Coexisting RET/Papillary Thyroid Cancer (PTC) and TERT Promoter Mutation Predict Poor Prognosis but Effective RET and MEK Targeting in Thyroid Cancer
Authors' 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.
Study context
- Population
- PTC patients with wild-type (WT) BRAF/RAS, complete clinical follow-up and genetic data; 112 women, 47 men, 4 unknown; median age 46.00 (IQR 33.00–61.00) yearsWT BRAF/RAS of 669 pooled
- Participants
- 163 patients
- Exposure
- Coexisting RET/PTC and TERT promoter mutation vs neither mutation
- Neither mutationn = 100reference
- TERT promoter mutation alonen = 18
- RET/PTC alonen = 31
- Bothn = 14
- Outcome
- Mortality
- Follow-up
- Median 16.13 (IQR 8.09-27.91) months
Methodological detailspooled data sets (TCGA-THCA, MSK-MetTropism, MSK-IMPACT), comparative genotype cohort analysis
- Pooled data sets (TCGA-THCA, MSK-MetTropism, MSK-IMPACT)
- Comparative genotype cohort analysis
Main finding
As reported in the abstract
Each group vs neither mutationHazard ratio (95% CI)
TERT promoter mutation alone
2.469(0.405–14.022)
Both
9.019(2.635–30.870)
- RET/PTC alone
- HR 3.296e-09 (95% CI 0-inf)
Observational data: associations, not effects.
Further findings
Concurrence index between RET/PTC and TERT promoter mutations
- Concurrence index
- 2.040 (95% CI, 1.110-3.747; P = .023)
BRAF/RAS and TERT promoter mutations
- Similar results observed with BRAF/RAS and TERT promoter mutations
Mechanism
- RET/PTC used the MAP kinase pathway to upregulate mutated TERT, not WT TERT; targeting RET and MEK suppressed mutated TERT but not WT TERT
Original publication
Coexisting RET/PTC and TERT Promoter Mutation Predict Poor Prognosis but Effective RET and MEK Targeting in Thyroid Cancer. J Clin Endocrinol Metab. Published 13 May 2024. doi:10.
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