Identification of Somatic Mutations in Parathyroid Tumors Using Whole-Exome Sequencing

• Published in: The journal of clinical endocrinology and metabolism 2012-09, Vol.97 (9), p.E1774-E1781
• Main Authors: Cromer, M. Kyle, Starker, Lee F, Choi, Murim, Udelsman, Robert, Nelson-Williams, Carol, Lifton, Richard P, Carling, Tobias
• Format: Article
• Language: English
• Subjects: Adenoma - genetics; Cohort Studies; DNA Mutational Analysis; DNA, Neoplasm - genetics; Enhancer of Zeste Homolog 2 Protein; Exons - genetics; Humans; JCEM Online: Advances in Genetics; Multiple Endocrine Neoplasia Type 1 - genetics; Mutation - genetics; Mutation - physiology; Parathyroid Neoplasms - genetics; Polycomb Repressive Complex 2 - genetics; Polymerase Chain Reaction; Reproducibility of Results; Sequence Analysis, DNA
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2012-1743

Context: The underlying molecular alterations causing sporadic parathyroid adenomas that drive primary hyperparathyroidism have not been thoroughly defined. Objective: The aim of the study was to investigate the occurrence of somatic mutations driving tumor formation and progression in sporadic parathyroid adenoma using whole-exome sequencing. Design: Eight matched tumor-constitutional DNA pairs from patients with sporadic parathyroid adenomas underwent whole-exome capture and high-throughput sequencing. Selected genes were analyzed for mutations in an additional 185 parathyroid adenomas. Results: Four of eight tumors displayed a frame shift deletion or nonsense mutation in MEN1, which was accompanied by loss of heterozygosity of the remaining wild-type allele. No other mutated genes were shared among the eight tumors. One tumor harbored a Y641N mutation of the histone methyltransferase EZH2 gene, previously linked to myeloid and lymphoid malignancy formation. Targeted sequencing in the additional 185 parathyroid adenomas revealed a high rate of MEN1 mutations (35%). Furthermore, this targeted sequencing identified an additional parathyroid adenoma that contained the identical, somatic EZH2 mutation that was found by exome sequencing. Conclusion: This study confirms the frequent role of the loss of heterozygosity of chromosome 11 and MEN1 gene alterations in sporadic parathyroid adenomas and implicates a previously unassociated methyltransferase gene, EZH2, in endocrine tumorigenesis.