<i>RET</i> Alterations Differentiate Molecular Profile of Medullary Thyroid Cancer.

Abstract

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 <i>RET</i> oncogene, and lower-frequency alterations are reported in <i>KRAS</i> and <i>BRAF</i>. 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. 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 <i>RET</i> novel mutation. Mutational landscape analysis shows expected <i>RET</i> mutations in 50% of the cases. Furthermore, we observed mutations in known cancer genes like <i>KRAS</i>, <i>HRAS</i>, <i>SF3B1</i>, and <i>BRAF</i> to be altered only in the <i>RET</i>-negative cohort. Pathway analysis showed differential enrichment of mutations in transcriptional deregulation genes in the <i>RET</i>-negative cohort. Furthermore, we observed novel RET kinase domain mutation Y900S showing affinity to RET inhibitors accessed via molecular docking and molecular dynamics simulation. 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.