Genomic Profiling Reveals the Variant Landscape of Sporadic Parathyroid Adenomas in Chinese Population

作者：Xiaohui Tao, Tian Xu, Xiaoyun Lin, Shuqin Xu, Youben Fan, Bomin Guo, Xianzhao Deng, Qiong Jiao, Lihui Chen, Zhe Wei, Chengkun Chen, Wendi Yang, Zhenlin Zhang, Xiangtian Yu, Hua Yue · 发表于：The Journal of Clinical Endocrinology & Metabolism · 年份：2023 · DOI：10.1210/clinem/dgad002 · 被引用次数：18 · 研究领域：Parathyroid Disorders and Treatments、Thyroid and Parathyroid Surgery、Genetic Syndromes and Imprinting

OBJECTIVE: To define somatic variants of parathyroid adenoma (PA) and to provide novel insights into the underlying molecular mechanism of sporadic PA. METHODS: 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. RESULTS: 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. CONCLUSION: Our study e...