Anaplastic Thyroid Cancer (THAP)

Overview

Anaplastic thyroid carcinoma (ATC/THAP) is the most aggressive thyroid malignancy, with a median survival of 3–6 months and near-universal lethality. On OncoTree it is a child of THYROID. ATC typically arises from dedifferentiation of a pre-existing differentiated thyroid cancer (DTC), particularly papillary thyroid carcinoma (THPA). It is characterized by a high mutation burden compared to PTC but fewer mutations than most other adult cancers.

Cohorts in the corpus

  • 213 ATC regions from 179 primary ATCs, plus 34 co-occurring DTC components; 115 papillary thyroid cancer regions; 13 ATC cell lines; from 292 patients across 15 institutions (GATCI consortium). WES (n=132), WGS (n=9), SNP arrays (n=110), RNA-seq (n=24). Dataset: thyroid_gatci_2024. PMID:38412093

Recurrent alterations

  • TP53 — mutations in 36.8% of ATCs vs. 0.9% of PTCs; frequency increases progressively from PTC to co-DTC (21.4%) to ATC; associated with elevated TP53 mRNA abundance (P=0.0067). PMID:38412093
  • BRAF — V600E in 21.3% of ATCs vs. 50.9% of PTCs; clonal/early subclonal timing; mutually exclusive with RAS; co-occurs with PIK3CA mutations (FDR=0.034). PMID:38412093
  • NRAS — recurrently mutated in ATC (top 5 by FDR); mutually exclusive with BRAF V600E. PMID:38412093
  • PIK3CA — co-occurs with BRAF V600E (FDR=0.034); preferentially mutated in ATCs and co-DTCs. PMID:38412093
  • CDKN2A — deleted in 42% of ATCs; recurrent in co-DTCs, rare in PTCs (~5%). PMID:38412093
  • BRCA2 — deleted in 33.6% of ATCs; deletion associated with better survival (HR=0.48, P=0.005). PMID:38412093
  • TERT — promoter mutations correlated with TP53 mutations (FDR<0.01). PMID:38412093
  • ATM, BRCA1 — recurrent somatic and germline alterations at both SNV and CNA level. PMID:38412093
  • RB1 — recurrent deletions in ATCs. PMID:38412093
  • USH2A — recurrently mutated (top 5 by FDR). PMID:38412093
  • Mutational burden: 3.8 +/- 1.2 SNVs/Mb and 120 +/- 44 CNAs per tumor; 42 recurrently mutated genes by SeqSig (FDR<0.05). PMID:38412093
  • MSK-IMPACT deep-sequencing of 33 ATC tumors found TP53 mutation in 73%, BRAF V600E in 45%, TERT promoter mutations in 73%, and enrichment of PI3K/AKT/mTOR (39%), SWI/SNF (36%), and histone-methyltransferase (24%) alterations; TERT-mutant ATCs had markedly shorter survival (median 147 vs 732 days, P=0.03) PMID:26878173

Subtypes

  • Five CNA subtypes (A-E) by consensus clustering, with characteristic genomic and clinical features: subtype A enriched for older patients with better survival; subtype D enriched for male patients with metastatic disease. PMID:38412093
  • Multi-region WGS (9 patients) confirmed that ATC and co-occurring DTC share a common clonal origin, with the common ancestor harboring ~95% of CNAs but only 19.1% of SNVs. PMID:38412093
  • Patients with lower mutation rate (>10 SNVs/Mb) had significantly better survival (HR=0.51, P=0.002). PMID:38412093

Therapeutic landscape

Sources

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

  • PMID:26878173 — Landa et al., MSK-IMPACT sequencing of 84 PDTC and 33 ATC; ATC characterized by TP53 (73%), BRAF V600E (45%), TERT promoter (73%), and SWI/SNF (36%) alterations

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