Genomic and Transcriptomic Characteristics of Metastatic Thyroid Cancers with Exceptional Responses to Radioactive Iodine Therapy

Purpose: The determinants of response or resistance to radio-iodine (RAI) are unknown. We aimed to identify genomic and transcriptomic factors associated with structural responses to RAI treatment of metastatic thyroid cancer, which occur infrequently, and to test whether high MAPK pathway output was associated with RAI refractoriness.Experimental Design: Exceptional response to RAI was deflned as reduction of tumor volume based on RECIST v1.1. We performed a retrospective case-control study of genomic and transcriptomic characteristics of exceptional responders (ER; n = 8) versus non-responders (NR; n = 16) matched by histologic type and stage at presentation on a 1:2 ratio.Results: ER are enriched for mutations that activate MAPK through RAF dimerization (RAS, class 2 BRAF, RTK fusions),whereas NR are associated with BRAFV600E, which signals as a monomer and is unresponsive to negative feedback. ER have a lower MAPK transcriptional output and a higher thyroid differentiation score (TDS) than NR (P < 0.05). NR are enriched for 1q-gain (P < 0.05) and mutations of genes regulating mRNA splicing and the PI3K pathway. BRAFV600E tumors with 1q-gain have a lower TDS than BRAFV600E/1q-quiet tumors and transcriptomic signatures associated with metastatic propensity. Conclusions: ER tumors have a lower MAPK output and higher TDS than NR, whereas NR have a high frequency of BRAFV600E and 1q-gain. Molecular proflling of thyroid cancers and further func-tional validation of the key flndings discriminating ER from NR may help predict response to RAI therapy.