Synonymous Variants: Necessary Nuance in Our Understanding of Cancer Drivers and Treatment Outcomes

Abstract

Once called “silent mutations” and assumed to have no effect on protein structure and function, synonymous variants are now recognized to be drivers for some cancers. There have been significant advances in our understanding of the numerous mechanisms by which synonymous single nucleotide variants (sSNVs) can affect protein structure and function by affecting pre-mRNA splicing, mRNA expression, stability, folding, miRNA binding, translation kinetics, and co-translational folding. This review highlights the need for considering sSNVs in cancer biology to gain a better understanding of the genetic determinants of human cancers and to improve their diagnosis and treatment. We surveyed the literature for reports of sSNVs in cancer and found numerous studies on the consequences of sSNVs on gene function with supporting in vitro evidence. We also found reports of sSNVs that have statistically significant associations with specific cancer types but for which in vitro studies are lacking to support the reported associations. Additionally, we found reports of germline and somatic sSNVs that were observed in numerous clinical studies and for which in silico analysis predicts possible effects on gene function. We provide a review of these investigations and discuss necessary future studies to elucidate the mechanisms by which sSNVs disrupt protein function and are play a role in tumorigeneses, cancer progression, and treatment efficacy. As splicing dysregulation is one of the most well recognized mechanisms by which sSNVs impact protein function, we also include our own in silico analysis for predicting which sSNVs may disrupt pre-mRNA splicing.

Protective Effect of HER2 Gene Polymorphism rs24537331 in the Outcome of Canine Mammary Tumors

“…The SNPs assessed herein are synonymous and, thus, do not involve amino acid changes; however, they may influence HER2 gene expression. Although neglected for several years, synonymous genetic variants are nowadays recognized as important players in the pathogenesis, progression, and treatment efficacy of cancer [ 46 , 47 ]. Synonymous SNPs do not alter the protein primary structure (and were, therefore, once termed “silent”) but may affect the conformation and function of the encoded protein.…”

“…Synonymous SNPs do not alter the protein primary structure (and were, therefore, once termed “silent”) but may affect the conformation and function of the encoded protein. Synonymous SNP may influence mRNA structure, stability and folding, translation kinetics, and access to regulatory factors (e.g., miRNA and RNA-biding proteins), driving changes in protein conformation, phosphorylation, function, and localization [ 46 , 47 ].…”

Clinical and molecular characterization of a patient with MBTPS1 related spondyloepiphyseal dysplasia: Evidence of pathogenicity for a synonymous variant

“…It was considered that synonymous variants have no influence on gene expression since they did not change the amino acid sequence. However, many advanced findings show that synonymous variants play important roles in RNA transcription and protein translation (7)(8)(9)(10), which requires us to perform the necessary functional assays to verify the pathogenicity of these variants.…”

Multiple mechanisms contribute to the phenotypic effects of synonymous variants

“…Due to lack of amino acid changes, synonymous variants were considered to not have any functional effects and frequently referred to as "silent" variants. However, this notion was dispelled by the critical mass of evidence accumulated over the last two decades implicating synonymous variants as the underlying cause for several diseases including cancers (Bali & Bebok, 2015;Kaissarian et al, 2022). While splicing dysregulation is the most appreciated mechanism, synonymous variants were demonstrated to induce their phenotypic effects through multiple mechanisms, sometimes in parallel, at both transcriptional and translational level including altered mRNA structure/stability, miRNA binding, translation efficiency, and cotranslational folding (Bali & Bebok, 2015;Hunt et al, 2014).…”