Division of Molecular Endocrinology, Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia.
Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia.
Endocrine. 2024 Sep;85(3):1278-1288. doi: 10.1007/s12020-024-03802-7. Epub 2024 Apr 5.
Long noncoding RNAs (lncRNAs) play an essential role in the epigenetic regulation of various key genes involved in vital cellular functions. A somatic dinucleotide mutation in the lncRNA GAS8-AS1 was reported in Chinese papillary thyroid cancer. However, GAS8-AS1 dinucleotide alteration and its impact have never been explored in differentiated thyroid cancers and other populations.
We extracted genomic DNA from 265 DTCs and 97 normal healthy subjects, PCR amplified and Sanger sequenced to examine the GAS8-AS1 dinucleotide alteration. Calculated genotype/allele frequency to test Hardy-Weinberg Equilibrium (HWE) and performed a genetic model of inheritance to determine its association with DTC risk. Correlated the GAS8-AS1 dinucleotide variant distribution with clinical characteristics to find the association. Predicted GAS8-AS1 RNA secondary structure for wild type and variant using RemuRNA and RNAfold to assess the conformational changes.
GAS8-AS1 dinucleotide alteration (n.713A > G, rs55742939; n.714T > C, rs61118444) identified in DTCs is a germline variant not somatic. The GAS8-AS1 genotype and allele frequency significantly deviated for HWE in DTCs (χ2 = 37.954; p = 0.0001) though not associated with its risk. Dinucleotide variant distribution was remarkably associated with early-stage disease (p = 0.002), lymph node (p = 0.01), and distant metastasis (p = 0.01) in DTCs. The GAS8-AS1 bearing dinucleotide variant markedly showed conformational change compared to that of its wild type.
These findings indicate that GAS8-AS1 is genetically deregulated and implicated in several stages of DTC tumorigenesis suggesting it could be a promising prognostic biomarker in DTCs.
长非编码 RNA（lncRNA）在涉及重要细胞功能的各种关键基因的表观遗传调控中发挥着重要作用。lncRNA GAS8-AS1 的体细胞二核苷酸突变已在中国人甲状腺乳头状癌中报道。然而，GAS8-AS1 二核苷酸改变及其影响从未在分化型甲状腺癌和其他人群中得到探索。
我们从 265 例 DTC 和 97 例正常健康受试者中提取基因组 DNA，进行 PCR 扩增和 Sanger 测序，以检查 GAS8-AS1 二核苷酸改变。计算基因型/等位基因频率以检验 Hardy-Weinberg 平衡（HWE），并进行遗传模型分析以确定其与 DTC 风险的关联。将 GAS8-AS1 二核苷酸变异的分布与临床特征相关联，以发现其关联。使用 RemuRNA 和 RNAfold 预测野生型和变异型 GAS8-AS1 RNA 二级结构，以评估构象变化。
在 DTC 中鉴定的 GAS8-AS1 二核苷酸改变（n.713A > G，rs55742939；n.714T > C，rs61118444）是一种种系变异，而不是体细胞变异。尽管与风险无关，但 DTC 中的 GAS8-AS1 基因型和等位基因频率明显偏离 HWE（χ2 = 37.954；p = 0.0001）。二核苷酸变异的分布与 DTC 的早期疾病（p = 0.002）、淋巴结（p = 0.01）和远处转移（p = 0.01）显著相关。与野生型相比，携带 GAS8-AS1 二核苷酸变异的 GAS8-AS1 明显显示出构象变化。
这些发现表明 GAS8-AS1 存在遗传调控异常，并参与 DTC 肿瘤发生的多个阶段，表明其可能成为 DTC 有前途的预后生物标志物。
