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Costa-Guda. J Transl Genet Genom 2018;2:5 I http://dx.doi.org/10.20517/jtgg.2018.08 Page 3 of 8

CDC73
A large percentage of sporadic parathyroid carcinomas also harbor mutations in the CDC73 tumor
suppressor gene. A wide range of mutation frequencies (13%-100%) have been reported [13-16] across studies,
likely due to inconsistencies in selection criteria. Among studies using the most stringent diagnostic criteria
for parathyroid cancer, namely extracapsular invasion and/or distant metastasis, the mutation frequency
is 77% [13-15] . In addition to intragenic mutations, gross deletions of CDC73 have also been reported [17-19] .
Biallelic inactivation of CDC73 can be demonstrated in many parathyroid cancers [13-15] . A substantial subset
of patients with sporadically-presenting parathyroid carcinoma possess germline CDC73 mutations, and
may represent new index cases of HPT-JT or a phenotypic variant [13,15,20,21] . Most parathyroid carcinomas
also exhibit aberrant immunohistochemical staining for parafibromin, the protein product of CDC73;
complete loss of parafibromin expression is the most common staining pattern. As the large majority of
benign parathyroid tumors (except in the setting of germline CDC73 mutation) display normal parafibromin
staining, parafibromin immunohistochemistry may be considered as a diagnostic adjunct for parathyroid
cancer in otherwise equivocal cases [22-24] but aberrant parafibromin staining alone is insufficient as a
diagnostic marker of parathyroid carcinoma .
[25]
Parafibromin is a ubiquitously expressed, evolutionarily conserved 531 amino acid protein with predominantly
nuclear expression. Cytoplasmic expression of parafibromin has also been described and may have functions
different than nuclear parafibromin [26,27] . Parafibromin’s C-terminal region contains moderate sequence
similarity to yeast Cdc73p, a cell-division protein that comprises part of the polymerase-associated factor 1
complex (Paf1c). The human PAF1 complex (hPAF1C) contains homologs of most of the same subunits and
shares similar functions. hPAF1C associates with RNA polymerase II during transcriptional initiation
and elongation and participates in some histone modifications and posttranscriptional events, including
modification of the poly (a) tail. Cdc73p homologs in higher-level organisms contain a metazoan-specific
N-terminal domain, capable of directly binding β-catenin, and function in Wnt signaling, a central
regulator of development and proliferation . Although parafibromin’s precise role in Wnt signaling,
[28]
which might vary by cell type [28-30] , has yet to be established, the involvement of parafibromin in canonical
Wnt/β-catenin signaling provides a possible mechanism for parafibromin’s tumor suppressive function(s).
Activation of canonical Wnt signaling leads to β-catenin-mediated gene transcription; targets of Wnt
signaling include cyclin D1, a parathyroid oncogene (described further below) [31,32] . Parafibromin can
inhibit cancer cell growth and cause G1 phase arrest in vitro, in part through effects on cyclin D1 [33,34] .
Loss of Wnt pathway components APC and GSK3β and accumulation of β-catenin have also been
[35]
described in parathyroid cancer . Cytoplasmic parafibromin interacts with cytoskeletal proteins and
[36]
[26]
p53 mRNA, modulating p53-mediated apoptosis . Parafibromin can also interact directly with the SV40
[27]
large T antigen; cell lines expressing SV40 large T exhibit different effects on proliferation subsequent to
perturbation of parafibromin levels , a finding which has complicated interpretation of some in vitro
[37]
functional analyses.
Conventional and conditional transgenic mouse knockouts of CDC73 have been developed. Homozygous
germline deletion of CDC73 is embryonic lethal and germline deletion of CDC73 at later stages of
development led to death within 20 days; increased apoptosis was observed in many tissues . No parathyroid
[38]
gland abnormalities were initially described in either CDC73 knockout . A later study, which followed
[38]
heterozygous CDC73 knockout mice out to 21 months, reported increased parathyroid proliferation and
histologic abnormalities commonly observed in atypical parathyroid adenomas and parathyroid carcinomas
in humans; frank features of parathyroid cancer, such as local invasion or distant metastasis were not
described. Deletion of CDC73 targeted to the parathyroid glands, by crossing floxed-CDC73 mice with PTH-
Cre mice, resulted in similar parathyroid gland abnormalities; heterozygous and homozygous null mice
were both affected . Further studies are necessary to understand how loss of CDC73 expression promotes
[39]
parathyroid tumorigenesis.