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Updated: May 19, 2026
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
A subset of papillary thyroid carcinomas contain KRAS mutant subpopulations at levels above normal thyroid
Meagan B Myers1, Karen L McKim, Barbara L Parsons
1Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas.
Abstract:
The molecular pathogenesis of papillary thyroid carcinoma (PTC) is largely attributed to chromosomal rearrangements and point mutations in genes within the MAPK pathway (i.e., BRAF and RAS). Despite KRAS being the 6th most frequently mutated gene for all cancers, the reported frequency in thyroid cancer is only 2%. This may be due, in part, to the use of insensitive mutation detection methods such as DNA sequencing. Therefore, using the sensitive and quantitative ACB-PCR approach, we quantified KRAS codon 12 GGT → GAT and GGT → GTT mutant fraction (MF) in 20 normal thyroid tissues, 17 primary PTC, 2 metastatic PTC, and 1 anaplastic thyroid carcinoma. We observed measurable levels of KRAS codon 12 GAT or GTT mutation in all normal thyroid tissues. For PTCs, 29.4% and 35.3% had KRAS codon 12 GAT and GTT MF above the 95% upper confidence interval for the corresponding MFs in normal thyroid. The highest observed KRAS codon 12 GTT MFs were associated with tumors with follicular characteristics and relatively high levels of tumor necrosis. The results indicate KRAS mutant subpopulations are present in a large number of thyroid tumors, a fact previously unrecognized. The presence of KRAS mutation may indicate a tumor with an aggressive phenotype, thus directing the course of clinical treatment.
Insights
KRAS mutations are common in thyroid tumors, often missed by standard tests. Sensitive methods reveal these mutations may indicate aggressive papillary thyroid cancer (PTC), guiding treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Papillary thyroid carcinoma (PTC) pathogenesis involves MAPK pathway mutations.
- KRAS mutations are frequent in cancers but rarely reported in thyroid cancer (2%).
- Insensitive mutation detection methods may explain the low reported frequency of KRAS mutations in thyroid cancer.
Purpose of the Study:
- To quantify KRAS codon 12 GGT→GAT and GGT→GTT mutant fractions (MF) in thyroid tissues using sensitive ACB-PCR.
- To investigate the prevalence and clinical significance of KRAS mutations in PTC.
Main Methods:
- Quantitative allele-competitive polymerase chain reaction (ACB-PCR) was used.
- KRAS codon 12 GAT and GTT mutant fractions were measured in normal thyroid tissues, primary PTC, metastatic PTC, and anaplastic thyroid carcinoma.
- Mutant fractions were compared to normal tissue upper confidence intervals.
Main Results:
- Measurable KRAS codon 12 GAT or GTT mutations were detected in all normal thyroid tissues.
- 29.4% of PTCs showed KRAS codon 12 GAT MF above normal levels.
- 35.3% of PTCs showed KRAS codon 12 GTT MF above normal levels.
- Higher KRAS codon 12 GTT MFs correlated with follicular features and tumor necrosis.
Conclusions:
- KRAS mutant subpopulations are present in a significant number of thyroid tumors.
- Previously unrecognized prevalence of KRAS mutations in thyroid cancer.
- KRAS mutations may signify an aggressive PTC phenotype, influencing clinical management.
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