APOBEC SBS13 Mutational Signature-A Novel Predictor of Radioactive Iodine Refractory Papillary Thyroid Carcinoma.

Standard surgery followed by radioactive iodine ( 131 I, RAI) therapy are not curative for 5-20% of papillary thyroid carcinoma (PTC) patients with RAI refractory disease. Early predictors indicating therapeutic response to RAI therapy in PTC are yet to be elucidated. Whole-exome sequencing was performed (at median depth 198x) on 66 RAI-refractory and 92 RAI-avid PTCs with patient-matched germline. RAI-refractory tumors were significantly associated with distinct aggressive clinicopathological features, including positive surgical margins ( p = 0.016) and the presence of lymph node metastases at primary diagnosis ( p = 0.012); higher nonsilent tumor mutation burden ( p = 0.011); TERT promoter ( TERT p) mutation ( p < 0.0001); and the enrichment of the APOBEC-related single-base substitution (SBS) COSMIC mutational signatures 2 ( p = 0.030) and 13 ( p < 0.001). Notably, SBS13 (odds ratio [OR] 30.4, 95% confidence intervals [CI] 1.43-647.22) and TERT p mutation (OR 41.3, 95% CI 4.35-391.60) were revealed to be independent predictors of RAI refractoriness in PTC ( p = 0.029 and 0.001, respectively). Although SBS13 and TERT p mutations alone highly predicted RAI refractoriness, when combined, they significantly increased the likelihood of predicting RAI refractoriness in PTC. This study highlights the APOBEC SBS13 mutational signature as a novel independent predictor of RAI refractoriness in a distinct subgroup of PTC.