Pediatric papillary thyroid carcinoma (PPTC) is clinically distinct from adult-onset disease. Although there are higher rates of metastasis and recurrence in PPTC, prognosis remains highly favorable. Molecular characterization of PPTC has been lacking. Historically, only 40% to 50% of childhood papillary thyroid carcinoma (PTC) were known to be driven by genomic variants common to adult PTC; oncogenic drivers in the remainder were unknown. This contrasts with approximately 90% of adult PTC driven by a discrete number of variants. In this study, 52 PPTCs underwent candidate gene testing, followed in a subset by whole-exome and transcriptome sequencing. Within these samples, candidate gene testing identified variants in 31 (60%) tumors, while exome and transcriptome sequencing identified oncogenic variants in 19 of 21 (90%) remaining tumors. The latter were enriched for oncogenic fusions, with 11 nonrecurrent fusion transcripts, including two previously undescribed fusions, STRN-RET and TG-PBF. Most fusions were associated with 3′ receptor tyrosine kinase (RTK) moieties: RET, MET, ALK, and NTRK3. For advanced (distally metastatic) tumors, a driver variant was described in 91%. Gene expression analysis defined three clusters that demonstrated distinct expression of genes involved in thyroid differentiation and MAPK signaling. Among RET-CCDC6–driven tumors, gene expression in pediatric tumors was distinguishable from that in adults. Collectively, these results show that the genomic landscape of pediatric PTC is different from adult PTC. Moreover, they identify genomic drivers in 98% of PPTCs, predominantly oncogenic fusion transcripts involving RTKs, with a pronounced impact on gene expression. Notably, most advanced tumors were driven by a variant for which targeted systemic therapy exists. Significance: This study highlights important distinctions between the genomes and transcriptomes of pediatric and adult papillary thyroid carcinoma, with implications for understanding the biology, diagnosis, and treatment of advanced disease in children.

中文翻译：

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不同的致癌融合和不同的基因表达模式定义了小儿甲状腺乳头状癌的基因组格局

小儿甲状腺乳头状癌 (PPTC) 在临床上与成人发病不同。尽管 PPTC 的转移和复发率较高，但预后仍然非常有利。PPTC的分子特征一直缺乏。从历史上看，已知只有 40% 到 50% 的儿童甲状腺乳头状癌 (PTC) 是由成人 PTC 常见的基因组变异驱动的。其余的致癌驱动因素未知。这与由离散数量的变体驱动的大约 90% 的成人 PTC 形成对比。在这项研究中，52 个 PPTC 接受了候选基因测试，随后在一个子集中进行了全外显子组和转录组测序。在这些样本中，候选基因检测鉴定了 31 个（60%）肿瘤中的变异，而外显子组和转录组测序鉴定了 21 个（90%）剩余肿瘤中的 19 个（90%）的致癌变异。后者富含致癌融合，具有 11 个非复发性融合转录本，包括两个以前未描述的融合，STRN-RET 和 TG-PBF。大多数融合与 3' 受体酪氨酸激酶 (RTK) 部分相关：RET、MET、ALK 和 NTRK3。对于晚期（远端转移）肿瘤，91% 的患者描述了驱动变异。基因表达分析定义了三个集群，这些集群证明了参与甲状腺分化和 MAPK 信号传导的基因的不同表达。在 RET-CCDC6 驱动的肿瘤中，儿童肿瘤中的基因表达与成人不同。总的来说，这些结果表明儿童 PTC 的基因组景观不同于成人 PTC。此外，他们在 98% 的 PPTC 中识别出基因组驱动因素，主要是涉及 RTK 的致癌融合转录本，对基因表达有显着影响。值得注意的是，大多数晚期肿瘤是由存在靶向全身治疗的变体驱动的。意义：本研究强调了儿童和成人甲状腺乳头状癌的基因组和转录组之间的重要区别，对了解儿童晚期疾病的生物学、诊断和治疗具有重要意义。