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

Abstract

Standard surgery followed by radioactive iodine (131I, 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 (TERTp) 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 TERTp 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 TERTp 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.

Keywords: APOBEC-related mutations; COSMIC mutational signatures; SBS13; papillary thyroid cancer; radioactive iodine refractory.

Figure 1

Box plots showing (A) the absolute number of alterations, including mutations (tumor mutation burden; TMB) and copy number variations (CNV) in RAI-refractory and avid PTC tumors, and (B) the number of mutations contributing to selected single-base substitution (S; SBS) mutational signatures, with Benjamini–Hochberg-adjusted p-values (Mann–Whitney Test; alpha level 0.05). For each SBS mutational signature, only tumors with ≥1 mutation contributing to the SBS mutational signature were included for box plot representation. S1 represents age-related mutations; S2 and S13 represent APOBEC-related mutagenesis; S6, S15, S20, S21 and S26 represent defective DNA mismatch-repair (MMR) mutations; S3 represents defective homologous recombination-related DNA repair (HR); S30 represents defective base-nucleotide excision repair (BER); S4 represents tobacco smoking; S7 represents ultraviolet (UV) exposure; S24 represents aflatoxin exposure; S29 represents chewing tobacco; and S5, S8, S12, S16, S19 and S23 are of unknown etiology.

Figure 2

(A) Overview of absolute number of mutations contributing to each mutational signature per sample. (B) Distribution of each mutational signature per sample. Patients are ordered by hierarchical clustering. An alpha level of 0.05 was used for statistical significance. S1 represents age-related mutations; S2 and S13 represent APOBEC-related mutagenesis; S6, S15, S20, S21 and S26 represent defective DNA mismatch-repair (MMR) mutations; S3 represents defective homologous recombination-related DNA repair (HR); S30 represents defective base-nucleotide excision repair (BER); S4 represents tobacco smoking; S7 represents ultraviolet (UV) exposure; S24 represents aflatoxin exposure; S29 represents chewing tobacco; and S5, S8, S12, S16, S19 and S23 are of unknown etiology.

Figure 3

Multivariable logistic regression model (when adjusting for age, tumor size and tumor purity as continuous variables), using mutational signatures, BRAF^V600E mutation, TERT promoter mutation and TMB to predict RAI refractoriness in PTC. An alpha level of 0.05 was used for statistical significance. S1 represents age-related mutations; S2 and S13 represent APOBEC-related mutagenesis; S6, S15, S20, S21 and S26 represent defective DNA mismatch-repair (MMR) mutations; S3 represents defective homologous recombination-related DNA repair (HR); S30 represents defective base-nucleotide excision repair (BER); S4 represents tobacco smoking; S7 represents ultraviolet (UV) exposure; S24 represents aflatoxin exposure; S29 represents chewing tobacco; and S5, S8, S12, S16, S19 and S23 are of unknown etiology.