Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing

John W. Kunstman, C. Christofer Juhlin, Gerald Goh, Taylor C. Brown, Adam Stenman, James M. Healy, Jill C. Rubinstein, Murim Choi, Nimrod Kiss, Carol Nelson-Williams, Shrikant Mane, David L. Rimm, Manju L. Prasad, Anders Höög, Jan Zedenius, Catharina Larsson, Reju Korah, Richard P. Lifton, Tobias Carling

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269 Scopus citations


Anaplastic thyroid carcinoma (ATC) is a frequently lethal malignancy that is often unresponsive to available therapeutic strategies. The tumorigenesis of ATC and its relationship to the widely prevalent well-differentiated thyroid carcinomas are unclear. We have analyzed 22 cases of ATC aswell as 4 established ATC cell lines using whole-exome sequencing. A total of 2674 somatic mutations (121/sample) were detected. Ontology analysis revealed that the majority of variants aggregated in the MAPK, ErbB and RAS signaling pathways. Mutations in genes related to malignancy not previously associated with thyroid tumorigenesis were observed, including mTOR, NF1, NF2, MLH1, MLH3, MSH5, MSH6, ERBB2, EIF1AX and USH2A; some of which were recurrent and were investigated in 24 additional ATC cases and 8 ATC cell lines. Somatic mutations in established thyroid cancer genes were detected in 14 of 22 (64%) tumors and included recurrent mutations in BRAF, TP53 and RAS-family genes (6 cases each), aswell as PIK3CA (2 cases) and single cases of CDKN1B, CDKN2C, CTNNB1 and RET mutations. BRAF V600E and RAS mutationswere mutually exclusive; all ATC cell lines exhibited a combination of mutations in either BRAF and TP53 or NRAS and TP53. A hypermutator phenotype in two cases with >8 times higher mutational burden than the remaining meanwas identified; both cases harbored unique somatic mutations in MLH mismatch-repair genes. This first comprehensive exome-wide analysis of the mutational landscape ofATC identifies novel genes potentially associated withATC tumorigenesis, some of whichmay be targets for future therapeutic intervention.

Original languageEnglish
Pages (from-to)2318-2329
Number of pages12
JournalHuman molecular genetics
Issue number8
StatePublished - Apr 15 2015


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