Genomic and Transcriptomic Characterization of Sporadic Medullary Thyroid Carcinoma
| Autor: | Shenglin Huang, Haixia Guan, Xiao Shi, Yu-Long Wang, Jia-Qian Hu, Ning Qu, Ting-Ting Zhang, Qinghai Ji, Yu Wang, Wei-Yan Liu, Jingjing Zhao, Tian Liao, Shishuai Wen, Rong-Liang Shi |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Adolescent Somatic cell Endocrinology Diabetes and Metabolism Thyroid Gland 030209 endocrinology & metabolism Biology medicine.disease_cause Germline Transcriptome 03 medical and health sciences 0302 clinical medicine Endocrinology Exome Sequencing medicine Humans Gene family Thyroid Neoplasms Gene Aged Proto-Oncogene Proteins c-ret Middle Aged Cell cycle Carcinoma Medullary 030220 oncology & carcinogenesis Mutation Cancer research Female Carcinogenesis FAT1 |
| Zdroj: | Thyroid. 30:1025-1036 |
| ISSN: | 1557-9077 1050-7256 |
| DOI: | 10.1089/thy.2019.0531 |
| Popis: | Background: Sporadic medullary thyroid carcinoma (MTC) is a relatively uncommon neuroendocrine malignancy and the molecular tumorigenesis of its sporadic type (sMTC) is only partially understood. In this study, 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, including 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. A Cell Counting Kit-8 (CCK-8) assay was used to evaluate cell proliferation. Results: Among the somatic mutations, RET was the only recurrently cancer-related mutated gene (5/18, 27.8%). In the germline, FAT1 and FAT4, two members of the FAT gene family, were identified as the two most common mutated genes. CNA analysis found that FAT1 and FAT4, both located on chromosome 4q, were also two of the genes most commonly affected by somatic chromosomal deletions (4/18, 22.2%). Using TT and MZ-CRC-1 cell lines, the CCK-8 assay showed that FAT1 and FAT4 knockdown could promote MTC cell proliferation. Based on the gene expression profile, patients were clustered into two molecular subtypes: the mesenchymal-like subtype is characterized by epithelial-mesenchymal transition, while the proliferative-like subtype is associated with enrichment of cell cycle pathways. Most events of structural recurrence (80%) occurred in the proliferative-like subtype. Conclusion: In addition to RET, these findings demonstrate that FAT1/FAT4 genomic alterations appear to be frequent in sMTC. Two molecular subtypes of sMTC with distinct biological behavior could be identified. However, these 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. |
| Databáze: | OpenAIRE |
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