目的:定义甲状旁腺腺瘤(PA)的体细胞变异,并为散发性PA的潜在分子机制提供新的见解。
方法:收集73例PA患者的基本临床特征和生化指标。对匹配的肿瘤构成DNA对进行全外显子组测序(WES)以检测体细胞改变。之后通过独创性路径分析(IPA)进行功能注释。通过免疫组织化学(IHC)证实变异基因的蛋白表达,分析基因型与表型的关系。
结果:在总共1549个基因中鉴定了体细胞变异,每个肿瘤平均有69个变体(范围13-2109;总计9083)。检测到几种新的复发性体细胞变异,如KMT2D(15/73),MUC4(14/73),POTEH(13/73),CD22(12/73),HSPA2(12/73),HCFC1(11/73),MAGEA1(11/73)和SLC4A3(11/73),除了先前报道的PA相关基因,包括MEN1(11/73),CASR(6/73),MTOR(4/73),ASXL3(3/73),FAT1(3/73),ZFX(5/73),EZH1(2/73),POT1(2/73)和EZH2(1/73)。其中,KMT2D可能是PA的候选驱动基因。至关重要的是,5例患者携带CDC73体细胞突变,表现出与甲状旁腺癌(PC)相似的侵袭性表型,纤维旁蛋白的表达降低。复发性潜在PA相关驱动变异基因的通路分析揭示了Notch信号通路中的功能富集。
结论:我们的研究扩展了PA的致病变异谱,并表明KMT2D可能是一种新的候选驱动基因,并被认为是PA的诊断生物标志物。同时,CDC73突变可能是从PA到PC的早期发育事件。该结果为阐明甲状旁腺肿瘤发生的发病机制提供了见解,为临床诊断和治疗提供了一定的依据。
To define somatic variants of parathyroid adenoma (PA) and to provide novel insights into the underlying molecular mechanism of sporadic PA.
Basic clinical characteristics and biochemical indices of 73 patients with PA were collected. Whole-exome sequencing was performed on matched tumor-constitutional DNA pairs to detect somatic alterations. Functional annotation was carried out by ingenuity pathway analysis afterward. The protein expression of the variant gene was confirmed by immunohistochemistry, and the relationship between genotype and phenotype was analyzed.
Somatic variants were identified in 1549 genes, with an average of 69 variants per tumor (range, 13-2109; total, 9083). Several novel recurrent somatic variants were detected, such as KMT2D (15/73), MUC4 (14/73), POTEH (13/73), CD22 (12/73), HSPA2 (12/73), HCFC1 (11/73), MAGEA1 (11/73), and SLC4A3 (11/73), besides the previously reported PA-related genes, including MEN1 (11/73), CASR (6/73), MTOR (4/73), ASXL3 (3/73), FAT1 (3/73), ZFX (5/73), EZH1 (2/73), POT1 (2/73), and EZH2 (1/73). Among them, KMT2D might be the candidate driver gene of PA. Crucially, 5 patients carried somatic mutations in CDC73, showed an aggressive phenotype similar to that of parathyroid carcinoma (PC), and had a decreased expression of
parafibromin. Pathway analysis of recurrent potential PA-associated driver variant genes revealed functional enrichments in the signaling pathway of Notch.
Our study expanded the pathogenic variant spectrum of PA and indicated that KMT2D might be a novel candidate driver gene and be considered as a diagnostic biomarker for PA. Meanwhile, CDC73 mutations might be an early developmental event from PA to PC. The results provided insights into elucidating the pathogenesis of parathyroid tumorigenesis and a certain basis for clinical diagnosis and treatment.