protein function. Structural analyses indicated that the nsSNPs could induce changes in residue interactions with neighboring residues, thereby affecting the protein stability and molecular interactions. Normal Mode Analysis confirmed that these variants could perturb the CFTR's conformational integrity. The genotyping analysis indicated that the heterozygous (AT) genotype of rs556880586 was highly prevalent in patients (70%) in comparison to controls (19%). Testing through Hardy-Weinberg Equilibrium (HWE) showed significant deviation in both patient and control groups for the nsSNPs, rs556880586 and rs949472192. Outcomes of the current study identified two deleterious nsSNPs in the CFTR gene that can possibly contribute to cancer progression. Moreover, these variants could act as preliminary biomarker candidates for clinical validation. The obtained knowledge gained from the current research could eventually assist in disease diagnosis and therapy design.
Abbas et al. (Tue,) studied this question.