Association of common genetic alterations with tumor recurrence in papillary thyroid cancer

BACKGROUND: To comprehensively investigate the relationship between common genetic alterations and tumor recurrence in patients with papillary thyroid cancer (PTC) and evaluate whether integrating genetic status could improve the performance of the 2025 American Thyroid Association (ATA) tumor recurrence risk stratification system (RSS). METHODS: This retrospective study included 2,056 patients (1,414 females and 642 males) with a median age of 39 years [interquartile range (IQR), 31-50 years] and a median follow-up time of 25 months (IQR, 13-35 months) who were treated for PTC at three medical centers in China between 2020 and 2024. RESULTS: Tumor recurrence rates were significantly higher in patients carrying RET fusions alone or genetic alteration combination, but not in patients carrying BRAF V600E alone, RAS mutations alone, or NTRK fusions alone, than that in patients without any genetic alteration, with an HR of 2.64 (95% CI, 1.31-5.32) and 3.37 (95% CI, 1.21-9.35) after adjusted for clinicopathological factors, respectively. RET fusions or genetic alteration combination were significantly associated with increased risk of tumor recurrence in all the ATA RSS categories, with an adjusted HR of 14.02 (95% CI, 3.75-52.48) in patients with ATA RSS low or low-intermediate categories, an HR of 3.01 (95% CI, 1.51-5.99) in the intermediate-high category, and an HR of 3.75 (95% CI, 2.17-6.48) in the high category, respectively. CONCLUSION: RET fusions and genetic alteration combination are independent prognostic markers for tumor recurrence of PTC, integrating tumors' genetic status into the 2025 ATA RSS system improves the accuracy of risk stratification for PTC.