Longitudinal Genomic Evolution of Conventional Papillary Thyroid Cancer With Brain Metastasis

Han Luo,Feiyang Shen,Wei Zhang,Li Yang,Jingqiang Zhu,Haining Chen,Zhinan Xue,Yang Shu,Yong Jiang,Tao Wei,Zhihui Li,Yuelan Wang,Yun Qin,Yang Liu,Lingyun Zhang,Lunzhi Dai,Huan Xu ,Song Liu ,Qing Hou ,Xueyang Liao

doi:10.3389/fonc.2021.620924

Abstract

BackgroundBrain 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.MethodChronologically 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.ResultsContrasting 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.ConclusionGenomic mutations in CDK4 and TP53 during the tumor evolution may contribute to the lymph node and brain metastasis of PTC.

Highlights

Papillary thyroid cancer (PTC) comprises approximately 85% of thyroid cancer, which is the most common endocrine malignancy [1]
Genomic mutations in CDK4 and TP53 during the tumor evolution may contribute to the lymph node and brain metastasis of PTC
To comprehensively analyze the lineage relationship between lymph node metastasis and Brain metastasis (BM), we retrospectively reviewed the clinical records of all thyroid cancer patients (n = 12,458) between 2000 and 2018

Summary

Introduction

Papillary thyroid cancer (PTC) comprises approximately 85% of thyroid cancer, which is the most common endocrine malignancy [1]. Trio samples (normal, primary tumor, and distant metastasis samples) from 14 patients were sequenced to identify shared and metastatic-specific genomic mutations [13] In another hand, PTC-related metastasis may be induced by primary high risk histological subtype of PTC (e.g., tall cell, columnar cell, and hobnail variants) or dedifferentiation, which can be determined by 131I uptake [14]. Whole genome sequencing was conducted for multiple samples from a single patient with synchronous follicular thyroid carcinoma (FTC), PDTC and ATC as well as regional lymph node metastasis, demonstrating the importance role of defects in DNA repair on clonal evolution of thyroid cancer [17].

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Conclusion