Comprehensive computational analysis of PKCδ non-synonymous variants identifies rs1703863535 as a potential breast cancer biomarker

PKCδ is a key isoform in the PKC subgroup of AGC-kinase proteins, known to be involved in various cellular processes. Dysregulation of its expression has been linked to multiple malignancies. Notably, PKCδ overexpression has been associated with breast cancer progression and poor prognosis. Previous research has shown that PKCδ phosphorylates specific serine residues on target proteins, leading to tumorigenesis and metastasis. However, the molecular mechanisms of PKCδ-driven breast cancer pathogenesis remain incompletely understood. Single-nucleotide polymorphisms (SNPs), the most common genetic variants, can contribute to cancer susceptibility by causing structural and functional changes in proteins. This study aimed to identify oncogenic non-synonymous variants in PKCδ and assess their impact on protein structure, stability, conservation, dynamics, and interactions. Analyzing a dataset of 613 non-synonymous variants with various computational and in silico tools based on sequence and structure approaches, four variants, including V114G, C189R, C189Y, W608R, were identified as highly oncogenic. Molecular dynamics simulations showed increased structural deviations and flexibility in these variants compared to the native protein, potentially leading to changes in structure, stability, and biophysical properties. These variants disrupted normal PKCδ function by causing surface distortion, changing net charge, and perturbing intramolecular interactions with STAT3, which may activate PKCδ in a non-canonical manner. The study also found an association between the oncogenic non-synonymous SNP W608R, located within the highly conserved AGC kinase domain, and breast cancer, with the TT genotype significantly linked to increased risk (OR = 2.7; RR = 1.6, p < 0.0001). Although further functional validation in cellular models is necessary, this research provides a foundation for future studies on the impact of oncogenic PKCδ variants in breast cancer.