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Page 4 of 8 Costa-Guda. J Transl Genet Genom 2018;2:5 I http://dx.doi.org/10.20517/jtgg.2018.08

Cyclin D1
CCND1, encoding cyclin D1, is a well-established oncogenic contributor to benign parathyroid adenomas
and DNA amplifications or gene rearrangements have been demonstrated in a variety of tumor types.
CCND1 gene amplification [40,41] and cyclin D1 overexpression [40,42] are common in parathyroid carcinoma.
Parathyroid-targeted cyclin D1 transgenic mice develop chronic biochemical hyperparathyroidism and
parathyroid gland hypercellularity, but parathyroid carcinoma has not been observed . These finding suggest
[43]
that cyclin D1 overexpression alone may be insufficient to drive malignant parathyroid tumorigenesis. The
precise mechanisms through which cyclin D1 drives tumorigenesis remain controversial. Cyclin D1’s primary
function is as a regulator of cell cycle progression, binding to, and activating, the cyclin-dependent kinases
CDK4/CDK6, which can then phosphorylate pRB, promoting G1-S phase transition. Loss of pRB expression
is also a frequent finding in parathyroid carcinomas [44,45] . Cyclin D1 levels are tightly regulated at multiple
levels and dysfunction of any of these control mechanisms may contribute to tumorigenesis . Cyclin D1
[46]
also has CDK-independent functions, such as a role in chromosomal stability, which may also contribute to
cyclin D1’s ability to drive tumorigenesis . While it remains to be determined which functions of cyclin D1
[47]
are most relevant, the frequent loss of pRB expression and occasional inactivation of CDK inhibitor genes
in parathyroid cancer underscore the importance of cell cycle dysregulation to the promotion of malignant
parathyroid tumorigenesis.

PRUNE2
PRUNE2 has recently been identified as a likely tumor suppressor gene subject to recurrent mutation in
parathyroid carcinoma [41,48] . Whole exome sequencing revealed one parathyroid carcinoma with a germline
missense PRUNE2 mutation accompanied by allelic loss and two carcinomas harboring biallelic, somatic
[48]
nonsense mutations [41,48] . Sanger sequencing, limited to exon 8 of PRUNE2, uncovered two additional
somatic missense mutations. PRUNE2 functions to suppress Ras homolog family member A (RhoA) activity,
resulting in suppression of oncogenic cellular transformation, consistent with a tumor suppressive role in
parathyroid carcinoma. Functional studies will be needed to determine if loss of PRUNE2 is capable of, or
sufficient to, driving malignant parathyroid tumorigenesis.

PI3K/mTOR
The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is an important
regulator of cell cycle progression, cell growth and survival, and is frequently subject to alteration in human
cancers. PIK3CA, encoding the p110-alpha subunit of PI3K, has been recognized as an oncogene capable of
driving tumorigenesis in many types of human tumors. A heterozygous PIK3CA mutation, resulting in a
glutamic acid to lysine change at amino acid 545 (p.E545K), was identified in a parathyroid carcinoma subjected
to whole genome sequencing, but interestingly this mutation was absent from two recurrent lesions from the
same patient . Whole exome sequencing revealed another established activating PIK3CA mutation (p.K111E) in
[11]
a parathyroid carcinoma . Targeted sequencing revealed two additional known activating PIK3CA mutations,
[41]
p.H1047R and p.E545A. Interestingly, across the two studies, PIK3CA and CDC73 mutations were mutually
exclusive, although the sample sizes were too low to determine statistical significance. Activating mutations
of MTOR, also commonly altered in human tumors, were seen in three parathyroid carcinomas in two next-
generation sequencing studies [11,41] . Functional studies are required to determine if activating mutations of the
PI3K/mTOR pathway are indeed capable of driving malignant parathyroid tumorigenesis.

Additional genetic and genomic considerations
A number of studies have sought to identify regions of genomic gains and losses relevant to the pathogenesis
of parathyroid carcinoma. Recurrent regions of allelic loss have been reported on chromosomes 1p, 3, 13q and
14, and recurrent regions of allelic gain on chromosomes 1q and 16 [3-5,9,49] . Such regions of recurrent genomic
alteration are expected to harbor important tumor suppressor genes and oncogenes, however both targeted
sequencing and whole genome/exome analyses have yet to uncover commonly altered tumor suppressor genes