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RET Alterations Differentiate Molecular Profile of Medullary Thyroid Cancer
Kumar Prabhash1,2, Elveera Saldanha1,3,4, Vijay Patil1,2
1Homi Bhabha National Institute (HBNI), Mumbai, India.
Purpose:
Medullary thyroid cancer (MTC) is a rare cancer originating from parafollicular C cells of the thyroid gland. Therapeutically relevant alterations in MTC are predominantly reported in RET oncogene, and lower-frequency alterations are reported in KRAS and BRAF. Nevertheless, there is an unmet need existing to analyze the MTC in the Indian cohort by using in-depth sequencing techniques that go beyond the identification of known therapeutic biomarkers.
Materials And Methods:
Here, we characterize MTC using integrative whole-exome and whole-transcriptome sequencing of 32 MTC tissue samples. We performed clinically relevant variant analysis, molecular pathway analysis, tumor immune-microenvironment analysis, and structural characterization of RET novel mutation.
Results:
Mutational landscape analysis shows expected RET mutations in 50% of the cases. Furthermore, we observed mutations in known cancer genes like KRAS, HRAS, SF3B1, and BRAF to be altered only in the RET-negative cohort. Pathway analysis showed differential enrichment of mutations in transcriptional deregulation genes in the RET-negative cohort. Furthermore, we observed novel RET kinase domain mutation Y900S showing affinity to RET inhibitors accessed via molecular docking and molecular dynamics simulation.
Conclusion:
Altogether, this study provides a detailed genomic characterization of patients with MTC of Indian origin, highlighting the possible utility of targeted therapies in this disease.
Insights
This study details the genomic landscape of Medullary Thyroid Cancer (MTC) in an Indian cohort, identifying novel RET mutations and potential therapeutic targets beyond known biomarkers.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Medullary Thyroid Cancer (MTC) arises from thyroid C-cells, with RET mutations being common.
- Existing research often focuses on known biomarkers, leaving gaps in understanding diverse MTC genomic profiles.
Purpose of the Study:
- To perform in-depth genomic characterization of Medullary Thyroid Cancer in an Indian cohort.
- To identify novel therapeutic biomarkers beyond established RET, KRAS, and BRAF alterations.
Main Methods:
- Integrative whole-exome and whole-transcriptome sequencing of 32 MTC tissue samples.
- Analysis of mutational landscape, molecular pathways, and tumor immune-microenvironment.
- Structural characterization of novel RET mutations using molecular docking and dynamics.
Main Results:
- RET mutations identified in 50% of cases, with other mutations in KRAS, HRAS, SF3B1, and BRAF found in the RET-negative cohort.
- Pathway analysis revealed enrichment of mutations in transcriptional deregulation genes in the RET-negative MTC cases.
- A novel RET kinase domain mutation, Y900S, demonstrated affinity for RET inhibitors.
Conclusions:
- Provides comprehensive genomic insights into Indian MTC patients.
- Suggests potential for targeted therapies in MTC, particularly for RET-negative cases.
- Highlights the importance of advanced sequencing for uncovering novel therapeutic strategies.
