Papillary Thyroid Carcinoma (TCGA, Cell 2014)

Overview

The TCGA multiplatform genomic characterization of 496 papillary thyroid carcinomas (PTCs) — the largest integrative genomic study of PTC at the time of publication. Accrued through TCGA from non-irradiated patients; focused on the most common subtype of thyroid cancer. The study aimed to define the complete landscape of oncogenic drivers, reduce the fraction of driver-negative “dark matter” cases, and propose a molecular reclassification based on BRAFV600E-like (BVL) vs. RAS-like (RL) signaling states.

Composition

  • Cancer type: Papillary thyroid carcinoma (THPA)
  • Sample count: 496 primary PTCs + 8 metastatic tumors; 402 tumor/normal pairs with whole-exome sequencing; 390 tumors profiled across all major platforms
  • Histology breakdown: 324 (69.4%) classical-type, 99 (21.2%) follicular-variant, 35 (7.5%) tall cell variant, 9 (2.0%) uncommon variants
  • Exclusions: Poorly differentiated and anaplastic thyroid cancers excluded
  • Reference genome: hg19

Assays / panels (linked)

Papers using this cohort

  • PMID:25417114 — TCGA Research Network, Cell 2014. “Integrated Genomic Characterization of Papillary Thyroid Carcinoma.”
  • PMID:26878173 — Landa et al., J Clin Invest 2016: used as reference comparator for MSKCC advanced thyroid cohort; BRS and TDS scores applied to PDTC and ATC.

Notable findings derived from this cohort

  • Seven significantly mutated genes (q<0.1): BRAF, NRAS, HRAS, KRAS, EIF1AX, PPM1D, and CHEK2; MAPK driver mutations (BRAF + RAS) were mutually exclusive in 74.6% of cases (Fisher’s exact P=1.1×10⁻⁵) PMID:25417114.
  • BRAF V600E was the dominant driver in 61.7% of PTCs; RAS mutations characterized the follicular variant (12.9%); EIF1AX was identified as a novel PTC driver (1.5%, q=5.3×10⁻⁸) near-mutually exclusive with MAPK drivers PMID:25417114.
  • Gene fusions identified in 15.3% (74/484) of cases — including RET (6.8%), BRAF (2.7%), NTRK3, ALK, PAX8/PPARG, and THADA fusions — all mutually exclusive with point-mutation drivers (Fisher’s exact P=4.9×10⁻⁴³) PMID:25417114.
  • TERT promoter mutations in 9.4% (36/384) of informative tumors; associated with older age, high MACIS recurrence risk scores, and lower thyroid differentiation score (TDS) PMID:25417114.
  • Fraction of PTC cases without an identified oncogenic driver reduced from ~25% (historical) to 3.5%; combining SSNVs, fusions, and SCNAs, putative drivers were identified in 397/402 (98.8%) of exome-sequenced PTCs PMID:25417114.
  • A 71-gene BRAFV600E-RAS Score (BRS) and a 16-gene Thyroid Differentiation Score (TDS) distinguished two fundamental PTC molecular classes with distinct MAPK/PI3K signaling profiles, epigenomic patterns, and clinical outcomes PMID:25417114.
  • Used as a reference comparator for the MSKCC advanced thyroid cohort (n=390–401 papillary thyroid carcinomas); BRAF-RAS score and thyroid differentiation score applied to validate driver associations in PDTC and ATC PMID:26878173

Sources

  • cBioPortal study: thca_tcga_pub
  • Citation: TCGA, Cell 2014 PMID:25417114

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