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. 2018 Jul 1;24(13):3059-3068.
doi: 10.1158/1078-0432.CCR-18-0373. Epub 2018 Apr 3.

Genetic Analysis of 779 Advanced Differentiated and Anaplastic Thyroid Cancers

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Free PMC article

Genetic Analysis of 779 Advanced Differentiated and Anaplastic Thyroid Cancers

Nikita Pozdeyev et al. Clin Cancer Res. .
Free PMC article

Abstract

Purpose: To define the genetic landscape of advanced differentiated and anaplastic thyroid cancer (ATC) and identify genetic alterations of potential diagnostic, prognostic, and therapeutic significance.Experimental Design: The genetic profiles of 583 advanced differentiated and 196 ATCs generated with targeted next-generation sequencing cancer-associated gene panels MSK-IMPACT and FoundationOne were analyzed.Results: ATC had more genetic alterations per tumor, and pediatric papillary thyroid cancer had fewer genetic alterations per tumor when compared with other thyroid cancer types. DNA mismatch repair deficit and activity of APOBEC cytidine deaminases were identified as mechanisms associated with high mutational burden in a subset of differentiated thyroid cancers and ATCs. Copy number losses and mutations of CDKN2A and CDKN2B, amplification of CCNE1, amplification of receptor tyrosine kinase genes KDR, KIT, and PDGFRA, amplification of immune evasion genes CD274, PDCD1LG2, and JAK2, and activating point mutations in small GTPase RAC1 were associated with ATC. An association of KDR, KIT, and PDGFRA amplification with the sensitivity of thyroid cancer cells to lenvatinib was shown in vitro Three genetically distinct types of ATCs are proposed.Conclusions: This large-scale analysis describes genetic alterations in a cohort of thyroid cancers enriched in advanced cases. Many novel genetic events previously not seen in thyroid cancer were found. Genetic alterations associated with anaplastic transformation were identified. An updated schematic of thyroid cancer genetic evolution is proposed. Clin Cancer Res; 24(13); 3059-68. ©2018 AACR.

Conflict of interest statement

Conflict of interest. Nikita Pozdeyev, Kelsi E. Deaver, Stephanie Davis, Jena D. French, Daniel V. LaBarbera, Aik-Choon Tan, Rebecca E. Schweppe, Lauren Fishbein, Bryan R. Haugen and Daniel W. Bowles declare no conflicts of interest. Laurie M. Gay, Ethan Sokol, Pierre Vanden Borre and Jeffrey S. Ross are employees and shareholders of Foundation Medicine Inc. Ryan Hartmaier was an employee and shareholder of Foundation Medicine Inc. at a time this study was done.

Figures

Figure 1
Figure 1. The number of genetic alterations per tumor in thyroid cancer subtypes
ATC had higher and pediatric PTC had lower number of genetic alterations per tumor, when compared to other thyroid cancer types (Kruskal-Wallis followed by post-hoc Tukey and Kramer test, p<0.01).
Figure 2
Figure 2. Hierarchical clustering of genetic alterations in ATC
Key associations of genetic alterations identified by Apriori algorithm characterizing each cluster are highlighted by different colors. Four clusters and three ATC types with distinct genetic alteration patterns are proposed.
Figure 3
Figure 3. Genetic evolution of thyroid cancer
Genetic alterations causing an increase in protein activity (activating point mutations, fusions and gene amplifications) are highlighted in red while loss-of-function mutation and copy number losses are shown in black. * - PAX/PPARg fusions were not tested by MSK-IMPACT and FoundationOne.

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