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Updated: Jun 26, 2025
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
Uncommon molecular alterations in follicular-derived thyroid carcinoma: A single institution study
Borislav A Alexiev1, Erica R Vormittag-Nocito1, Jochen Lorch2
1Department of Pathology, Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital, 251 East Huron St, Feinberg 7-342A, Chicago, IL 60611, USA.
Abstract:
Thyroid carcinomas are the most common endocrine malignancy and commonly have alterations in the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K)/AKT signaling pathways in well-differentiated tumors. Alternative molecular alterations driving thyroid carcinomas have been identified rarely in the literature and are more likely to occur in poorly differentiated or anaplastic cases. In this study, uncommon genetic alterations such as MLH1, MSH2, NSD3::NUTM1, RET::SPECC1L, and G3BP2::FGFR2 were identified in patients with papillary thyroid carcinoma, poorly differentiated thyroid carcinoma, and differentiated high-grade thyroid carcinoma. Most of these tumors demonstrated an aggressive biological behavior. Atypical driver mutations in thyroid carcinomas can occur in patients with cancer predisposition syndromes as demonstrated by an NTRK1::TPM3 fusion in a patient with Li Fraumeni syndrome. In these settings of more aggressive disease, molecular testing targeting actionable fusions and mutations is important. As demonstrated in our case cohort, 100% of cases diagnosed as high-grade follicular-derived thyroid carcinoma had a mutation or fusion that is associated with worse prognosis, has a germline syndrome association requiring further work up, or an actionable mutation. This high yield seen in this cohort for molecular testing in patients with high-grade follicular-derived thyroid carcinoma suggests more routine molecular testing in this population would be a beneficial clinical practice.
Insights
Uncommon genetic alterations drive aggressive thyroid cancers, including papillary and poorly differentiated types. Molecular testing is crucial for identifying actionable mutations and fusions in high-grade thyroid carcinomas, improving patient management.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Thyroid carcinomas are common endocrine malignancies, often linked to MAPK and PI3K/AKT pathway alterations in well-differentiated tumors.
- Less common molecular alterations are increasingly recognized in poorly differentiated or anaplastic thyroid cancers, often associated with aggressive behavior.
Purpose of the Study:
- To identify and characterize uncommon genetic alterations in various thyroid carcinoma subtypes.
- To investigate the clinical significance and potential therapeutic targets of these rare mutations and fusions.
- To evaluate the utility of molecular testing in high-grade follicular-derived thyroid carcinomas.
Main Methods:
- Comprehensive molecular profiling of thyroid carcinoma patient samples.
- Identification of genetic alterations including gene fusions (e.g., NSD3::NUTM1, RET::SPECC1L, G3BP2::FGFR2, NTRK1::TPM3) and mutations (e.g., MLH1, MSH2).
- Correlation of molecular findings with tumor histology, grade, and clinical behavior.
Main Results:
- Uncommon genetic alterations were identified in papillary, poorly differentiated, and high-grade differentiated thyroid carcinomas.
- Several identified alterations, such as MLH1, MSH2, and various fusions, were associated with aggressive tumor behavior.
- A patient with Li Fraumeni syndrome exhibited an NTRK1::TPM3 fusion, highlighting the link between driver mutations and cancer predisposition syndromes.
- 100% of high-grade follicular-derived thyroid carcinomas in the cohort harbored a mutation or fusion with prognostic, germline, or actionable implications.
Conclusions:
- Atypical driver mutations and fusions are present in aggressive thyroid carcinomas, including rare subtypes.
- Molecular testing for actionable alterations is critical in managing high-grade thyroid carcinomas.
- Routine molecular profiling in high-grade follicular-derived thyroid carcinomas can yield significant clinical insights and guide treatment decisions.
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