BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer.

CONTEXT: Use of BRAF mutation in papillary thyroid cancer (PTC) has the potential to improve risk stratification of this cancer. OBJECTIVE: The objective of the study was to investigate the prognostic value of BRAF mutation in patients with PTC. DESIGN, SETTING, AND SUBJECTS: In a multicenter study of 219 PTC patients, data on their clinicopathological characteristics and clinical courses between 1990 and 2004 were retrospectively collected, and their tumor BRAF mutation status was determined. Associations of BRAF mutation with initial tumor characteristics and subsequent recurrence were analyzed. MAIN OUTCOME MEASURE: Relationships between the BRAF mutation status and clinicopathological outcomes, including recurrence, were measured. RESULTS: We found a significant association between BRAF mutation and extrathyroidal invasion (P < 0.001), lymph node metastasis (P < 0.001), and advanced tumor stage III/IV (P = 0.007) at initial surgery. This association remained significant on multivariate analysis, adjusting for conventional clinicopathological predictors of recurrence excluding the histological PTC subtype, but was lost when the tumor subtype was included in the model. BRAF mutation was also significantly associated with tumor recurrence, 25 vs. 9% with and without mutation, respectively (P = 0.004), during a median of 15 (interquartile range, 3-29) months of follow-up. This association remained significant on multivariate analysis adjusting for conventional clinicopathological predictors of recurrence, even including the PTC subtype (odds ratio, 4.0; 95% confidence interval, 1.1-14.1; P = 0.03). BRAF mutation was even an independent predictor of recurrence in patients with stage I/II disease, 22 vs. 5% with and without BRAF mutation, respectively (P = 0.002). BRAF mutation was also more frequently associated with absence of tumor I-131 avidity and treatment failure of recurrent disease. CONCLUSIONS: In patients with PTC, BRAF mutation is associated with poorer clinicopathological outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.

High prevalence and possible de novo formation of BRAF mutation in metastasized papillary thyroid cancer in lymph nodes.

CONTEXT: The role of the T1799A BRAF mutation in lymph node metastasis of papillary thyroid cancer (PTC) is not clear. OBJECTIVE: Our objective was to explore the relationship between BRAF mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. DESIGN: We isolated genomic DNA from primary thyroid tumors and paired lymph node metastases and performed direct sequencing of exon 15 of the BRAF gene mutation that carries the T1799A mutation. RESULTS: In a series of 33 cases, 21 harbored the T1799A mutation in the primary tumors, and 17 (81%) of them harbored the same mutation also in the paired lymph node metastases. Twelve cases did not harbor the T1799A mutation in the primary tumors, among which nine cases also did not harbor BRAF mutation in the lymph node-metastasized tumors, whereas the other three did harbor the T1799A mutation in lymph node-metastasized tumor tissues. A novel tandem TG1799-1800AA mutation within one allele was found in a lymph node-metastasized tumor but not in the primary tumor. This mutation results in the change of codon 600 (GTG) of the gene to GAA with the consequent amino acid change (V600E) in the B-type Raf (BRAF) protein, same as that caused by the T1799A mutation alone. CONCLUSION: The high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.