Pediatric papillary thyroid carcinomas (pPTCs) are often indolent tumors with excellent long-term outcome, although subsets of cases are clinically troublesome and recur. Although it is generally thought to exhibit similar molecular aberrancies as their counterpart tumors in adults, the pan-genomic landscape of clinically aggressive pPTCs has not been previously described. In this study, five pairs of primary and synchronously metastatic pPTC from patients with high-risk phenotypes were characterized using parallel whole-genome and -transcriptome sequencing. Primary tumors and their metastatic components displayed an exceedingly low number of coding somatic mutations and gross chromosomal alterations overall, with surprisingly few shared mutational events. Two cases exhibited one established gene fusion event each (SQSTM1-NTRK3 and NCOA4-RET) in both primary and metastatic tissues, and one case each was positive for a BRAF V600E mutation and a germline truncating CHEK2 mutation, respectively. One single case was without apparent driver events and was considered as a genetic orphan. Non-coding mutations in cancer-associated regions were generally not present. By expressional analyses, fusion-driven primary and metastatic pPTC clustered separately from the mutation-driven cases and the sole genetic orphan. We conclude that pPTCs are genetically indolent tumors with exceedingly stable genomes. Several mutations found exclusively in the metastatic samples which may represent novel genetic events that drive the metastatic behavior, and the differences in mutational compositions suggest early clonal divergence between primary tumors and metastases. Moreover, an overrepresentation of mutational and expressional dysregulation of immune regulatory pathways was noted among fusion-positive pPTC metastases, suggesting that these tumors might facilitate spread through immune evasive mechanisms.

中文翻译：

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高危小儿甲状腺乳头状癌的泛基因组特征。

小儿甲状腺乳头状癌 (pPTC) 通常是惰性肿瘤，具有良好的长期结果，尽管部分病例在临床上很麻烦并且会复发。尽管通常认为它在成人中表现出与其对应的肿瘤相似的分子异常，但以前没有描述过临床侵袭性 pPTC 的泛基因组景观。在这项研究中，使用平行的全基因组和转录组测序对来自具有高风险表型的患者的五对原发性和同步转移性 pPTC 进行了表征。原发性肿瘤及其转移性成分显示出极少的编码体细胞突变和总体染色体改变，令人惊讶的是很少有共同的突变事件。两个病例在原发组织和转移组织中均表现出一个已确定的基因融合事件（SQSTM1-NTRK3 和 NCOA4-RET），一个病例分别为 BRAF V600E 突变和种系截短 CHEK2 突变阳性。一个病例没有明显的驱动事件，被认为是遗传孤儿。癌症相关区域中的非编码突变通常不存在。通过表达分析，融合驱动的原发性和转移性 pPTC 与突变驱动的病例和唯一的遗传孤儿分开聚集。我们得出结论，pPTCs 是具有极其稳定基因组的遗传惰性肿瘤。仅在转移样本中发现的几种突变可能代表驱动转移行为的新遗传事件，突变组成的差异表明原发性肿瘤和转移瘤之间存在早期克隆差异。此外，在融合阳性 pPTC 转移灶中发现免疫调节途径的突变和表达失调过多，这表明这些肿瘤可能通过免疫逃避机制促进扩散。