RET 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 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.

Landscape of toll-like receptors expression in tumor microenvironment of triple negative breast cancer (TNBC): Distinct roles of TLR4 and TLR8.

TNBC is the most aggressive and hormone receptor-negative subtype of breast cancer with molecular heterogeneity in bulk tumors hindering effective treatment. Toll-like receptors (TLRs) have the potential to ignite diverse immune responses in the tumor microenvironment (TME). This encouraged us to screen their transcript expression in the publically available TCGA datasets. Reported molecular subtypes of TNBC may represent different TMEs and we observed differentially expressed TLRs (DETs) i.e. TLR3/4/6/8/9 have unique expression pattern in the TNBC subtypes, particularly in Immunomodulatory (IM) TNBC subtype. We then dissected expression of the DETs in immune and other components of the TME. TLR4 and TLR8 showed significant (p-value ≤ 0.05) negative partial correlation with tumor purity compared to other DETs. Interestingly, TLR4 and TLR8 expression showed a significant (adjusted p-value ≤ 0.05) correlation with different subsets of immune infiltrating cells having the highest correlation with monocytes/macrophage/dendritic cell populations mediating both innate and adaptive response in TNBC. The co-expression network identified genes correlated with these immune cells. Further, GSEA analysis of co-expressed genes showed a significant association of TLR8 partners with 'Peptide ligand binding', 'Gά-signaling', and 'Cytokine-cytokine interaction' while TLR4 associated genes correlated with 'Adaptive immune system' and 'Systemic lupus erythematosus' interactome. Finally, the expression of TLR4 protein was validated in a panel of TNBC cell lines. TLR4 expression in chemoresponsive TNBC was also validated in TNBC cell lines upon Paclitaxel (PTX) treatment. Collectively, the present study identified specific DETs in TNBC and discovered a prospective role of TLR4 and TLR8 in the maintenance of tumor-immune-microenvironment.