Genomic profiling reveals the variant landscape of sporadic parathyroid adenomas in Chinese population.

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 PA patients were collected. Whole-exome sequencing (WES) was performed on matched tumor-constitutional DNA pairs to detect somatic alterations. Functional annotation was carried out by Ingenuity Pathway Analysis (IPA) afterward. The protein expression of the variant gene was confirmed by immunohistochemistry (IHC), and the relationship between genotype and phenotype was analyzed.

RESULTS: Somatic variants were identified in a total of 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, five 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 expanded the pathogenic variant spectrum of PA, and indicated that KMT2D might be a novel candidate driver gene and to 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.