Whole-exome sequencing studies of parathyroid carcinomas reveal novel PRUNE2 mutations, distinctive mutational spectra related to APOBEC-catalyzed DNA mutagenesis and mutational enrichment in kinases associated with cell migration and invasion

Willie Yu, John R. McPherson, Mark Stevenson, Ronald van Eijk, Hong Lee Heng, Paul Newey, Anna Gan, Dina Ruano, Dachuan Huang, Song Ling Poon, Choon Kiat Ong, Tom van Wezel, Branca Cavaco, Steven G. Rozen, Patrick Tan, Bin T. Teh (Lead / Corresponding author), Rajesh V. Thakker (Lead / Corresponding author), Hans Morreau (Lead / Corresponding author)

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Abstract

Context: Cell division cycle 73 (CDC73), encoding the protein parafibromin, is the most prevalent mutated gene in familial and sporadic parathyroid carcinoma (PC).

Objective: To identify additional genetic abnormalities in PCs.

Design: Whole-exome sequencing was performed using DNA from seven pairs of matched PCs and one triplet containing double primary tumor and normal leukocyte. Somatic variants were confirmed using Sanger sequencing and recurrently mutated genes were assessed in 13 additional PCs as well as 40 parathyroid adenomas (PA).

Results: PC had an average of 51 somatic variants/tumor (range 3-176) with approximately 58% of variants occurring as nonsynonymous single nucleotide variants. The importance of CDC73 in PC is reinforced with a remarkable preferential amplification of the mutant CDC73 allele. Furthermore, recurrent germ line and somatic mutations in prune homolog 2 [Drosophila] (PRUNE2) were found in PC and computationally predicted to be deleterious; in addition, recurrent mutations in kinase genes related to cell migration and invasion were found. PRUNE2 showed recurrent mutations in 18% (4/22) of PCs with additional screening in 40 PAs revealing only one rare missense polymorphism (Asp1677Asn). For the first time, the mutational signature associated with apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-catalyzed cytosine-to-uracil deamination is found in a subset of PC.

Conclusion: This study outlines the genetic landscape of PC and attempts to characterize the mutational processes shaping the PC genome.

Original languageEnglish
Pages (from-to)E360-E364
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Volume100
Issue number2
Early online date11 Nov 2014
DOIs
Publication statusPublished - 1 Feb 2015

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Keywords

  • Adolescent
  • Adult
  • Aged
  • Carcinoma
  • Cell movement
  • DNA mutational analysis
  • Exome
  • Female
  • Humans
  • Male
  • Middle aged
  • Mutagenesis
  • Mutation
  • Neoplasm invasiveness
  • Neoplasm proteins
  • Parathyroid neoplasms
  • Young adult

Cite this

Yu, W., McPherson, J. R., Stevenson, M., van Eijk, R., Heng, H. L., Newey, P., Gan, A., Ruano, D., Huang, D., Poon, S. L., Ong, C. K., van Wezel, T., Cavaco, B., Rozen, S. G., Tan, P., Teh, B. T., Thakker, R. V., & Morreau, H. (2015). Whole-exome sequencing studies of parathyroid carcinomas reveal novel PRUNE2 mutations, distinctive mutational spectra related to APOBEC-catalyzed DNA mutagenesis and mutational enrichment in kinases associated with cell migration and invasion. Journal of Clinical Endocrinology and Metabolism, 100(2), E360-E364. https://doi.org/10.1210/jc.2014-3238