Molecular Characteristics of Differentiated Thyroid Cancer (DTC)

Differentiated thyroid cancer (DTC):
- Which includes papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and oncocytic thyroid carcinoma (OTC):
  - Is characterized by specific molecular alterations that affect key signaling pathways:
    - The mitogen‑activated protein kinase (MAPK) pathway
    - Phosphatidylinositol 3 – kinase – protein kinase B (PI3K-AKT) pathway
Key Genetic Alterations:
- Papillary Thyroid Carcinoma (PTC):
  - BRAF Mutations:
    - Found in 45% to 75% (29% to 83%) of PTCs, particularly the BRAF V600E mutation (62% if the cases):
      - Which activates the MAPK pathway:
    - It is associated with aggressive features like extrathyroidal extension and advanced stage
  - RET / PTC Rearrangements:
    - Present in 10% to 20% (2.5% to 73%) of PTCs
    - These fusions also activate the MAPK pathway
  - RAS Mutations:
    - Occur in ~10% to 15% of PTCs:
      - Often in follicular-variant PTC
  - TERT Promoter Mutations:
    - Found in advanced cases
    - They are often co-mutated with BRAF V600E:
      - Indicating worse prognosis
- Follicular Thyroid Carcinoma (FTC):
  - RAS Mutations:
    - Predominantly found (~30% to 50%)
    - Driving tumorigenesis via the MAPK and PI3K / AKT pathways
  - PAX8 / PPARγ Rearrangements:
    - Seen in ~30%
    - These are unique to FTC and are mutually exclusive with RAS mutations
- Other Mutations Across DTC:
  - NTRK 1/3 Fusions:
    - Rare (~1% to 3%) but significant in some PTCs
  - PI3K / AKT Pathway Alterations:
    - Common in advanced or dedifferentiated cases
Molecular Subtypes of PTC:
- Recent studies have identified four molecular subtypes based on transcriptomic and genomic profiling:
  - Immune-Enriched Subtype (Subtype 2):
    - Characterized by:
      - High immune infiltration
      - Overexpression of immune checkpoints
  - BRAF-Enriched Subtype (Subtype 4):
    - Associated with:
      - BRAF mutations
      - Advanced TNM stage
      - Aggressive behavior
  - Stromal Subtype (Subtype 3):
    - Features high stromal content and distinct gene expression
  - CNV-Enriched Subtype (Subtype 6):
    - Defined by somatic copy number variations
Pathway Dysregulation:
- MAPK Pathway:
  - Activated by:
    - BRAF, RAS (intracellular signal
      transducers)
    - RET /PTC and NTRK 1/3 mutations (cell-membrane receptor tyrosine kinases:
      - Leading to increased tumor proliferation
- PI3K / AKT Pathway:
  - Frequently altered in FTC and advanced DTC:
    - Contributing to tumor growth and survival
- TSHR cAMP Pathway:
  - Altered in FTC through mutations like:
    - TSHR or GNAS
Prognostic Implications:
- Co-occurrence of BRAF V600E and TERT promoter mutations significantly worsens outcomes
- Molecular profiling aids in risk stratification, guiding treatment decisions such as targeted therapies
Therapeutic Implications:
- Targetable alterations include:
  - BRAF inhibitors for BRAF-mutant tumors
  - RET inhibitors for RET fusion-positive cancers
  - Immune checkpoint inhibitors for immune-enriched subtypes
- Molecular understanding of DTC provides a foundation for personalized treatment approaches and improved prognostication