Endocrinol Metab.  2021 Oct;36(5):1086-1094. 10.3803/EnM.2021.1132.

Whole-Exome Sequencing in Papillary Microcarcinoma: Potential Early Biomarkers of Lateral Lymph Node Metastasis

• Kim M
• Kwon CH
• Jang MH
• Kim JM
• Kim EH
• Jeon YK
• Kim SS
• Choi KU
• Kim IJ
• Park M
• Kim BH

• KMID: 2521956
• DOI: http://doi.org/10.3803/EnM.2021.1132

Abstract

Background
Early identification of patients with high-risk papillary thyroid microcarcinoma (PTMC) that is likely to progress has become a critical challenge. We aimed to identify somatic mutations associated with lateral neck lymph node (LN) metastasis (N1b) in patients with PTMC.
Methods
Whole-exome sequencing (WES) of 14 PTMCs with no LN metastasis (N0) and 13 N1b PTMCs was performed using primary tumors and matched normal thyroid tissues.
Results
The mutational burden was comparable in N0 and N1b tumors, as the median number of mutations was 23 (range, 12 to 46) in N0 and 24 (range, 12 to 50) in N1b PTMC (P=0.918). The most frequent mutations were detected in PGS1, SLC4A8, DAAM2, and HELZ in N1b PTMCs alone, and the K158Q mutation in PGS1 (four patients, Fisher’s exact test P=0.041) was significantly enriched in N1b PTMCs. Based on pathway analysis, somatic mutations belonging to the receptor tyrosine kinase-RAS and NOTCH pathways were most frequently affected in N1b PTMCs. We identified four mutations that are predicted to be pathogenic in four genes based on Clinvar and Combined Annotation-Dependent Depletion score: BRAF, USH2A, CFTR, and PHIP. A missense mutation in CFTR and a nonsense mutation in PHIP were detected in N1b PTMCs only, although in one case each. BRAF mutation was detected in both N0 and N1b PTMCs.
Conclusion
This first comprehensive WES analysis of the mutational landscape of N0 and N1b PTMCs identified pathogenic genes that affect biological functions associated with the aggressive phenotype of PTMC.

Keyword

Biomarkers; Mutation; Neoplasm metastasis; Papillary thyroid microcarcinoma; Whole exome sequencing

Figure

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  Fig. 1. OncoPrint representation of DNA profiles obtained by whole-exome sequencing. The top 20 genomic alterations in N0 and N1b papillary thyroid carcinomas (PTCs) concerning matched non-tumoral thyroid tissue are shown. Data from (A) 27 micro-PTCs in our study cohort and (B) 291 PTCs in the The Cancer Genome Atlas (TCGA) database is shown. The color of the grid map indicates the type of alterations. LN, lymph node.

• 

  Fig. 2. Oncogenic pathway identification. (A) Pathway alteration frequencies in total, N0, and N1b papillary thyroid microcarcinomas (PTMCs). (B) Mutations in genes that affect the receptor tyrosine kinase (RTK)-RAS signaling pathway. LN, lymph node.

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