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Updated: Mar 24, 2026
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
Genomic Alterations of Anaplastic Thyroid Carcinoma Detected by Targeted Massive Parallel Sequencing in a BRAF(V600E)
Min Ji Jeon1, Sung-Min Chun2, Deokhoon Kim3
11 Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
Background:
Anaplastic thyroid carcinoma (ATC), the most aggressive type of thyroid cancer, has no effective therapy. Due to its dismal prognosis, it is vital to understand the genetic alterations of ATC and identify effective molecular targets. Targeted next-generation sequencing was performed to investigate the mutational profile of ATC using a massive parallel sequencing approach.
Methods:
DNA from formalin-fixed, paraffin-embedded archival samples of 11 ATCs and normal matched pairs were used. A total of 48 genetic alterations were identified by targeted exome sequencing. These alterations were validated by mass spectrometric genotyping and direct Sanger sequencing.
Results:
The most commonly mutated gene was BRAF, identified in 10 samples (91%), all showing the V600E point mutation. A KRAS point mutation was observed in the one sample (9%) without the BRAF(V600E) mutation. All 11 ATCs harbored BRAF or RAS mutations, reflecting the possibility that differentiated thyroid carcinomas progress to ATCs after the accumulation of mutations. A loss of function mutation of TP53 was observed in eight samples (73%), a PIK3CA mutation was observed in two samples (18%), and a frameshift mutation of PTEN was observed in one sample (9%). Twenty-eight novel mutated genes were found that had not previously been associated with ATC. Of these, loss of function mutations of NF2, KMT2D, and PKHD1 were repeatedly seen in three samples (27%), two samples (18%), and two samples (18%), respectively. Using direct Sanger sequencing, two samples (18%) were also found with a RASAL1 mutation. KMT2D and RASAL1 mutations were significantly associated with shorter ATC patient survival.
Conclusions:
This comprehensive analysis of ATCs using targeted massive parallel sequencing identified several novel mutations in ATCs, such as loss of function mutations of NF2 or KMT2D. Future studies are needed to confirm the role of these novel mutations as independent drivers of ATC development.
Insights
Anaplastic thyroid carcinoma (ATC) genetic analysis reveals BRAF mutations in 91% of cases. Novel mutations in NF2 and KMT2D were identified, with KMT2D and RASAL1 mutations linked to shorter survival in advanced thyroid cancer.
Area of Science:
- Genomics and Molecular Biology
- Oncology
- Cancer Genetics
Background:
- Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid cancer with limited therapeutic options.
- Understanding the genetic landscape of ATC is crucial for identifying effective molecular targets.
- Previous research highlighted the need for comprehensive mutational profiling in ATC.
Purpose of the Study:
- To investigate the comprehensive mutational profile of anaplastic thyroid carcinoma (ATC).
- To identify potential novel molecular targets for ATC therapy.
- To correlate genetic alterations with patient survival in ATC.
Main Methods:
- Targeted next-generation sequencing (NGS) was employed on DNA from 11 formalin-fixed, paraffin-embedded ATC samples and matched normal pairs.
- Identified genetic alterations were validated using mass spectrometric genotyping and direct Sanger sequencing.
- Massive parallel sequencing approach was utilized for comprehensive mutational analysis.
Main Results:
- BRAF mutations, predominantly V600E, were found in 91% of ATC samples; all samples harbored BRAF or RAS mutations.
- Loss of function mutations in TP53 (73%) and PIK3CA (18%) were frequently observed.
- Novel mutations in NF2, KMT2D, PKHD1, and RASAL1 were identified, with KMT2D and RASAL1 mutations significantly associated with shorter patient survival.
Conclusions:
- Targeted massive parallel sequencing revealed a distinct mutational profile in ATC, including novel mutations.
- Loss of function mutations in NF2 and KMT2D represent potential new targets for ATC treatment.
- Further research is required to validate the role of these novel mutations in ATC pathogenesis and as therapeutic targets.
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