Background: Lymph node metastasis is the most common metastasis associated with papillary thyroid carcinoma (PTC). There are few data on gene mutations associated with lymph node metastasis from PTC. At present, the mechanism underlying lymph node metastasis of PTC is still poorly understood.Methods: Whole exome sequencing (WES) was performed for PTC of 10 primary tumor tissues and 10 lymph node metastasis tissues (non-match) for gene mutations. Gene ontology (GO) analysis was used to study biological functions and processes related to lymph node metastasis. Sanger sequencing was used to verify these genes in the lymph node metastasis group.Results: A total of 2772 gene mutations were identified in the primary tumor group. A total of 3033 gene mutations were enriched in the lymph node metastasis group. There were 50 gene mutations that were found to be present at higher frequency in the lymph node metastasis group than in the primary tumor group. Among 50 gene mutations, nonsynonymous mutations of 5 genes (LPP, MSLN, MAEA, VCAN, and MUC16) involved in cell adhesion were present. Three nonsynonymous mutations were also found in RP1L1, QSER1, and TLR4. These high-frequency genetic mutations that showed significant enrichment were targeted sequencing and validated by Sanger sequencing.Conclusion: Thyroid cancer and corresponding metastatic lymph nodes contain a large number of SNPs and 50 SNP genes associated with lymph node metastasis. Genes related to cell adhesion (LPP, MSLN, MAEA, VCAN, and MUC16) may play an important role in the process of lymph node metastasis. The contribution of BRAF in lymph node metastasis may not be high.