How can synonymous mutations lead to cancerous or tumorous phenotypes?

Question

After analyzing DNA sequences of an oncogene from many human cancer patients, you found that synonymous substitutions occur in a specific codon of this oncogene. Assuming that these synonymous substitutions do not exist in normal populations but do contribute to tumor development, what would be possible mechanisms that would explain how such alterations can lead to tumor phenotype?

Answer 1

I think you assumed that synonymous mutation means silent mutation. But this is not correct.

From Wikipedia (synonymous mutation) :

Synonymous substitutions and mutations affecting noncoding DNA are often considered silent mutations, however this is not always the case. Synonymous mutations can affect transcription, splicing, mRNA tranport, and translation, any of which could alter phenotype, rendering the synonymous mutation non-silent

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From wikipedia (Oncogene):

The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic methods of activation:

• A mutation within a proto-oncogene, or within a regulatory region (for example the promoter region), can cause a change in the protein structure, causing
  • an increase in protein (enzyme) activity
  • a loss of regulation
• An increase in the amount of a certain protein (protein concentration), caused by
  • an increase of protein expression (through misregulation)
  • an increase of protein (mRNA) stability, prolonging its existence and thus its activity in the cell
  • gene duplication (one type of chromosome abnormality), resulting in an increased amount of protein in the cell
• A chromosomal translocation (another type of chromosome abnormality)
  • There are 2 different types of chromosomal translocations that can occur:
    1. translocation events which relocate a proto-oncogene to a new chromosomal site that leads to higher expression
    2. translocation events that lead to a fusion between a proto-oncogene and a 2nd gene (this creates a fusion protein with increased cancerous/oncogenic activity)
       • the expression of a constitutively active hybrid protein. This type of mutation in a dividing stem cell in the bone marrow leads to adult leukemia
       • Philadelphia Chromosome is an example of this type of translocation event. This chromosome was discovered in 1960 by Peter Nowell and David Hungerford, and it is a fusion of parts of DNA from chromosome 22 and chromosome 9. The broken end of chromosome 22 contains the "BCR" gene, which fuses with a fragment of chromosome 9 that contains the "ABL1" gene. When these two chromosome fragments fuse the genes also fuse creating a new gene: "BCR-ABL". This fused gene encodes for a protein that displays high protein tyrosine kinase activity (this activity is due to the "ABL1" half of the protein). The unregulated expression of this protein activates other proteins that are involved in cell cycle and cell division which can cause a cell to grow and divide uncontrollably (the cell becomes cancerous). As a result, the Philadelphia Chromosome is associated with Chronic Myelogenous Leukemia (as mentioned before) as well as other forms of Leukemia.

You might be especially interested in the second point (An increase in the amount of a certain protein)

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Therefore, there is nothing impressive to find some synonymous mutations that are involved in oncogenes.

Answer 2

This paper here talks about how synonymous mutations are over-represented in oncogenes and cause mis-splicing of the gene. http://www.sciencedirect.com/science/article/pii/S0092867414001457#bib22

In addition to that, synonymous mutations could also work by affecting a regulatory region like a transcription factor binding site, enhancers, etc., leading to enhanced or decreased expression of the corresponding gene.