Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers
Iñigo Landa, … , Ian Ganly, James A. Fagin
Iñigo Landa, … , Ian Ganly, James A. Fagin
Published February 15, 2016
Citation Information: J Clin Invest. 2016;126(3):1052-1066. https://doi.org/10.1172/JCI85271.
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Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

Abstract

BACKGROUND. Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization.

METHODS. We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC).

RESULTS. Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs were BRAF-like irrespective of driver mutation.

CONCLUSIONS. These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared with PDTC underscore their greater virulence and higher mortality.

FUNDING. This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family Foundation; the Society of Memorial Sloan Kettering; the Byrne fund; and Cycle for Survival.

Authors

Iñigo Landa, Tihana Ibrahimpasic, Laura Boucai, Rileen Sinha, Jeffrey A. Knauf, Ronak H. Shah, Snjezana Dogan, Julio C. Ricarte-Filho, Gnana P. Krishnamoorthy, Bin Xu, Nikolaus Schultz, Michael F. Berger, Chris Sander, Barry S. Taylor, Ronald Ghossein, Ian Ganly, James A. Fagin

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Figure 7

M2 macrophage signature and TDS of 17 PDTCs and 20 ATCs.

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M2 macrophage signature and TDS of 17 PDTCs and 20 ATCs. (A) Unsupervise...
(A) Unsupervised clustering based on a 68-gene M2-macrophage signature in advanced thyroid tumors (35). Expression values are displayed as Z-scores after scaling the values of each gene across the 37 samples. The 11 most discriminatory genes (variance greater than 2) are shown; the complete 68-gene signature is shown in Supplemental Figure 6. ATCs clearly cluster apart from PDTCs consistent with their extensive macrophage infiltration. (B) Relative expression of the 16 genes of the TDS in 20 ATCs and 17 PDTCs, compared with 9 PTCs from He et al. (39) evaluated with the same mRNA array platform. ATCs have low TDS values for virtually all TDS genes, whereas PDTCs are comparable to PTCs. The 16-gene TDS signature discriminates ATCs and PDTCs (see unsupervised clustering in Supplemental Figure 7). (C) Correlation plots between TDS and BRS in PTCs from TCGA (top) and PDTCs and ATCs (bottom). Trend lines, Pearson’s correlation coefficients (r) and associated P values are shown in the graphs. TDS and BRS are positively correlated in PTCs (r = 0.74, P < 0.0001) and PDTCs (r = 0.72, P < 0.01); i.e., RAS-like tumors tend to be more differentiated than BRAF-like cancers. This relationship is lost in ATCs, which are profoundly undifferentiated (r = –0.43, P = 0.06). (D) Comparison of TDS values in BRAF- and RAS-mutated PDTCs and ATCs. Whereas ATCs are undifferentiated regardless of their driver alteration (Mann-Whitney U test, P = 0.21), BRAF-mutated PDTCs show a decrease in TDS compared with their RAS-mutant counterparts (P = 0.06). Box plots from B and D were generated using the Tukey method: horizontal lines within each box represent median values; box heights symbolize the IQR (IQR = Q3–Q1); Q3 and Q1 quartiles correspond to the top and bottom boundaries of the box, respectively; and whiskers represent values up to 1.5 times IQR greater than Q3 (top: Q3 + 1.5 × IQR) or smaller than Q1 (bottom: Q1 – 1.5 × IQR). Values outside these limits are considered outliers and are represented by dots.