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Updated: Mar 28, 2026
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
The genomic and transcriptomic landscape of anaplastic thyroid cancer: implications for therapy
Katayoon Kasaian1, Sam M Wiseman2, Blair A Walker3
1Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. kkasaian@bcgsc.ca.
Background:
Anaplastic thyroid carcinoma is the most undifferentiated form of thyroid cancer and one of the deadliest of all adult solid malignancies. Here we report the first genomic and transcriptomic profile of anaplastic thyroid cancer including those of several unique cell lines and outline novel potential drivers of malignancy and targets of therapy.
Methods:
We describe whole genomic and transcriptomic profiles of 1 primary anaplastic thyroid tumor and 3 authenticated cell lines. Those profiles augmented by the transcriptomes of 4 additional and unique cell lines were compared to 58 pairs of papillary thyroid carcinoma and matched normal tissue transcriptomes from The Cancer Genome Atlas study.
Results:
The most prevalent mutations were those of TP53 and BRAF; repeated alterations of the epigenetic machinery such as frame-shift deletions of HDAC10 and EP300, loss of SMARCA2 and fusions of MECP2, BCL11A and SS18 were observed. Sequence data displayed aneuploidy and large regions of copy loss and gain in all genomes. Common regions of gain were however evident encompassing chromosomes 5p and 20q. We found novel anaplastic gene fusions including MKRN1-BRAF, FGFR2-OGDH and SS18-SLC5A11, all expressed in-frame fusions involving a known proto-oncogene. Comparison of the anaplastic thyroid cancer expression datasets with the papillary thyroid cancer and normal thyroid tissue transcriptomes suggested several known drug targets such as FGFRs, VEGFRs, KIT and RET to have lower expression levels in anaplastic specimens compared with both papillary thyroid cancers and normal tissues, confirming the observed lack of response to therapies targeting these pathways. Further integrative data analysis identified the mTOR signaling pathway as a potential therapeutic target in this disease.
Conclusions:
Anaplastic thyroid carcinoma possessed heterogeneous and unique profiles revealing the significance of detailed molecular profiling of individual tumors and the treatment of each as a unique entity; the cell line sequence data promises to facilitate the more accurate and intentional drug screening studies for anaplastic thyroid cancer.
Insights
Anaplastic thyroid carcinoma (ATC) is aggressive. Genomic and transcriptomic profiling reveals unique mutations and potential therapeutic targets like the mTOR pathway, offering new treatment avenues for this deadly cancer.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Anaplastic thyroid carcinoma (ATC) is a highly aggressive and lethal form of thyroid cancer.
- Understanding ATC's molecular landscape is crucial for developing effective therapies.
Purpose of the Study:
- To perform the first comprehensive genomic and transcriptomic profiling of ATC.
- To identify novel drivers of malignancy and potential therapeutic targets in ATC.
Main Methods:
- Whole genome and transcriptome sequencing of one primary ATC tumor and three cell lines.
- Comparative analysis with transcriptomes from papillary thyroid carcinoma and normal thyroid tissues (The Cancer Genome Atlas).
Main Results:
- Prevalent mutations in TP53 and BRAF; alterations in epigenetic machinery (HDAC10, EP300, SMARCA2) and novel gene fusions (MKRN1-BRAF, FGFR2-OGDH, SS18-SLC5A11).
- Genomic instability with aneuploidy and copy number variations; common gains on chromosomes 5p and 20q.
- Lower expression of known drug targets (FGFRs, VEGFRs, KIT, RET) in ATC; mTOR signaling identified as a potential therapeutic target.
Conclusions:
- ATC exhibits heterogeneous and unique molecular profiles, emphasizing the need for individualized tumor profiling.
- Established cell lines provide a valuable resource for targeted drug screening and development in ATC.
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