Int J Med Sci 2021; 18(12):2532-2544. doi:10.7150/ijms.50916

Research Paper

Somatic Mutation Profiling of Papillary Thyroid Carcinomas by Whole-exome Sequencing and Its Relationship with Clinical Characteristics

Tingyue Qi1,2*, Xin Rong1*, Qingling Feng2, Hongguang Sun1, Haiyan Cao1, Yan Yang1, Hao Feng1, Linhai Zhu3, Lei Wang4, Qiu Du5,6✉

1. Department of Ultrasound, Medical Imaging Center, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China.
2. Department of Critical Care Medicine, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China.
3. Department of Thyroid and Breast Surgery, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China.
4. Department of Pathology, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China.
5. Department of Neurosurgery, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China.
6. Central Laboratory, the Affiliated Hospital of Yangzhou University, Yangzhou 225012, Yangzhou University, China.
* These authors contributed equally to this work.

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Citation:
Qi T, Rong X, Feng Q, Sun H, Cao H, Yang Y, Feng H, Zhu L, Wang L, Du Q. Somatic Mutation Profiling of Papillary Thyroid Carcinomas by Whole-exome Sequencing and Its Relationship with Clinical Characteristics. Int J Med Sci 2021; 18(12):2532-2544. doi:10.7150/ijms.50916. Available from https://www.medsci.org/v18p2532.htm

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Abstract

The incidence of papillary thyroid carcinomas (PTCs) has increased rapidly during the past several decades. Until now, the mechanisms underlying the tumorigenesis of PTCs have remained largely unknown. Next-generation-sequencing (NGS) provides new ways to investigate the molecular pathogenesis of PTCs. To characterize the somatic alterations associated with PTCs, we performed whole-exome sequencing (WES) of PTCs from 23 Chinese patients. This study revealed somatic mutations in genes with relevant functions for tumorigenesis, such as BRAF, BCR, CREB3L2, DNMT1, IRS2, MSH6, and TP53. We also identified novel somatic gene alterations which may be potentially involved in PTC progression. Gene set enrichment analysis revealed that the cellular response to hormone stimulus, epigenetic modifications, such as protein/histone methylation and protein alkylation, as well as MAPK, PI3K-AKT, and FoxO/mTOR signaling pathways, were significantly altered in the PTCs studied here. Moreover, Protein-Protein Interaction (PPI) network analysis of our mutated gene selection highlighted EP300, KRAS, PTEN, and TP53 as major core genes. The correlation between gene mutations and clinicopathologic features of the PTCs defined by conventional ultrasonography (US) and contrast-enhanced ultrasonography (CEUS) were assessed. These analyses established significant associations between subgroups of mutations and respectively taller-than-wide, calcified, and peak time iso- or hypo-enhanced and metastatic PTCs. In conclusion, our study supplements the genomic landscape of PTCs and identifies new actionable target candidates and clinicopathology-associated mutations. Extension of this study to larger cohorts will help define comprehensive genomic aberrations in PTCs and validate target candidates. These new targets may open methods of individualized treatments adapted to the clinicopathologic specifics of the patients.

Keywords: Papillary thyroid carcinomas, Whole-exome sequencing, Genetic mutations, Cluster analysis, Ultrasonography.