Genomic Profiling of Medullary Thyroid Cancer. RET alterations differentiate molecular profile and microbiome of medullary thyroid cancer

Medullary thyroid cancer (MTC) is 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 in KRAS and BRAF. However, an unmet need exists to characterize the MTC using in-depth sequencing beyond known therapeutic biomarkers. Here we attempt to characterize MTC wherein we performed whole exome and whole transcriptome sequencing of 19 fresh-frozen and 23 FFPE MTC tissue samples. The mutational landscape analysis shows expected RET mutations at 48% frequency, and other hallmark genes like KMT2A, NRAS, SF3B1, etc., observed at variable frequency. Furthermore, we observed specific known genes like KRAS (12%), HRAS (12%), SF3B1 (18%), and BRAF (6%) to be altered only in RET negative cohort. Pathway analysis showed differential enrichment of mutations in transcriptional deregulation genes in the RET-negative cohort. Furthermore, we observe microbiome dysbiosis in RET-negative cohort governed by organisms like Leishmania spp., Streptomyces spp., Oscillospiraceae spp., which are known to be pro-tumorigenic. Altogether, this study provides a detailed genomic characterization of medullary thyroid cancer, highlighting the possible utility of targeted therapies in this disease. Furthermore, we report the first evidence of RET oncogene associated microbial dysbiosis, which may open new avenues of research.