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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.

Publication ,  Journal Article
Yu, W; McPherson, JR; Stevenson, M; van Eijk, R; Heng, HL; Newey, P; Gan, A; Ruano, D; Huang, D; Poon, SL; Ong, CK; van Wezel, T; Cavaco, B ...
Published in: J Clin Endocrinol Metab
February 2015

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.

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Published In

J Clin Endocrinol Metab

DOI

EISSN

1945-7197

Publication Date

February 2015

Volume

100

Issue

2

Start / End Page

E360 / E364

Location

United States

Related Subject Headings

  • Young Adult
  • Parathyroid Neoplasms
  • Neoplasm Proteins
  • Neoplasm Invasiveness
  • Mutation
  • Mutagenesis
  • Middle Aged
  • Male
  • Humans
  • Female
 

Citation

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ICMJE
MLA
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Yu, W., McPherson, J. R., Stevenson, M., van Eijk, R., Heng, H. L., Newey, P., … 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. J Clin Endocrinol Metab, 100(2), E360–E364. https://doi.org/10.1210/jc.2014-3238
Yu, Willie, John R. McPherson, Mark Stevenson, Ronald van Eijk, Hong Lee Heng, Paul Newey, Anna Gan, et al. “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.J Clin Endocrinol Metab 100, no. 2 (February 2015): E360–64. https://doi.org/10.1210/jc.2014-3238.
Yu W, McPherson JR, Stevenson M, van Eijk R, Heng HL, Newey P, Gan A, Ruano D, Huang D, Poon SL, Ong CK, van Wezel T, Cavaco B, Rozen SG, Tan P, Teh BT, Thakker RV, Morreau H. 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. J Clin Endocrinol Metab. 2015 Feb;100(2):E360–E364.
Journal cover image

Published In

J Clin Endocrinol Metab

DOI

EISSN

1945-7197

Publication Date

February 2015

Volume

100

Issue

2

Start / End Page

E360 / E364

Location

United States

Related Subject Headings

  • Young Adult
  • Parathyroid Neoplasms
  • Neoplasm Proteins
  • Neoplasm Invasiveness
  • Mutation
  • Mutagenesis
  • Middle Aged
  • Male
  • Humans
  • Female