TY - JOUR
T1 - Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers
AU - Pozdeyev, Nikita
AU - Gay, Laurie M.
AU - Sokol, Ethan S.
AU - Hartmaier, Ryan
AU - Deaver, Kelsi E.
AU - Davis, Stephanie
AU - French, Jena D.
AU - Borre, Pierre Vanden
AU - LaBarbera, Daniel V.
AU - Tan, Aik Choon
AU - Schweppe, Rebecca E.
AU - Fishbein, Lauren
AU - Ross, Jeffrey S.
AU - Haugen, Bryan R.
AU - Bowles, Daniel W.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85049372836
U2 - 10.1158/1078-0432.CCR-18-0373
DO - 10.1158/1078-0432.CCR-18-0373
M3 - Article
C2 - 29615459
AN - SCOPUS:85049372836
SN - 1078-0432
VL - 24
SP - 3059
EP - 3068
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -
