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Updated: Apr 18, 2026
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing
John W Kunstman1, C Christofer Juhlin2, Gerald Goh3
1Yale Endocrine Neoplasia Laboratory, Department of Surgery.
Abstract:
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 as well 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), as well as PIK3CA (2 cases) and single cases of CDKN1B, CDKN2C, CTNNB1 and RET mutations. BRAF V600E and RAS mutations were 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 mean was identified; both cases harbored unique somatic mutations in MLH mismatch-repair genes. This first comprehensive exome-wide analysis of the mutational landscape of ATC identifies novel genes potentially associated with ATC tumorigenesis, some of which may be targets for future therapeutic intervention.
Insights
Anaplastic thyroid carcinoma (ATC) is a deadly cancer. Whole-exome sequencing revealed new mutations in signaling pathways and DNA repair genes, offering potential therapeutic targets for this aggressive malignancy.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Anaplastic thyroid carcinoma (ATC) is an aggressive, often fatal thyroid cancer with limited treatment options.
- The molecular mechanisms driving ATC tumorigenesis and its relationship to differentiated thyroid cancers remain poorly understood.
Purpose of the Study:
- To comprehensively analyze the mutational landscape of anaplastic thyroid carcinoma using whole-exome sequencing.
- To identify novel genetic alterations and signaling pathways implicated in ATC development.
- To discover potential therapeutic targets for ATC treatment.
Main Methods:
- Whole-exome sequencing was performed on 22 ATC tumor samples and 4 ATC cell lines.
- Somatic mutations were identified and analyzed for enrichment in specific signaling pathways.
- Recurrent mutations and novel candidate genes were further investigated in additional ATC cases and cell lines.
Main Results:
- A total of 2674 somatic mutations were detected, predominantly affecting MAPK, ErbB, and RAS signaling pathways.
- Mutations in known thyroid cancer genes (BRAF, TP53, RAS) were found in 64% of tumors.
- Novel candidate genes (mTOR, NF1, MLH1, ERBB2, etc.) were identified, with some showing recurrent mutations.
- Two hypermutator cases with unique MLH mismatch-repair gene mutations were observed.
- BRAF V600E and RAS mutations were mutually exclusive; cell lines showed BRAF/TP53 or NRAS/TP53 combinations.
Conclusions:
- This study provides the first comprehensive exome-wide analysis of ATC's mutational landscape.
- Novel genes and pathways implicated in ATC tumorigenesis have been identified.
- These findings may lead to the development of new therapeutic strategies for anaplastic thyroid carcinoma.
