YES1 c.596C>T (p.Arg199His) and YES1 c.868C>T (p.Glu290Lys) missense polymorphism linked to hematological and reproductive organ cancer: A hidden Markov model (HMM) based approach

Abstract

YES1 is a novel proto-oncogene that has largely gained popularity in oncology over the last few years owing to its pivotal role in tumorigenesis, and drug resistance to various targeted therapy (EGFR, HER2) and cancer chemotherapy, resulting in poor survival outcomes, which has been frequently linked with its amplification rather than the mutation. Thus, this study hypothesizes that cancer development might also be linked with a mutation in YES1, not merely amplification of the gene. In the present study, YES1 gene-associated missense SNPs were retrieved from the dbSNP-NCBI database, which were screened for deleterious/damaging and pathogenicity. The pathogenic SNPs were assessed for their stability and potential to cause cancer. The oncogenic SNPs were further evaluated for its location in the domain, conservation, structural effect, and interactions. Further, YES1 expression in cancer, its hallmark efficiency and mutation in cancer was assessed to support the study findings. A total of 381 SNPs were identified from dbSNP-NCBI of which 7 SNPs were found to be deleterious, damaging and pathogenic by applying six tools. Out of these 7 SNPs, YES1 c.596C > T (p.Arg199His) and YES1 c.868C > T (p.Glu290Lys) were predicted destabilize the protein and associated with blood cancer, and solid cancer like reproductive organ cancer, and gastrointestinal (GI) cancer respectively. Both these oncogenic SNPs occurs in core biologically active conserved domain (SH2 and tyrosine kinase) of YES1 protein thereby influences the protein geometry, electrostatic interaction, impairs the ATP/substrate binding and kinase activity of the protein which might dysregulate the protein-protein interaction and modulate various cancer pathways. Further, its significant expression in cancer (hematologic, reproductive and GI cancer), role in driving invasion/metastasis, and evidence of YES1 mutation profile in cancer cohort strengthen the findings of current study. Thus, R199H and E290K SNPs are the most probable SNPs that should be screened among cancer patients to establish a plausible link which can guide towards the precision therapy to counter the drug resistance and enhance the clinical benefit in upcoming years.