局部晚期或转移性儿童及青少年分化型甲状腺癌的基因特征与临床特征及131I疗效的关系

背景与目的： 儿童及青少年分化型甲状腺癌（differentiated thyroid cancer,DTC）的分子生物学特征及其临床指导意义尚不明确。本研究拟初步探讨局部晚期或转移性DTC患儿的基因特征分布及其与临床特征及¹³¹I疗效的关系。方法： 采用甲状腺癌相关基因panel（ThyroLead^®）对2020年12月—2021年7月就诊于中国医学科学院北京协和医学院北京协和医院的儿童及青少年侵袭性DTC的原发灶进行测序,并回顾性收集患儿的临床病理学特征及¹³¹I治疗相关资料,分析其基因特征与其临床病理学特征及¹³¹I疗效的关系。结果： 本队列纳入39例局部晚期或转移性患儿,可及数据中所有患儿均存在淋巴结转移,侧方区受累率达91.4%（32/35）,远处转移率达61.5%（24/39）。61.5%（24/39）的患儿检出甲状腺癌相关基因变异,其中以RET融合（38.5%,15/39）和BRAF V600E点突变（12.8%,5/39）最为常见。突变组与非突变组的临床特征差异无统计学意义（P>0.05）。远处转移中,91.7%（22/24）的患儿在¹³¹I治疗后仍呈结构性疗效不佳（structural incomplete response,SIR）状态,其中9例患儿呈放射性碘难治（radioactive iodine-refractory,RAIR）状态。RAIR状态患儿中88.9%（8/9）检出相关基因变异,其中NCOA4/RET融合占62.5%（5/8）。进一步将RET变异组患儿细化分组显示,与其他形式的RET融合相比,NCOA4/RET融合阳性者远处转移率更高（33.3% vs 88.9%,P=0.089）,提示其具有更高的远处侵犯倾向。结论： 局部晚期或转移性DTC患儿的基因突变以融合突变尤其是RET融合为主,其中NCOA4/RET融合阳性者似乎显示出更强的侵袭性,更易呈RAIR状态。

The relationship between genetic characteristics and clinical characteristics and the efficacy of 131I therapy in children and adolescents with locally advanced or metastatic differentiated thyroid cancer

Background and purpose: The molecular characteristics of differentiated thyroid cancer (DTC) in children and adolescents and its role in clinical practice remain unclear. This study intended to explore the genetic characteristics and its relationship with clinical characteristics and efficacy of ¹³¹I therapy in locally advanced or metastatic pediatric and adolescent DTC patients. Methods: A thyroid cancer-related gene panel (ThyroLead®) was used to test the primary tumors from children and adolescents with DTC treated in Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from December 2020 to July 2021. The samples were sequenced, the clinicopathological characteristics and ¹³¹I treatment history were retrospectively collected, and the relationship between their genetic characteristics and clinicopathological characteristics and the efficacy of ¹³¹I therapy was analyzed. Results: All the 39 children present locally advanced or metastatic disease. All the children with accessible data had lymph node metastasis, 91.4% (32/35) of whom had lateral lymph node metastasis, and 61.5% (24/39) patients had distant metastasis. Thyroid cancer-related gene variants were detected in 61.5% (24/39) of the patients, among which RET fusion (38.5%, 15/39) and BRAF V600E point mutation (12.8%, 5/39) were the most common. No statistically significant differences were found in clinical characteristics between the mutation group and the non-mutation group (P>0.05). Most of the children (91.7%, 22/24) with distant metastases remained structural incomplete response (SIR) status after ¹³¹I treatment. Nine patients were considered radioactive iodine-refractory (RAIR) status, and 8 of them had thyroid cancer driver mutations, among which NCOA4/RET accounted for 62.5% (5/8). Among cases with RET genetic variations, NCOA4/RET fusion-positive patients tended to present more distant metastasis than those with other forms of RET fusion (33.3% vs 88.9%, P=0.089). Conclusion: Compared with point mutations, fusion gene mutations, especially RET fusions, are more common in locally advanced or metastatic pediatric and adolescent DTC patients. NCOA4/RET fusion-positive tumor has more aggressive behaviors and are more likely to become RAIR.