Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers
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
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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Clinical Research and Public Health Oncology

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 5

Recurrent MSK-IMPACT–derived CNAs found in 84 PDTC and 33 ATC.

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Recurrent MSK-IMPACT–derived CNAs found in 84 PDTC and 33 ATC. Represent...
Representation of arm-level regions recurrently gained or lost in PDTCs and/or ATCs. CNAs were corrected for tumor purity in each sample with known driver mutations (see Methods and Supplemental Figure 2). (A) IGV representation of the altered chromosomal regions, with approximate locations shown on the top panel (genome build hg19), expressed as red (gain) or blue (loss), with shading intensity proportional to the log-ratio (lr) values. Samples are grouped by tumor type and sorted by genetic driver alteration: BRAF, RAS, fusions (RET/PTC, PAX8-PPARG, and ALK), or none/unknown. Color key and annotations are shown on the left. (B) Frequencies of the indicated CNAs in PDTCs and ATCs. Copy number gains (red) or losses (blue) were defined using two lr thresholds: ±0.1 (lighter shading) and ±0.4 (darker shading). Asterisks denote significant differences expressed as Fisher’s exact test P values for ±0.4 threshold: PDTC, 0.06 for 1p loss; ATC, < 2 × 10–4 for 8p loss, 17p loss, and 20q gain. (C) Kaplan-Meier survival curves for PDTCs harboring chromosome 1q gain (left, log-rank P values for ±0.1 and ±0.4 thresholds are 0.03 and 0.06, respectively) and for ATCs with 13q loss (middle, P = 0.07 and 0.02) or 20q gain (right, P = 0.01 and 0.06).