Alterations Differentiate Molecular Profile of Medullary Thyroid Cancer.

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 oncogene, and lower-frequency alterations are reported in and . 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 novel mutation.

Results: Mutational landscape analysis shows expected mutations in 50% of the cases. Furthermore, we observed mutations in known cancer genes like , , , and to be altered only in the -negative cohort. Pathway analysis showed differential enrichment of mutations in transcriptional deregulation genes in the -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.