Related Experiment Video
Updated: Nov 12, 2025
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Histology-based molecular profiling improves mutation detection for advanced thyroid cancer
Markus Eszlinger1,2, Moosa Khalil3, Aaron Hill Gillmor4
1Departments of Oncology, Pathology and Laboratory Medicine, Biochemistry and Molecular Biology, and Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Abstract:
Advanced cancers frequently show histologic and molecular intratumoral heterogeneity. Therefore, we comprehensively characterized advanced, metastatic, radioiodine-resistant (RAIR) thyroid carcinomas at the molecular level in the context of histologic heterogeneity with the aim to identify potentially actionable mutations that may guide the use of specific tyrosine kinase inhibitor (TKI) treatment. Whole exome sequencing (WES) was applied to 29 macrodissected tissue samples of histologically heterogeneous and homogeneous areas, lymph node and lung metastases from six clinically and histologically well-characterized metastatic RAIR thyroid cancer patients with structural incomplete response to treatment. WES data were analyzed to identify potential driver mutations in oncogenic pathways, copy number alterations, microsatellite instability, mutant-allele tumor heterogeneity, and the relevance of histologic heterogeneity to molecular profiling. In addition to known driver mutations in BRAF, NRAS, EIF1AX, NCOA4-RET, and TERT, further potentially actionable drivers were identified in AKT1, ATM, E2F1, HTR2A, and MLH3. The analysis of the evolutionary history of the mutations and the reconstruction of the molecular phylogeny of the cancers show a remarkable association between histologic and molecular heterogeneity. A comprehensive molecular analysis of the primary tumor guided by histologic analysis may help to better stratify patients for precision medicine approaches. Given the association between the molecular and the histologic heterogeneity, the selection of tumor samples for molecular analysis should be based on meticulous histologic evaluation of the entire tumor.
Insights
Histologic heterogeneity in advanced thyroid cancer correlates with molecular differences. Comprehensive molecular profiling guided by histology can identify actionable mutations for targeted tyrosine kinase inhibitor (TKI) therapy.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Advanced thyroid carcinomas often exhibit significant intratumoral heterogeneity.
- Radioiodine-resistant (RAIR) thyroid cancers present therapeutic challenges due to this heterogeneity.
- Understanding molecular drivers is crucial for effective treatment strategies.
Purpose of the Study:
- To comprehensively characterize advanced, metastatic RAIR thyroid carcinomas at the molecular level.
- To investigate the relationship between histologic and molecular heterogeneity.
- To identify actionable mutations for guiding tyrosine kinase inhibitor (TKI) treatment.
Main Methods:
- Whole exome sequencing (WES) of 29 macrodissected tissue samples from heterogeneous and homogeneous areas, and metastases.
- Analysis of potential driver mutations, copy number alterations, and microsatellite instability.
- Reconstruction of molecular phylogeny to assess evolutionary history and heterogeneity.
Main Results:
- Identified known driver mutations (BRAF, NRAS, TERT, etc.) and novel actionable drivers (AKT1, ATM, MLH3, etc.).
- Demonstrated a strong association between histologic heterogeneity and molecular profiling results.
- Revealed mutant-allele tumor heterogeneity within samples.
Conclusions:
- Histologic heterogeneity significantly impacts molecular profiling in advanced thyroid cancer.
- Comprehensive molecular analysis guided by meticulous histologic evaluation is essential for patient stratification.
- This approach can optimize the use of targeted therapies like TKIs for improved precision medicine outcomes.
