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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.
- Source :
-
The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2015 Feb; Vol. 100 (2), pp. E360-4. Date of Electronic Publication: 2014 Nov 11. - Publication Year :
- 2015
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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).<br />Objective: To identify additional genetic abnormalities in PCs.<br />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).<br />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.<br />Conclusion: This study outlines the genetic landscape of PC and attempts to characterize the mutational processes shaping the PC genome.
- Subjects :
- Adolescent
Adult
Aged
Carcinoma metabolism
Carcinoma pathology
DNA Mutational Analysis
Exome
Female
Humans
Male
Middle Aged
Mutagenesis
Neoplasm Invasiveness pathology
Neoplasm Proteins metabolism
Parathyroid Neoplasms metabolism
Parathyroid Neoplasms pathology
Young Adult
Carcinoma genetics
Cell Movement genetics
Mutation
Neoplasm Invasiveness genetics
Neoplasm Proteins genetics
Parathyroid Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7197
- Volume :
- 100
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of clinical endocrinology and metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 25387265
- Full Text :
- https://doi.org/10.1210/jc.2014-3238