Longitudinal Genomic Evolution of Conventional Papillary Thyroid Cancer With Brain Metastasis

Han Luo; Xue Liao; Yun Qin; Qianqian Hou; Zhinan Xue; Yang Liu; Feiyang Shen; Yuelan Wang; Yong Jiang; Linlin Song; Haining Chen; Lingyun Zhang; Tao Wei; Lunzhi Dai; Li Yang; Wei Zhang; Zhihui Li; Heng Xu; Jingqiang Zhu; Yang Shu

doi:10.3389/fonc.2021.620924

Longitudinal Genomic Evolution of Conventional Papillary Thyroid Cancer With Brain Metastasis

Front Oncol. 2021 Jun 23:11:620924. doi: 10.3389/fonc.2021.620924. eCollection 2021.

Authors

Han Luo¹, Xue Liao², Yun Qin³, Qianqian Hou², Zhinan Xue², Yang Liu^{1

4}, Feiyang Shen⁴, Yuelan Wang², Yong Jiang⁵, Linlin Song^{1

4}, Haining Chen⁶, Lingyun Zhang^{1

4}, Tao Wei¹, Lunzhi Dai², Li Yang², Wei Zhang⁷, Zhihui Li¹, Heng Xu^{2

8}, Jingqiang Zhu¹, Yang Shu^{2

6}

Affiliations

¹ Department of Thyroid and Parathyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
² State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
³ Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.
⁴ West China School of Medicine, Sichuan University, Chengdu, China.
⁵ Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.
⁶ Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
⁷ Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha, China.
⁸ Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

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 (CDK4 ^R24C , TP53^R342*) were observed in lyn3/4 and BM. Frequencies of these mutations gradually increase along with the metastasis progression. Consistently, TP53 knockout and CDK4 ^R24C 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.

Keywords: CDK4; brain metastasis; cancer evolution; genetics; thyroid cancer.