Clinicopathological and molecular characteristics of papillary thyroid carcinoma with BRAF V600E and TERT promoter co-mutations.

Background: BRAF V600E and TERT promoter co-mutations are common in thyroid cancer and linked to poor prognosis. We aimed to study their relationship with PTC clinicopathological features and predict affected molecular pathways.

Methods: Customized mutation detection panels were designed according to PTC's unique mutational landscape. Multiplex PCR and gene sequencing were used to detect gene mutations in 73 tumor samples. Gene mutations were determined through bioinformatics analysis and their correlations with clinicopathological characteristics were evaluated. Thyroid cancer data from TCGA were retrieved, normalized in R Studio, and analyzed for clinical correlations, differential genes, and weighted gene co-expression network analysis (WGCNA). Genes from differential gene expression (P < 0.05 and |logFoldChange| > 1) and WGCNA (4 as soft threshold (power)) intersection were analyzed by gene ontology and KEGG pathway enrichment to find related molecular pathways.

Results: BRAF V600E and TERT C228T co-mutations were found in 10.96 % of PTC patients. Co-mutated patients had an older onset age, higher MACIS scores, larger tumors, and greater radioactive iodine therapy resistance. TCGA data analysis showed they were older at onset, more likely to have lymph node metastasis, advanced stages, higher MACIS scores, and lower differentiation scores. Survival analysis indicated poorer overall and progression-free survival compared to single-mutated or non-mutated patients. Transcriptomic analysis identified 324 overlapping differentially expressed genes in co-mutated PTC, mainly involved in thyroid hormone synthesis, with 10 related genes' expression significantly downregulated.

Conclusions: Our findings suggested BRAF V600E and TERT promoter co-mutations in thyroid cancer contributed to disease progression and poor prognosis via modulating specific molecular pathways. The expression of genes related to thyroid hormone synthesis in co-mutated PTC was significantly downregulated, which may cause iodine therapy resistance by down-regulating iodide transporters (SLC5A5, SLC26A4 and LRP2) and biosynthesis (TPO, DUOX2 and DUOXA2).