AUTHOR=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 TITLE=Longitudinal Genomic Evolution of Conventional Papillary Thyroid Cancer With Brain Metastasis JOURNAL=Frontiers in Oncology VOLUME=11 YEAR=2021 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.620924 DOI=10.3389/fonc.2021.620924 ISSN=2234-943X ABSTRACT=Background

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.

Method

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.

Results

Contrasting with lyn1, ipsilateral metastatic lesions (lyn2–4 and BM) with shared biallelic mutations of TSC2 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 (CDK4R24C, TP53R342*) were observed in lyn3/4 and BM. Frequencies of these mutations gradually increase along with the metastasis progression. Consistently, TP53 knockout and CDK4R24C introduction in PTC cells significantly decreased radioiodine uptake and increased metastatic ability.

Conclusion

Genomic mutations in CDK4 and TP53 during the tumor evolution may contribute to the lymph node and brain metastasis of PTC.