Papillary Thyroid Cancer (THPA)

Overview

Papillary thyroid carcinoma (PTC/THPA) is the most common thyroid malignancy, with generally excellent prognosis. On OncoTree it is a child of Well-Differentiated Thyroid Carcinoma (WDTC). It is driven predominantly by BRAF V600E or RAS mutations and characterized by a low mutation burden. A minority of PTCs undergo dedifferentiation to anaplastic thyroid carcinoma (THAP).

Cohorts in the corpus

  • 115 PTC regions from the GATCI consortium (same 292-patient cohort as THAP), profiled by WES, SNP arrays, and RNA-seq. Dataset: thyroid_gatci_2024. PMID:38412093
  • THPA identified as an acquired BRAF fusion histology in 1/15 patients who acquired BRAF fusions after prior targeted therapy (prior driver: unknown). PMID:38922339

Recurrent alterations

  • BRAF — V600E is the dominant driver in PTC (50.9% of PTCs vs. 21.3% of ATCs); mutually exclusive with RAS; half of BRAF V600E variants in co-occurring cases were found only in the DTC component. PMID:38412093
  • NRAS — recurrently mutated in PTC/ATC; no frequency difference between PTC and ATC. PMID:38412093
  • TP53 — rare in PTC (0.9% vs. 36.8% in ATC); stepwise enrichment defines dedifferentiation to ATC. PMID:38412093
  • TERT — promoter mutations; co-occurs with TP53 mutations in BRAF fusion-positive thyroid cancers (73% of BRAF fusion thyroid cancers). PMID:38922339
  • CDKN2A — rare in PTC (~5%) vs. 42% in ATC; marks dedifferentiation. PMID:38412093
  • TCGA multiplatform genomic characterization of 496 PTCs identified 7 significantly mutated genes (BRAF V600E in 61.7%, RAS in 12.9%, EIF1AX, PPM1D, CHEK2), reduced ‘dark matter’ from ~25% to 3.5%, and defined BRAFV600E-like vs. RAS-like molecular subtypes with distinct signaling, differentiation, and clinical outcomes PMID:25417114.
  • TCGA papillary thyroid carcinoma cohort (n=390) used as comparator; BRAF-RAS score (BRS) tracked driver mutation in PDTCs but ATCs were uniformly BRAF-like irrespective of driver, indicating a stepwise progression model from differentiated precursors PMID:26878173

Subtypes

  • PTC shares common clonal ancestor with co-occurring ATC regions, with the ATC diverging through acquisition of TP53, PIK3CA, and CDKN2A alterations. PMID:38412093
  • BRAF fusion-positive thyroid cancers (THPA subset) identified as an acquired resistance mechanism to prior targeted therapy in 1/15 patients with acquired BRAF fusions. PMID:38922339
  • BRAF fusions co-occur with TERT mutations in 73% of BRAF fusion thyroid cancers. PMID:38922339

Therapeutic landscape

  • BRAF V600E-targeted therapy (vemurafenib, dabrafenib + trametinib) is effective in BRAF V600E-mutant differentiated thyroid cancer. PMID:38412093
  • BRAF fusions acquired as a resistance mechanism to prior targeted therapy were identified in THPA, underscoring the importance of post-progression genotyping. PMID:38922339

Sources

  • PMID:38412093 — The genomic and evolutionary landscapes of anaplastic thyroid carcinoma (Cell Reports, 2024)

  • PMID:38922339 — Tumor-agnostic genomic and clinical analysis of BRAF fusions identify actionable targets (Clinical Cancer Research, 2024)

  • PMID:25417114

  • PMID:26878173 — Landa et al., MSK-IMPACT deep-sequencing study; TCGA PTC cohort (n=390) used as comparator; BRAF-RAS score tracks driver in PDTC but ATCs are uniformly BRAF-like

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