Molecular Genetics of Thyroid Cancer Part 1

Most of the data that has been gathered is associated with somatic mutations:
- Many of which occur early in the
  transformation process and are crucial for cancer development
In thyroid cancer, vital genes are commonly mutated via two separate molecular mechanisms:
- Point mutations
- Chromosomal rearrangements
Point mutations:
- Are the result of a single nucleotide change within the DNA chain:
  - Which activates or inactivates a
    protein
Chromosomal rearrangements:
- Represent a large-scale genetic abnormality with breakage and fusion of parts of the same chromosome or different chromosomes
The molecular pathogenesis of thyroid cancer:
- Is relatively simple with two molecular pathways:
  - The mitogen‑activated protein kinase (MAPK) pathway
  - The phosphatidylinositol 3 – kinase – protein kinase B (PI3K-AKT) pathway (Figure)
These pathways are activated in most thyroid cancers:
- Via distinct molecular mechanisms mentioned previously, like:
  - Point mutations (single nucleotide variant):
    - Where a single nucleotide is
      changed:
      - Which activates or inactivates a protein
  - Gene fusions:
    - Were parts of two different genes located in the same or different chromosome are fused to each other:
      - That results in the generation of chimeric protein
  - Copy number alterations (CNA):
    - That have been recently accepted as a driver mutation for oncocytic cell tumors
Activation of the MAPK pathway:
- Is a critical step for tumor initiation
- The mutated genes that impact
  these pathways encode:
  - The cell-membrane receptor tyrosine kinases:
    - RET and NTRK1
  - Intracellular signal transducers:
    - RAS and BRAF
- These mutually exclusive mutations:
  - They do not overlap with each other because they activate the same pathway and only one event is sufficient to activate the process for cancer development:
    - Occur in roughly 70% to 75% of patients with PTC and are associated with specific clinical, pathologic, and biological tumor characteristics (Table)
- In follicular thyroid cancer (FTC), in addition to mutations of RAS:
  - Another common event is PAX8 / PPARG rearrangement
Thyroid cancer progression and dedifferentiation involves a number of additional mutations:
- That affects the PI3K-AKT pathway and other cell signaling pathways