PO.EN01.02 · 内分泌肿瘤
利用多组学分析对甲状腺滤泡癌中 DICER1 突变及双打击肿瘤发生机制的全面表征
Comprehensive characterization of DICER1 mutations and two hit tumorigenesis mechanisms in follicular thyroid carcinoma using multi-omics analysis
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摘要 Abstract
中文摘要
背景:DICER1 是 microRNA(miRNA)加工所必需的 RNase III 酶。种系功能丧失(LoF)变异导致 DICER1 综合征,并使较年轻个体易患包括甲状腺滤泡癌(FTC)在内的肿瘤。体细胞 RNase IIIb 热点突变具有特征性,但种系 LoF、体细胞打击和组织特异性调控网络如何驱动 FTC 尚未完全阐明。
方法:我们使用全外显子组测序、miRNA-seq、RNA-seq 和蛋白质组学分析了 DICER1 突变型 FTC(n=20),并将其与野生型肿瘤(wt-T,n=61)进行比较。肿瘤被分类为综合征相关型(syn-T,n=7)或散发型(spo-T,n=13)。整合分析包括等位基因失衡、通路富集和网络建模(WGCNA)。
结果:临床上,spo-T 患者显著比 wt-T 患者年轻,提示存在 DICER1 驱动的 FTC 的年龄特异性窗口。大多数肿瘤通过 RNase IIIb 热点突变伴继发 LoF 事件表现出双等位基因破坏,即使仅检测到一个突变,等位基因失衡也证实了双打击失活。在综合征相关的正常组织中,发生了大量 mRNA 失调而无 miRNA 改变,提示 DICER1 单倍剂量不足独立于全局 miRNA 丧失而发挥作用。在 DICER1 突变型肿瘤中,细胞周期、mTOR 和 Wnt 通路强烈上调,而免疫程序被广泛抑制。甲状腺干细胞标志物 REXO1 特异性升高,提示干细胞样表型。网络分析强调 CTNNB1 和 let-7i 是 DICER1 转录程序的关键调控因子。尽管 DICER1 突变型和 RAS 突变型 FTC 共享一些下游信号模块,但 DICER1 突变型肿瘤保留了独特的表达特征。WGCNA 鉴定出一个 DICER1 特异性细胞周期模块和一个部分共享的 DICER1-RAS Wnt/MAPK 模块。
结论:DICER1 在 FTC 中作为一个独特的致癌驱动因素,遵循双等位基因失活模型,产生独特的增殖、免疫抑制和干细胞样转录状态。这些发现完善了 DICER1 相关甲状腺肿瘤发生的机制,并提示了潜在的谱系特异性治疗靶点。
查看英文原文 English abstract
Background: DICER1 is an essential RNase III enzyme for microRNA (miRNA) processing. Germline loss-of-function (LoF) variants cause DICER1 syndrome and predispose younger individuals to tumors including follicular thyroid carcinoma (FTC). Somatic RNase IIIb hotspot mutations are characteristic, but how germline LoF, somatic hits, and tissue-specific regulatory networks drive FTC is not fully understood.
Methods: We analyzed DICER1-mutant FTC (n=20) using whole-exome sequencing, miRNA-seq, RNA-seq, and proteomics, and compared them with wild-type tumors (wt-T, n=61). Tumors were classified as syndrome-associated (syn-T, n=7) or sporadic (spo-T, n=13). Integrative analyses included allelic imbalance, pathway enrichment, and network modeling (WGCNA).
Results: Clinically, spo-T patients were significantly younger than wt-T, indicating an age-specific window for DICER1-driven FTC. Most tumors showed biallelic disruption through RNase IIIb hotspot mutations with secondary LoF events, and allelic imbalance confirmed two-hit inactivation even when only one mutation was detected.In syndrome-normal tissues, substantial mRNA dysregulation occurred without miRNA changes, suggesting DICER1 haploinsufficiency acts independently of global miRNA loss.In DICER1-mutant tumors, cell-cycle, mTOR, and Wnt pathways were strongly upregulated, whereas immune programs were broadly suppressed. The thyroid stem-cell marker REXO1 was specifically elevated, indicating a stem-like phenotype. Network analysis highlighted CTNNB1 and let-7i as key regulators of the DICER1 transcriptional program. Although DICER1- and RAS-mutant FTCs shared some downstream signaling modules, DICER1-mutant tumors retained a distinct expression identity. WGCNA identified a DICER1-specific cell-cycle module and a partially shared DICER1-RAS Wnt/MAPK module.
Conclusion: DICER1 functions as a distinct oncogenic driver in FTC, following a biallelic inactivation model and producing unique proliferative, immune-suppressed, and stem-like transcriptional states. These findings refine the mechanism of DICER1-associated thyroid tumorigenesis and suggest potential lineage-specific therapeutic targets.
利益披露 Disclosure
D. Lee, None..
Y. Lee, None..
Y. Kyoung, None..
S. Yoo, None..
S. Im, None..
J. Choi, None..
Y. Kim, None..
D. Han, None..
Y. Park, None..
J. Kim, None.