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

Cancers

Mohammed AlDawish¹  Khawar S. Siddiqui²  Saif S. Al-Sobhi³  Sarah Siraj⁴  Saud Azam⁴  Sandeep K. Parvathareddy⁴  Khawla S. Al-Kuraya⁴  Rong Bu⁴  Abdul K. Siraj⁴  Tariq Masoodi⁴  Zeeshan Qadri⁴ 

[1] Department of Endocrinology and Diabetes, Prince Sultan Military Medical City, P.O. Box 261370, Riyadh 11342, Saudi Arabia;Department of Pediatric Hematology-Oncology, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia;Department of Surgery, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia;Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia;

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

DOI  :  10.3390/cancers14061584

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown