Abstract：
BACKGROUND: Atypical parathyroid tumor (APT) represents a neoplasm characterized by histological features typical of parathyroid carcinoma (PC) but lacking local infiltration and/or distant metastasis, leading to uncertainty regarding its malignant potential.
OBJECTIVE: To characterize the molecular landscape and deregulated pathways in APT.
METHODS: Whole exome sequencing (WES) was conducted on 16 APTs. DNA from tumors and matched peripheral blood underwent WES using Illumina HiSeq3000.
RESULTS: A total of 192 nonsynonymous variants were identified. The median number of protein-altering mutations was 9. The most frequently mutated genes included BCOR, CLMN, EZH1, JAM2, KRTAP13-3, MUC16, MUC19, and OR1S1. Seventeen mutated genes belong to the Cancer Gene Census list. The most consistent hub genes identified through STRING network analysis were ATM, COL4A5, EZH2, MED12, MEN1, MTOR, PI3, PIK3CA, PIK3CB, and UBR5. Deregulated pathways included the PI3 K/AKT/mTOR pathway, Wnt signaling, and extracellular matrix organization. Variants in genes such as MEN1, CDC73, EZH2, PIK3CA, and MTOR, previously reported as established or putative/candidate driver genes in benign adenoma (PA) and/or PC, were also identified in APT.
CONCLUSIONS: APT does not appear to have a specific molecular signature but shares genomic alterations with both PA and PC. The incidence of CDC73 mutations is low, and it remains unclear whether these mutations are associated with a higher risk of recurrence. Our study confirms that PI3 K/AKT/mTOR and Wnt signaling represents the pivotal pathways in parathyroid tumorigenesis and also revealed mutations in key epigenetic modifier genes (BCOR, KDM2A, MBD4, and EZH2) involved in chromatin remodeling, DNA, and histone methylation.
OBJECTIVE: To characterize the molecular landscape and deregulated pathways in APT.
METHODS: Whole exome sequencing (WES) was conducted on 16 APTs. DNA from tumors and matched peripheral blood underwent WES using Illumina HiSeq3000.
RESULTS: A total of 192 nonsynonymous variants were identified. The median number of protein-altering mutations was 9. The most frequently mutated genes included BCOR, CLMN, EZH1, JAM2, KRTAP13-3, MUC16, MUC19, and OR1S1. Seventeen mutated genes belong to the Cancer Gene Census list. The most consistent hub genes identified through STRING network analysis were ATM, COL4A5, EZH2, MED12, MEN1, MTOR, PI3, PIK3CA, PIK3CB, and UBR5. Deregulated pathways included the PI3 K/AKT/mTOR pathway, Wnt signaling, and extracellular matrix organization. Variants in genes such as MEN1, CDC73, EZH2, PIK3CA, and MTOR, previously reported as established or putative/candidate driver genes in benign adenoma (PA) and/or PC, were also identified in APT.
CONCLUSIONS: APT does not appear to have a specific molecular signature but shares genomic alterations with both PA and PC. The incidence of CDC73 mutations is low, and it remains unclear whether these mutations are associated with a higher risk of recurrence. Our study confirms that PI3 K/AKT/mTOR and Wnt signaling represents the pivotal pathways in parathyroid tumorigenesis and also revealed mutations in key epigenetic modifier genes (BCOR, KDM2A, MBD4, and EZH2) involved in chromatin remodeling, DNA, and histone methylation.
摘要：
背景：非典型甲状旁腺肿瘤（APT）是一种肿瘤，其特征是典型的甲状旁腺癌（PC）的组织学特征，但缺乏局部浸润和/或远处转移，导致其恶性潜力的不确定性。
目的：表征APT中的分子景观和失调途径。
方法：对16个APT进行全外显子组测序（WES）。使用IlluminaHiSeq3000对来自肿瘤和匹配的外周血的DNA进行WES。
结果：共鉴定出192种非同义变体。蛋白质改变突变的中位数为9。最常见的突变基因包括BCOR，CLMN,EZH1、JAM2、KRTAP13-3、MUC16、MUC19和OR1S1。17个突变基因属于癌症基因普查名单。通过STRING网络分析确定的最一致的集线器基因是ATM，COL4A5,EZH2,MED12,MEN1,MTOR,PI3,PIK3CA,PIK3CB,UBR5去调节途径包括PI3K/AKT/mTOR途径，Wnt信号,和细胞外基质组织。基因如MEN1、CDC73、EZH2、PIK3CA、和MTOR，先前报道为良性腺瘤（PA）和/或PC中已建立或推定/候选的驱动基因，在APT中也被确定。
结论：APT似乎没有特定的分子特征，但与PA和PC共享基因组改变。CDC73突变的发生率很低，目前尚不清楚这些突变是否与较高的复发风险相关.我们的研究证实，PI3K/AKT/mTOR和Wnt信号代表了甲状旁腺肿瘤发生的关键途径，也揭示了关键表观遗传修饰基因的突变（BCOR，KDM2A,MBD4和EZH2）参与染色质重塑，DNA,和组蛋白甲基化。
目的：表征APT中的分子景观和失调途径。
方法：对16个APT进行全外显子组测序（WES）。使用IlluminaHiSeq3000对来自肿瘤和匹配的外周血的DNA进行WES。
结果：共鉴定出192种非同义变体。蛋白质改变突变的中位数为9。最常见的突变基因包括BCOR，CLMN,EZH1、JAM2、KRTAP13-3、MUC16、MUC19和OR1S1。17个突变基因属于癌症基因普查名单。通过STRING网络分析确定的最一致的集线器基因是ATM，COL4A5,EZH2,MED12,MEN1,MTOR,PI3,PIK3CA,PIK3CB,UBR5去调节途径包括PI3K/AKT/mTOR途径，Wnt信号,和细胞外基质组织。基因如MEN1、CDC73、EZH2、PIK3CA、和MTOR，先前报道为良性腺瘤（PA）和/或PC中已建立或推定/候选的驱动基因，在APT中也被确定。
结论：APT似乎没有特定的分子特征，但与PA和PC共享基因组改变。CDC73突变的发生率很低，目前尚不清楚这些突变是否与较高的复发风险相关.我们的研究证实，PI3K/AKT/mTOR和Wnt信号代表了甲状旁腺肿瘤发生的关键途径，也揭示了关键表观遗传修饰基因的突变（BCOR，KDM2A,MBD4和EZH2）参与染色质重塑，DNA,和组蛋白甲基化。
