Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas

Paul J. Newey, M. Andrew Nesbit, Andrew J. Rimmer, Moustafa Attar, Rosie T. Head, Paul T. Christie, Caroline M. Gorvin, Michael Stechman, Lorna Gregory, Radu Mihai, Greg Sadler, Gil McVean, David Buck, Rajesh V. Thakker

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    Abstract

    Context: Genetic abnormalities, such as those of multiple endocrine neoplasia type 1 (MEN1) and Cyclin D1 (CCND1) genes, occur in

    Objective: To identify genetic abnormalities in nonhereditary parathyroid adenomas by whole-exome sequence analysis.

    Design: Whole-exome sequence analysis was performed on parathyroid adenomas and leukocyte DNA samples from 16 postmenopausal women without a family history of parathyroid tumors or MEN1 and in whom primary hyperparathyroidism due to single-gland disease was cured by surgery. Somatic variants confirmed in this discovery set were assessed in 24 other parathyroid adenomas.

    Results: Over 90% of targeted exons were captured and represented by more than 10 base reads. Analysis identified 212 somatic variants (median eight per tumor; range, 2-110), with the majority being heterozygous nonsynonymous single-nucleotide variants that predicted missense amino acid substitutions. Somatic MEN1 mutations occurred in six of 16 (similar to 35%) parathyroid adenomas, in association with loss of heterozygosity on chromosome 11. However, no other gene was mutated in more than one tumor. Mutations in several genes that may represent low-frequency driver mutations were identified, including a protection of telomeres 1 (POT1) mutation that resulted in exon skipping and disruption to the single-stranded DNA-binding domain, which may contribute to increased genomic instability and the observed high mutation rate in one tumor.

    Conclusions: Parathyroid adenomas typically harbor few somatic variants, consistent with their low proliferation rates. MEN1 mutation represents the major driver in sporadic parathyroid tumorigenesis although multiple low-frequency driver mutations likely account for tumors not harboring somatic MEN1 mutations. (J Clin Endocrinol Metab 97: E1995-E2005, 2012)

    Original languageEnglish
    Pages (from-to)E1995-E2005
    Number of pages11
    JournalJournal of Clinical Endocrinology and Metabolism
    Volume97
    Issue number10
    DOIs
    Publication statusPublished - 1 Oct 2012

    Keywords

    • PRIMARY HYPERPARATHYROIDISM
    • SOMATIC MUTATION
    • CANCER GENOMES
    • MEN1 GENE
    • TUMORS
    • POT1
    • DNA
    • HETEROZYGOSITY
    • EPIDEMIOLOGY
    • ACTIVATION

    Cite this

    Newey, P. J., Nesbit, M. A., Rimmer, A. J., Attar, M., Head, R. T., Christie, P. T., Gorvin, C. M., Stechman, M., Gregory, L., Mihai, R., Sadler, G., McVean, G., Buck, D., & Thakker, R. V. (2012). Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas. Journal of Clinical Endocrinology and Metabolism, 97(10), E1995-E2005. https://doi.org/10.1210/jc.2012-2303