BRAF ^V600E Co-mutations predict aggressive clinicopathological features in Chinese patients with differentiated...

The BRAF ^V600E mutation is a common driver variant in differentiated thyroid carcinoma (DTC); however, the clinical significance of its co-mutation patterns in the Chinese population remains unclear. This study aimed to analyze the predictive value of BRAF ^V600E co-mutations for aggressive clinicopathological features in DTC by detecting a 10-gene panel, providing molecular evidence for refined risk stratification.

A multicenter cohort of 240 DTC patients from two medical centers was retrospectively enrolled. A 10-gene panel (BRAF V600E, TERT, NRAS, HRAS, KRAS, PIK3CA, RET, PPARG, NTRK1, NTRK3) was assessed using Polymerase Chain Reaction (PCR) for mutations and fusion events. Based on mutation status, patients were categorized into three groups: BRAF V600E-mutation alone, BRAF V600E co-mutation, and non-BRAF ^V600E mutation groups. Immunohistochemistry (IHC) was performed to evaluate P53 and Ki-67 expression. Clinicopathological characteristics were compared using chi-square, Fisher's exact, or Kruskal-Wallis tests as appropriate. Log-rank test assessed differences in recurrence-free survival (RFS), while binary/ordinal logistic regression analyzed the predictive role of BRAF ^V600E co-mutations for aggressiveness (capsular invasion, ATA risk stratification, lymph node metastasis, and recurrence).

The BRAF ^V600E co-mutation group (n = 21) exhibited significantly higher rates of capsular invasion (52.4 %vs. 13.2 % and 23.1 %, *p*<0.01) and ATA high-risk classification (57.1 %vs. 25.7 % and 28.8 %, *p*<0.05) compared to the BRAF^V600E -mutation alone group (n = 167) and non-BRAF^V600E mutation group (n = 52). Tumor stage distribution (AJCC 8th edition) also differed significantly among the three groups, with the co-mutation group showing the highest proportion of advanced T stage (T3-T4) (*p*<0.05). TERT was the most frequently co-mutated gene. Logistic regression revealed that the BRAF^V600E co-mutation group had significantly increased risks of capsular invasion (OR = 3.667, 95 % CI: 1.325-10.713) and ATA high-risk status (OR=2.881, 95 % CI: 1.217-6.839). Although P53/Ki-67 expression did not differ significantly among groups (*p* > 0.05), the co-mutation group showed a trend toward higher proportions of cases with Ki-67 ≥ 10 % (9.5 %vs. 7.2 % and 5.7 %, *p*=0.09).

These results suggest that BRAF^V600E co-mutations are associated with more aggressive DTC features in a Chinese patient cohort. The 10-gene panel used in this analysis may offer potential as a tool for identifying subsets of patients with adverse pathology, such that it warrants further investigation as a tool for refined risk stratification. However, prospective studies are needed to confirm its clinical utility and clarify its potential for optimized patient management..