Genetic Abnormalities Associated with Papillary Thyroid Cancer

Papillary thyroid cancer (PTC) is characterized by two major molecular signatures: BRAF-predominant and RAS-predominant genetic alterations, with BRAF V600E mutation being the most common genetic abnormality occurring in approximately 45-50% of cases. 1

Major Genetic Alterations in PTC

BRAF Mutations

BRAF V600E mutation:
- Present in approximately 45-50% of sporadic papillary thyroid cancers 1, 2
- More common in conventional/classical PTC (51%), less common in follicular variant PTC (24.1%) 3
- Associated with aggressive clinicopathological features:
  - Older patient age (>45 years) 3, 4
  - Lymph node metastasis 3, 4
  - Distant metastasis 3
  - Higher TNM stage 3
  - Recurrent and persistent disease 3
  - Vascular invasion 4
  - Thyroid capsule invasion 4
  - Extrathyroidal tissue invasion 4
- Occurs exclusively in PTC and PTC-derived anaplastic thyroid cancer 5
- More common in aggressive histologic variants (tall cell, columnar, solid, hobnail) 1

RAS Mutations

Predominant in the follicular variant of PTC 1
Associated with less aggressive behavior compared to BRAF-mutated tumors 1
Present in follicular-patterned thyroid lesions

RET/PTC Rearrangements

Mutually exclusive with BRAF mutations 5
More common in younger patients 5
Found in conventional PTC 1

Other Genetic Alterations

NTRK fusions: Present in a subset of PTC 1
ALK fusions: Found in some PTC cases 1
PAX8/PPARγ: More common in follicular carcinoma but can be seen in follicular variant PTC 1
EIF1AX mutations: Associated with follicular-patterned lesions 1

Molecular Profiles Based on PTC Variants

Classical/Conventional PTC

BRAF V600E mutation (51%) 3
RET/PTC rearrangements
Morphologically distinct features when BRAF-positive:
- Infiltrative growth pattern
- Stromal fibrosis
- Psammoma bodies
- Plump eosinophilic tumor cells
- Classic nuclear features 6

Follicular Variant PTC

RAS mutations predominant
BRAF mutations less common (24.1%) 3
Encapsulated growth pattern when BRAF-negative 6
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) typically harbors RAS mutations but not BRAF V600E 1

Aggressive Variants

Tall cell variant:
- High prevalence of BRAF V600E mutations 1, 6
Solid variant:
- BRAF V600E mutations
Hobnail variant:
- BRAF V600E mutations
Oncocytic/Warthin-like variant:
- BRAF V600E mutations (2/2 cases in one study) 6

Prognostic Implications and Fatal Forms

The most aggressive forms of PTC typically harbor BRAF or RAS mutations plus additional genomic alterations, including:

TERT promoter mutations
TP53 mutations
POLE mutations
PI3K/AKT/mTOR pathway alterations
SWI/SNF chromatin remodeling complex mutations
Histone methyltransferase mutations 1

These additional mutations significantly increase the aggressiveness of PTC and may represent potential therapeutic targets.

Clinical Implications

Diagnostic value: BRAF V600E testing in fine-needle aspiration specimens can refine diagnostic accuracy in indeterminate cytology 2
Prognostic value: BRAF mutation status is an independent prognostic marker for recurrent and persistent disease 3
Therapeutic implications:
- Targeted therapies for BRAF-mutated advanced thyroid cancers (dabrafenib) 1
- Multi-kinase inhibitors for various genetic alterations 1

Pitfalls and Caveats

Not all BRAF-mutated PTCs behave aggressively; additional genetic alterations contribute to aggressive behavior
Molecular testing should be interpreted in conjunction with clinical and pathological features
The presence of BRAF mutation alone is not an indication for more aggressive initial therapy in low-risk patients
Routine BRAF genotyping for all PTCs has not been established as standard practice 1

Understanding the genetic landscape of PTC is crucial for risk stratification and may guide personalized treatment approaches, particularly in patients with aggressive disease or recurrence.

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