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Costa-Guda. J Transl Genet Genom 2018;2:5 I http://dx.doi.org/10.20517/jtgg.2018.08 Page 5 of 8

or oncogenes within those predicted genomic locations [11,41,44,48,50-54] . Notably, despite the high frequency of both
allelic loss at the RB1 locus on chromosome 13q [44,54-57] and loss of pRB expression [44,45] , intragenic mutation of
RB1 has yet to be identified in parathyroid cancer [11,41,48,54] . Preferential amplification of mutant CDC73 alleles
has been reported, which could account, at least in part, for observed alleic gain of chromosome 1q . Whole
[48]
genome/exome next-generation sequence analyses have identified a number of genes that may be important
to the pathogenesis of parathyroid cancer and merit further study. Recurrent mutations have been reported
in AKAP9, a gene frequently altered in epithelial cancers, ADCK1, a putative kinase, NOTCH1, which may
function as either an oncogene or tumor suppressor gene, and ZEB1, a transcriptional regulator of epithelial-
mesenchymal transition . Several mutations which were identified in only one tumor but affecting genes
[41]
linked to other types of human cancer were also identified. These genes included MLL2, a MEN1-interacting
tumor suppressor gene, THRAP3, a gene involved in regulating cyclin D1 expression, and the canonical Wnt
pathway genes APC and RNF43. Several genes encoding kinases with postulated roles in cell migration and
invasion, including MAP3K11, JAK1 and RIOK3, and chromatin structure-regulating genes, including ARID2,
ARID4A, KDM5C, KDM4C, KDM4E, JMJD1C and SETD1B were also mutated. Identification of these novel
mutations is an important next step in furthering our knowledge of the molecular pathogenesis of parathyroid
cancer. It remains to be determined, through further sequence analysis and functional studies, which of these
mutated genes will emerge as important driver genes in parathyroid cancer.

CONCLUSION
Several important advances have been made towards the goal of understanding the molecular basis of
parathyroid cancer. Observations of mutational and allelic imbalance patterns suggest that parathyroid
cancer generally arises de novo, rather than evolving from a preexisting typical benign adenoma. Mutations
in the CDC73 tumor suppressor gene are the most common finding in malignant parathyroid carcinomas.
Alterations in additional genes such as CCND1/CyclinD1, PIK3CA, MTOR and PRUNE2 and others
identified by next-generation sequencing methods have also been described in parathyroid cancer, however
their abilities to drive malignant parathyroid tumorigenesis remains to be demonstrated experimentally.
Additional genes important to the development of parathyroid carcinoma are likely to be identified and the
extent and nature of their involvement will need to be carefully examined and validated with genetic and
experimental-functional approaches.

DECLARATIONS
Authors’ contributions
Costa-Guda J contributed solely to the paper.

Financial support and sponsorship
This work was supported in part by the Murray-Heilig Fund in Molecular Medicine.

Conflicts of interest
There are no conflicts of interest.

Patient consent
Not applicable.

Ethics approval
Not applicable.

Copyright
© The Author(s) 2018.