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Genomic and Transcriptomic Characterization of Sporadic Medullary Thyroid Carcinoma.

Background: Sporadic medullary thyroid carcinoma (MTC) is a relatively uncommon neuroendocrine malignancy, and the molecular tumorigenesis of its sporadic type (sMTC) is not clear enough. Here we performed a study focusing on the genomic and transcriptomic characterization of sMTC. Methods: Twenty-nine sMTC patients were included. Whole-exome sequencing (WES) was carried out in 18 patients with both tumor samples and matched noncancerous tissues. Whole transcriptome sequencing (RNA-Seq) was performed in all 29 tumors. WES, RNA-Seq and copy number alteration (CNA) data were analyzed. Cell Counting Kit-8 (CCK-8) assay was used to evaluate cell proliferation. Results: In the somatic setting, RET was the only recurrently cancer-related mutated gene (5/18, 27.8%). In the germline setting, FAT1 and FAT4, two members of the FAT gene family, were identified as the two most common mutated genes. Meanwhile, CNA analysis found that FAT1 and FAT4, both located at chromosome 4q, were also two of the most commonly affected genes by somatic chromosomal deletions (4/18, 22.2%). Using TT and MZ-CRC-1 cell lines, CCK-8 assay showed that FAT1 and FAT4 knockdown could both promote MTC cell proliferation. Based on the gene expression profile, patients were clustered into two molecular subtypes: the mesenchymal-like subtype was characterized by epithelial-mesenchymal transition, while the proliferative-like subtype was associated with enrichment of cell cycle pathways. Most events of structural recurrence (80%) occurred in the proliferative-like subtype. Conclusion: In addition to RET, our research also shows there may be high-frequency FAT1/FAT4 genomic alterations in sMTC. Two molecular subtypes of sMTC with distinct biological behaviors are also identified. However, our results need to be validated by larger samples and more comprehensive experiments in the future, especially for the frequency and function of FAT1/FAT4 germline variants.