Luo Han, Liao Xue, Qin Yun, Hou Qianqian, Xue Zhinan, Liu Yang, Shen Feiyang, Wang Yuelan, Jiang Yong, Song Linlin, Chen Haining, Zhang Lingyun, Wei Tao, Dai Lunzhi, Yang Li, Zhang Wei, Li Zhihui, Xu Heng, Zhu Jingqiang, Shu Yang
Department of Thyroid and Parathyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Front Oncol. 2021 Jun 23;11:620924. doi: 10.3389/fonc.2021.620924. eCollection 2021.
Brain metastasis is extremely rare but predicts dismal prognosis in papillary thyroid cancer (PTC). Dynamic evaluation of stepwise metastatic lesions was barely conducted to identify the longitudinal genomic evolution of brain metastasis in PTC.
Chronologically resected specimen was analyzed by whole exome sequencing, including four metastatic lymph nodes (lyn 1-4) and brain metastasis lesion (BM). Phylogenetic tree was reconstructed to infer the metastatic pattern and the potential functional mutations.
Contrasting with lyn1, ipsilateral metastatic lesions (lyn2-4 and BM) with shared biallelic mutations of indicated different genetic originations from multifocal tumors. Lyn 3/4, particularly lyn4 exhibited high genetic similarity with BM. Besides the similar mutational compositions and signatures, shared functional mutations (CDK4 , TP53) were observed in lyn3/4 and BM. Frequencies of these mutations gradually increase along with the metastasis progression. Consistently, knockout and CDK4 introduction in PTC cells significantly decreased radioiodine uptake and increased metastatic ability.
Genomic mutations in and during the tumor evolution may contribute to the lymph node and brain metastasis of PTC.
脑转移在甲状腺乳头状癌（PTC）中极为罕见，但预示着预后不良。几乎未对逐步转移病灶进行动态评估以确定PTC脑转移的纵向基因组进化。
通过全外显子组测序分析按时间顺序切除的标本，包括四个转移淋巴结（lyn 1-4）和脑转移病灶（BM）。重建系统发育树以推断转移模式和潜在的功能突变。
与lyn1相比，具有共享双等位基因突变的同侧转移病灶（lyn2-4和BM）表明其起源于多灶性肿瘤的不同遗传来源。Lyn 3/4，特别是lyn4与BM表现出高度的遗传相似性。除了相似的突变组成和特征外，在lyn3/4和BM中还观察到共享的功能突变（CDK4 ，TP53）。这些突变的频率随着转移进展而逐渐增加。一致地，在PTC细胞中敲除 和引入CDK 的显著降低了放射性碘摄取并增加了转移能力。
肿瘤进化过程中 和 的基因组突变可能促成PTC的淋巴结转移和脑转移。
