Background: Although most differentiated thyroid carcinomas (DTCs) have indolent behavior, DTCs with distant metastasis have a poor prognosis. However, there are no validated markers that predict the risk of distant metastasis and the prognosis of DTC. We aimed to develop a genetic classifier for predicting the outcomes of DTC patients with distant metastases. Methods: Targeted deep sequencing of 157 cancer-related genes was performed for 61 DTCs with distant metastases. A candidate mutation was validated with independent thyroid cancer samples using digital polymerase chain reaction. Results: The most frequently mutated gene in the 61 DTCs was BRAF (n = 31, 51%), followed by TERT promoter (n = 28, 46%), NRAS (n = 13, 11%), PLEKHS1 promoter (n = 6, 10%), and STK11 (n = 6, 10%) mutations. PLEKHS1 promoter mutations were more common in the radioactive iodine (RAI)-refractory cases (p = 0.003). Losses of 9q and 11q were associated with RAI-refractory disease (p = 0.002) and cancer-specific mortality (p = 0.028), respectively. In multivariate analysis, bone metastasis (adjusted odds ratio [aOR] = 15.17, 95% confidence interval [CI 3.38-68.06], p < 0.001) and at least one mutation in the TERT promoter, the PLEKHS1 promoter, or TP53 (aOR = 7.64 [CI 1.78-32.76], p = 0.006) remained significant factors associated with RAI-refractoriness. In independently collected papillary thyroid carcinomas without initial distant metastasis (n = 75), a PLEKHS1 promoter mutation was only found in one case that developed distant metastasis during the follow-up period. We developed a genetic classifier consisting of BRAF, RAS, the TERT promoter, the PLEKHS1 promoter, and TP53 for categorizing the prognosis of patients with DTC with distant metastasis. In the poor-prognosis group, 61% of the patients were RAI-refractory and death occurred in 21% during the follow-up. In the intermediate-prognosis group, 29% were RAI-refractory, but no death occurred. In the good-prognosis group, all patients were RAI-responsive and no death occurred. Conclusions: Mutations in the PLEKHS1 promoter are a novel genetic marker of aggressive DTC. Our genetic classifier can be useful for predicting RAI-refractory disease and poor prognosis in DTC patients with distant metastases.
Keywords: PLEKSH1; TERT; copy number alteration; differentiated thyroid cancer; metastasis; somatic mutation.