Coexisting RET/PTC and TERT Promoter Mutation Predict Poor Prognosis but Effective RET and MEK Targeting in Thyroid Cancer

Context The role of RET/PTC rearrangement in the clinical outcomes of papillary thyroid cancer (PTC) is controversial and remains to be clearly undefined.Objective This work aimed to investigate the role of coexisting RET/PTC rearrangement and TERT promoter mutation in the prognosis and therapeutic targeting in PTC.Methods A total of 669 PTC patients with complete clinical follow-up and genetic data were pooled from thyroid cancer data sets TCGA-THCA, MSK-MetTropism, and MSK-IMPACT, from whom 163 patients (112 women and 47 men, 4 unknown) with wild-type (WT) BRAF/RAS were identified, with a median age (interquartile range [IQR]) of 46.00 (33.00-61.00) years and a median follow-up time (IQR) of 16.13 (8.09-27.91) months for comparative genotype cohort analysis of mortality.Results There was a significant concurrence index between RET/PTC and TERT promoter mutations, being 2.040 (95% CI, 1.110-3.747; P = .023). Mortality occurred in 5 of 100 (5%) patients harboring neither mutation, 2 of 18 (11.1%) patients harboring a TERT promoter mutation alone, 0 of 31 (0%) patients harboring a RET/PTC alone, and 7 of 14 (50%) patients harboring both genetic alterations, corresponding to hazard ratios (95% CI) of 1 (reference), 2.469 (0.405-14.022), 3.296e-09 (0-inf), and 9.019 (2.635-30.870), respectively, which remained essentially unchanged after adjustment for patient race, sex, and age. Similar results were observed with BRAF/RAS and TERT promoter mutations. Mechanistically, RET/PTC used the MAP kinase pathway to upregulate the mutated TERT, but not the WT TERT, and, correspondingly, targeting RET and MEK could suppress mutated TERT but not the WT TERT.Conclusion Coexisting RET/PTC and TERT promoter mutation identify PTC as a unique clinical entity with high mortality, providing new implications for genetic-based prognostication and potential therapeutic targeting of RET and MEK guided by RET/PTC and TERT status.