Siraj Sarah, Masoodi Tariq, Siraj Abdul K, Azam Saud, Qadri Zeeshan, Parvathareddy Sandeep K, Bu Rong, Siddiqui Khawar S, Al-Sobhi Saif S, AlDawish Mohammed, Al-Kuraya Khawla S
Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia.
Department of Pediatric Hematology-Oncology, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia.
Cancers (Basel). 2022 Mar 21;14(6):1584. doi: 10.3390/cancers14061584.
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.
标准手术联合放射性碘（131I，RAI）治疗对5%-20%的放射性碘难治性乳头状甲状腺癌（PTC）患者无效。目前仍未阐明PTC中提示对RAI治疗有反应的早期预测指标。对66例放射性碘难治性PTC和92例放射性碘亲和性PTC进行全外显子测序（中位深度198x），并与患者匹配的种系进行比对。放射性碘难治性肿瘤与明显侵袭性的临床病理特征显著相关，包括手术切缘阳性（p = 0.016）和初次诊断时存在淋巴结转移（p = 0.012）；更高的非沉默肿瘤突变负荷（p = 0.011）；TERT启动子（TERTp）突变（p < 0.0001）；以及APOBEC相关单碱基替换（SBS）COSMIC突变特征2（p = 0.030）和13（p < 0.001）的富集。值得注意的是，SBS13（优势比[OR] 30.4，95%置信区间[CI] 1.43-647.22）和TERTp突变（OR 41.3，95% CI 4.35-391.60）被发现是PTC中放射性碘难治性的独立预测指标（分别为p = 0.029和0.001）。虽然单独的SBS13和TERTp突变高度预测放射性碘难治性，但联合起来时，它们显著增加了预测PTC中放射性碘难治性的可能性。本研究强调了APOBEC SBS13突变特征是PTC一个独特亚组中放射性碘难治性的新型独立预测指标。
