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Activated RAS binds to various downstream
effector molecules such as GAP, NORE1, PKC,
MEKK, PI3K, and RAF, which regulate cell proliferation and survival. Point mutations in RAS
in thyroid tumors typically occur in codon 12/13
inexon1andcodon61inexon2.Thesemutations cause increased affinity to GTP or decreased
affinity to GTPase, which in turn leads to constitutive activation of downstream effector molecules. The mitogen-activated protein kinase
(MAPK) pathway via BRAF and the PI3K/Akt
pathway are the main signal pathways that are
activated by RAS mutation in thyroid tumors.
Hou et al. [9] have suggested that RAS-PI3K/Akt
activation contributes to FTC development while
RAS–RAF–MAPK pathway activation selectively
leads to PTC, based on their findings of more
frequent PI3K/Akt-related genetic changes in
FTC.
In thyroid cancer, the prevalence of RAS mutations is variable. Vasko et al. [10] performed a
pooled analysis of 269 mutations in H-RAS,
K-RAS, and N-RAS from 39 previous studies.
The rates of mutation involving N-RAS exon 1
and K-RAS exon 2 were less than 1%. Mutations
of codon 61 of N-RAS were significantly more
frequent in follicular tumors (19%) than in
PTC (5%) and significantly more frequent in
malignant (25%) compared with benign (14%)
tumors. H-RAS mutations in codons 12/13 were
found in 2–3% of all types of tumors, but H-RAS
mutations in codon 61 were observed in only
1.4% of tumors, and almost all of them were
malignant. Both H-RAS mutations in codons
12/13 and mutations of codon 61 of N-RAS
occur more frequently in follicular adenoma
than in follicular thyroid carcinomas (FTC).
Nikiforova et al. [11] have also reported a higher
frequencyof RAS mutation in follicular adenoma
compared with follicular carcinoma. RAS mutations are also found in some PTCs [12].
RAS point mutations have been suggested to
be an early event in the tumorigenesis of FTC
because they occur in both follicular adenomas
and FTC. However, considerable variability in
the prevalence of RAS mutation has been reported. These variations may be due to factors such
as radiation exposure, iodine intake, different
pathologic classification, or technical factors [8].
Poorly differentiated and ATCs are more likelyto
have RAS mutations in some reports [13].
RAS mutations may also be associated with
more aggressive disease and a poorer prognosis
in thyroid cancer. In a recent report, transgenic
mice carrying the N-RAS gene mutation developed poorly differentiated thyroid carcinomas
[14]. Furthermore, RAS signaling through the
downstream MAPK and PI3K/Akt pathways stimulate dedifferentiation of follicular thyroid
cells [15]. Taken together, these findings suggest
that RAS is involved in both the initiation and
the progression of some thyroid cancers.
RET/PTC Rearrangement
Another important mechanism in the activation
of the RET tyrosine kinase in follicular thyroid
cells is the inter- or intrachromosomal rearrangement of RET to another gene; unlike the
activating point mutations in the RET protooncogene in medullary thyroid cancer, this predominant mutation in cancers of follicular cell
origin is an RET rearrangement. The RET/PTC
rearrangement leads to reparative fusion of the
0
3
coding region of RET to the 50region of another
gene by virtue of their proximity [16]. These
fusion genes have the ability to self-dimerize
and constitutively activate downstream signal
pathways through autophosphorylation of the
docking sites Y905, Y1015, and Y1062 [17]. This
signal is mainly mediated through the RAS–
RAF–MAPK and PI3K/Akt pathways; however,
alternative pathways may also exist, as in the
case of Rap1, a small G protein which can mediate signals to BRAF [18].
Fusco et al. first reported the fusion of RET
and the H4 gene (now referred to as the RET/
PTC1 rearrangement) [19]. Since then, more
than 15 forms of RET rearrangement with other
partner genes have been reported [3]. Among
the known rearrangements, RET/PTC1 and
RET/PTC3 (fusion of RET and the RFG gene)
represent over 90% ofRET/PTC rearrangements;
others include RET/PTC2, ELKS/RET, and other
rarer forms associated with radiation-induced
thyroid cancers [20].
The main cause of RET/PTC rearrangements
in PTC is radiation exposure. In human normal
thyroid tissues transplanted into SCID mice,
RET/PTC rearrangement was detected after
X-ray exposure of 50 Gy [21]. Furthermore,
investigations of patients with PTC associated
with the Chernobyl nuclear reactor accident
had a higher prevalence of RET/PTC rearrangement (up to 80%) than in PTC patients with no
history of radiation exposure where BRAF
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MOLECULAR BIOLOGY OF THYROID CANCER
mutations are more common [22]. Nevertheless, the presence (however infrequent) of
RET/PTC rearrangement in patients without
known radiation exposure implies another,
radiation-independent mechanism [23].
The prevalence of RET rearrangement varies
from 5 to 85%, with higher rates in pediatric
and irradiated patients [23–25]. Most RET/PTC
rearrangements are found only in PTC; however, some investigators have found these rearrangements in Hu¨rthle cell adenomas and
Hu¨rthle cell carcinomas (HCC) [26]. HCC is
considered to be a variant of FTC by the World
Health Organization, but differences in clinical
behavior such as higher rates of LN metastasis
and different subtypes of HCC have led many
investigators to conclude that it is a separate
and distinct subtype of thyroid cancer. In this
light, RET/PTC rearrangements may play a role
in the development of the specific papillary type
of HCC as opposed to FTC.
RET/PTC rearrangements appear to be an
early event in carcinogenesis of PTC, based on
their presence in occult papillary thyroid cancers
[27]. RET/PTC has also been shown to transform follicular thyroid cells after transfection
[28]. Different types of RET/PTC rearrangements
may be associated with distinct biological behaviors. Patients with RET/PTC1 usually have slow
indolent cancers, whereas RET/PTC3 is found
in a solid variant of PTC with a more aggressive
tumor phenotype [22, 29, 30]. Nevertheless, several reports have failed to identify RET/PTC rearrangements in aggressive forms of PTC [31].
BRAF
BRAF mutation is the most frequent mutation
in PTC [32]. It has recently become the subject
of active investigation because of its relationship to a more aggressive clinical phenotype. It
also presents new opportunities for the development of diagnostic markers and a target for
therapy.
The protein product of BRAF is one of three
isoforms belonging to the RAF family of serine/
threonine kinases, along with ARAF and CRAF.
The BRAF gene is located on chromosome 7q23
and encodes a 95-kDa cytoplasmic protein. It
is composed of three conserved regions – CR1,
CR2, and CR3. CR1 is located at the amino terminal and is thought to serve a regulatory function
via its RAS-binding and cysteine-rich domains.
CR2 is an activation loop with phosphorylation
sites at S445 and S448 [33], and the CR3 region
has akinase domain at the carboxy terminal [34].
Activation of RAF by phosphorylation occurs
immediately downstream of the membrane or
cytoplasmic receptor; this phosphorylation in
turn relays signals through the MAPK pathway,
which plays a significant role incell proliferation,
migration, and survival [35]. After the initial
report by Davies et al. of the link between the
BRAF somatic mutations in exon 11 and exon 15
in human cancers [36], BRAF mutations have
been identified in a wide variety of tumors such
as malignantmelanoma andcancers of the breast,
colon, ovary, lung, and thyroid [37].
In thyroid cancers, BRAF mutations are
usually confined to exon 15 in the T1799A position,whichresultsinanaminoacidchangefrom
valine to glutamate (V600E) in the kinase domain.
This V600E mutation represents almost all of the
BRAF mutations found in thyroid cancer. In
addition to the T1799A point mutation, however, other rarer forms of BRAF mutation have
also been reported, including a point mutation
in A1801G [38], tandem TG1800AA mutation,
AKAP8–BRAF rearrangement, G1800_1802AAdel
and T1799_1801TGAdel mutation in metastatic
lymph node tissue, and V599Ins mutation [39].
No germ line BRAF mutations have as yet been
identified [40].
TheprevalenceofBRAFmutationsvariesfrom
36 to 86% in papillary thyroid cancers [38,
41–44]. Interestingly, some geographic regions
and ethnic groups appear to have a higher BRAF
mutation rate. In Korea, for example, reports of
prevalence range from 58 to 86% [44]. BRAF
mutation is found less frequently in pediatric
patients with PTC, or in patients with PTC following radiation exposure. Only 4–6 % of PTCs
from Chernobyl had BRAF mutations, whereas
RET/PTC rearrangements occurred in 35–58%.
Younger patients are also more likely, with or
without a history of radiation exposure, to have
RET/PTC rearrangements [45,46]. In contrast, a
BRAF mutation is much more prevalent compared to RET/PTC rearrangements in PTCs
from adults with or without a history of radiation exposure [46]. Indeed, this finding has also
been confirmed in older patients without radiation exposure history [47].
It is rare for BRAF, RAS, or RET/PTC rearrangement to be present simultaneously. All but
one study have shown mutual exclusivity of
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these mutations in PTC [46]. This represents one
of the most distinctive characteristics found in
genetic mutations of PTC. This mutual exclusivity suggests that a single genetic alteration may
be enough to drive follicular cell transformation
and the development of PTC.
The V600E BRAF mutation results in conformational change in the CR2 activation loop
which leads to higher ERK1/2 kinase activity
and constitutive MAPK pathway activation [48,
49]. The ability of the other forms of BRAF mutations to cause MAPK activation has not been
completely elucidated, but seems likely given
that the T1799-1801del and T1799-1816ins forms
are in the activation loop of the protein [50].
Furthermore, the BRAF pathway also can be
modulated by other signals such as FGF. For
example, restoration of FGFR2 by stable transfection in PTC cell lines attenuates BRAF and
MAPK phosphorylation [51].
The presence of a BRAF mutation is closely
related to PTC development. Thus, Knauf et al.
[52] showed development of PTC in a transgenic
BRAF mutant mouse model. Furthermore, it
seems that BRAF mutations play a role in
tumorigenicity, growth, and proliferation of
PTC, based on in vitro studies of BRAF
knocked-out or inhibited cancer cell lines [53].
As mentioned previously, a BRAF mutation is
the most common somatic mutation in PTC;
however, it also exists in variants of PTC such as
tall-cell PTC, poorly differentiated PTC, and
anaplastic thyroid cancer BRAF copy number
gain, as measured by fluorescence in situ hybridization, is common in FTC and follicular adenomabutnotinPTC[54].Ingeneral,more
aggressive phenotypes such as tall-call variant
of PTC are more likely to have a BRAF mutation
than well-differentiated PTC. Recently, Trovisco et al. reported that 40% of oncocytic variants of PTC and 75% of Warthin-like variants
had BRAF mutations, whereas no BRAF mutations were found in columnar variants of PTC,
in diffuse sclerosing variants of PTC, or in hyalinizing trabecular thyroid tumor [38]. The absence
of BRAF mutations in columnar variants seems
surprising as these tumors are similar to tall-cell
variants.
As mentioned above, BRAF mutation is
mutually exclusive of the other main genetic changes and the most prevalent mutation in PTC [42,
43]. Some investigators have suggested testing
for the BRAF V600E mutation may improve the
diagnostic accuracy of FNA biopsy. BRAF mutation analysis in needle biopsy samples had a sensitivity of 37–85.3%, and specificity 100% [42, 55].
Some investigators have reported that the
presence of a BRAF mutation in PTC is associated with a more aggressive clinical behavior.
A BRAF mutation is associated with older age
[47], extrathyroidal invasion [56], male gender
[57], regional lymph node metastasis [44, 56],
higher stage [56], andrecurrence [44, 56]. Several
investigations suggest possible mechanisms for
the BRAF V600E mutation and its more aggressive tumor phenotype. Expression of thyroidspecific iodine-transfer genes, including TPO
[58], sodium and iodine symporter [59], Tg
[60], and pendrin [61], are decreased in BRAF
mutation-associated PTC. The presence of a
BRAF mutation is also associated with angiogenesis and local invasion [62], as evidenced by
increased expression of MMP3/9/13 after BRAF
mutant transfection [63]. The correlation between
BRAF mutation and aggressive behavior is further
supported by a study that demonstrated restoration of the expression of iodide-metabolizing
genes in PTC cells with a BRAF mutation after
suppression of the BRAF/MEK/MAPK pathway
[64].
Not all investigations, however, demonstrate
an association between BRAF mutation status
and PTC behavior. Fugazzola et al. reported no
association between BRAF mutation and aggressive behavior of PTC in a multicenter study of
260 patients [65]; there have been other studies
that have supported these findings [41, 42, 66].
Possibleexplanations for these discordant results
are study cohort size, geographic area, inclusion
of nonconventional papillary thyroid cancer,
methods for BRAF detection, lack of multivariate analysis, and insufficient follow-up time
to determine patient outcome. A recent metaanalysis including 1,168 patients from 12 studies showed association of BRAF mutation with
clinical stage and extrathyroidal invasion but
did not include all the studies to date [67].
It remains unclear whether the use of a more
aggressive treatment modality (such as routine
prophylactic bilateral central lymph node dissection or high-dose radioactive iodine ablation)
is mandated at this time for localized PTC harboring a BRAF mutation. Recently, Fagin et al.
demonstrated that DUSP5 and MKP3, (MAPK
pathway inhibitor enzymes) are up-regulated by
BRAF activation [63]. This suggests that certain
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MOLECULAR BIOLOGY OF THYROID CANCER
molecular markers play a role in modulating activated BRAF signals and may influence the effect of
a BRAF mutation on tumor aggressiveness. Thus,
it may be possible to find molecular changes that
affect prognosis in PTCs with a BRAF mutation.
NTRK Rearrangement
The NTRK1 gene is located on chromosome
1q22 and encodes the receptor for nerve growth
factor. Similar to RET, NTRK1 undergoes oncogenic activation by chromosomal rearrangement
to the 5
of rearrangements have been reported depending on the subtype of TRK. NTRK1 is formed
through intrachromosomal rearrangement with
the 5
gene. TRK-T1 and TRK-T2 are formed by fusion
with the TPR gene, while TRK-T3 is formed with
the TAG gene [68, 69]. TRK1 rearrangements are
found only in PTC and are considerably less
prevalent than RET/PTC rearrangements [70].
0
region of another gene. Several types
0
region of the nonmuscle tropomyosin
PAX8/PPARg Fusion
PAX8 is a transcription factor that is expressed
at higher levels in follicular thyroid cells, and
regulate the expression of thyroid-specific genes
[71]. PPAR is a nuclear hormone receptor and
transcription factor which regulates cellular
proliferation and differentiation. PAX8/PPAR
fusion is generated from chromosomal translocation t(2;3)(q13;p25). The fusion gene contains
the promoter 5
coding region of PPAR. This fusion gene
encodes a protein called PAX8/PPAR fusion
protein (PPFP). PPFP is found predominantly
in FTC, with a prevalence of 26–63% [72, 73].
PAX8/PPAR has been suggested to play an
important role as a tumor suppressor gene by
inhibiting the function of wild-type PPAR.
Similar to the case of BRAF mutation and
PTC, the possibility of PAX8/PPAR as a diagnostic and prognostic marker for FTC has been
proposed [74]. Furthermore, recent findings
that PPAR agonists can induce redifferentiation of FTC cell lines lead to intriguing ideas of
possible therapeutic applications [75].
P53
P53 is one of the most important tumor suppressor genes in human malignancies, as evidenced
0
region of PAX8 along with the
by the finding that its inactivating point mutation is found in 50% of human cancers. The gene
is located on chromosome 17p13 and encodes a
53-kDa protein product. P53 integrates multiple
stress signals and regulates cell response to DNA
damage by the induction of a series of target
genes which attenuate cell-cycle progression. In
thyroid cancer, only 10% of all thyroid cancers
harbor the P53 mutation, and are most frequently found in poorly differentiated thyroid
carcinomas (75%) and ATC [76, 77]. As these
data imply, P53 mutations are late events in the
progression from differentiated carcinoma to
undifferentiated carcinoma and ATC. P63 and
P73, which are transcriptionally active and inactive isoforms of P53, have also been reported to
play a role in carcinogenesis of differentiated
thyroid carcinoma [78].
PTEN
PTEN is a tumor suppressor gene located on
chromosome 10q23.3. It encodes a tyrosine
phosphatase, which serves to inactivate tyrosine
kinase-mediated pathways. In thyroid tissue,
PTEN mutation leads to activation of the PI3K/
Akt pathway and development of FTC [79]. Inactivating germline mutations of PTEN are frequently found in Cowden’s syndrome, which is
characterized by hamartomas, breast cancer, thyroid cancer, and multinodular goiter. The prevalence of somatic PTEN mutations in thyroid
carcinoma is low (6%), but it is present in approximately 26% of benign thyroid tumors [80].
Thyroid-stimulating hormone receptor Thyroid-stimulating hormone receptor (TSHR) is a
transmembrane glycoprotein which on binding
TSH functions as the primary regulator of follicular thyroid cell function. Activating TSHR
mutations primarily occur in autonomous thyroid adenomas, with prevalence rates ranging
from 3 to 82% [81]. TSHR mutation is rare in
malignant thyroid tumors, and their role in thyroid carcinogenesis is unclear [82].
Others Molecular Factors Involved
in Thyroid Cancer of Follicular Cell
Origin
In addition to the above-mentioned mutations,
several other genetic changes have been reported
in thyroid tumors. The protein product of MET,
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a receptor of hepatocyte growth factor (HGF),
has been shown to be overexpressed in 75% of
PTC and 25% of ATC but activating mutations
have only beenfound in 7% of well-differentiated
thyroid carcinomas [83]. Point mutation of the
gene for stimulating G protein (GSP) has been
reported in nonfunctioning autonomous adenomas and thyroid carcinomas, with a prevalence
of 7–28% [84]. Simultaneous occurrence of RAS
and GSP mutations may be associated with more
aggressive behavior of differentiated thyroid carcinomas, but is rare [85]. A -catenin mutation
is only observed in poorly differentiated thyroid carcinoma (0–25%) and ATC (up to 66%)
but not in well-differentiated carcinoma [86].
-Catenin gene mutations induce nuclear
localization of the -catenin product, and may
contribute to progression toward poorly differentiated carcinoma and ATC [87]. Other less
well-established or less-frequent genetic changes
associated with thyroid cancer include EGFR/cerb2, APC, MTS1, Rb, cyclin D1, E-cadherin, and
FGFR [8, 88].
Epigenetic Changes in Thyroid
gene, thereby silencing its expression as well as
that of any number of other downstream genes.
Covalent histone modification occurs via deacetylation and methylation at specific lysine residues, which causes the protein to more tightly
bind and compact the DNA sequence within the
chromatin structure and thus prevent its ability
to be transcribed. Nucleosome remodeling refers
to a variety of ATP-dependent polypeptide complexes, including the nucleosome-remodeling
and deacetylase complex (NuRD) and SWI/SNF
that appear to have central roles in local noncovalent chromatin modification and transcriptional repression. It is important to note that the
three mechanisms described above increasingly
appear to intimately interact with one another
to cause the permanent silencing of cancerrelated genes [89].
Prior investigations studying the epigenetics
of thyroid cancer have largely focused on DNA
methylation but we will also briefly discuss other
mechanisms.
DNA Methylation and Thyroid
Tumorigenesis
Cancer
Epigenetics refers to changes in gene expression, usually in the form of gene silencing, that
occur due to processes that do not fundamentally alter genomic DNA. The term encompasses
a variety of mitotically heritable mechanisms
that are designed to play important roles in normal eukaryotic processes, including embryogenesis, differentiation, and genomic imprinting.
Thus, derangements by epigenetic mechanisms
could result in a variety of disease states, including carcinogenesis. Indeed, in the past two
decades there has been a growing body of evidence that suggests that epigenetic changes, as
well as their intricate association with classic
genomic mutations, contribute to the pathogenesis of cancer.
There are generally thought to be three major
categories of epigenetic mechanisms – DNA
methylation, histone modification, and nucleosome remodeling. DNA methylation, by far the
most studied and characterized, classically
involves the methylation of a cytosine residue
in a CpG dinucleotide-rich area (known as a
CpG island) within the 5
0
promoter region of a
There is growing evidence that DNA methylation-mediated silencing of genes is an important mechanism of thyroid carcinogenesis. Most
of the silenced genes that have been studied are
associated with thyroid function and tumor suppression (Table 7.2). In addition, DNA methylation has been shown to correlate with known
geneticmutationsthat predisposeto thyroid cancer [90]. BRAF is an example of this phenomenon. As described above, mutation in this gene
can cause constitutive activation of the BRAF/
MAPK pathway and the development of PTC.
A recent study has shown that PTC specimens
with methylated tumor suppressor genes, including TIMP3, SLC5A8, DAPK,andRAR2,had
a significantly higher percentage of BRAF mutations and also predicted a greater degree of
clinical aggressiveness [91]. This suggests that
inactivation of these tumor suppressor genes
can contribute to the constitutive activation of
the mitogen BRAF/MAPK pathway in PTC. This
is further supported by the finding that FGFR2,
which encodes a fibroblast growth factor receptor protein that downregulates BRAF/MAPK
signal transduction, is methylated and silenced
in several thyroid cancer cell lines [92].
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MOLECULAR BIOLOGY OF THYROID CANCER
Table 7.2. Genes involved in thyroid cell function that are epigenetically silenced by DNA methylation
Gene Normal function of encoded protein
DAPK Calcium/calmodulin-dependent serine threonine kinase; acts as a tumor suppressor via proapoptosis
FGFR2 Tyrosine kinase receptor that competitively binds FGF; acts as a tumor suppressor by downregulating
the BRAF/MAPK pathway
NIS Sodium/iodide symporter; transports iodide from blood into thyroid cell through basal membrane
p16 Competitive binder of CDK-4 and CDK-6; acts as a tumor suppressor by blocking cell-cycle progression at G1/S phase
PTEN Phosphatase; acts as a tumor suppressor by dephosphorylating PIP3 with resultant downregulation of the PI3K/Akt
signal transduction pathway
RAR2 Retinoic acid receptor, acts as a tumor suppressor by regulating the growth of epithelial cells
RASSF1A Signaling protein, acts as a tumor suppressor probably by inhibiting the Ras pathway
RIZ1 Nuclear protein methyltransferase; acts as a tumor suppressor by binding Rb
SLC5A8 Sodium/iodide symporter; transports iodide into thyroid cell through apical membrane; also acts as a tumor
suppressor via proapoptosis
SLC26A4 Sodium/iodide symporter; transports iodide into thyroid cell through apical membrane
TIMP3 Tissue inhibitor of metalloproteinase via binding of Zn-binding site; acts as a tumor suppressor by inhibiting
growth, angiogenesis, and invasion
TSHR TSH receptor; binds TSH in the upstream regulation of iodide-dependent thyroid hormone formation
Other genes associated with thyroid cancer
have recently been demonstrated to be methylated, including PTEN and RASSF1A [93, 94].
The case of RASSF1A is particularly interesting
because it is a tumor suppressor gene which
encodes a signaling protein that probably acts
in the Ras pathway by blocking cell-cycle progression and inhibiting cyclin D1 accumulation.
Suppression of its expression has been reported
in a variety of solid organ cancers, including
lung, breast, kidney, prostate, ovary, and colon
[95]. In thyroid cancer, methylation of RASSF1A
appears to occur throughout all subtypes of follicularepithelialcell-derived carcinomas, including papillary thyroid cancer, follicular thyroid
cancer and anaplastic thyroid cancer [93, 96].
However, the pattern of its epigenetic silencing
varies depending on the subtype of thyroid
tumor. For example, RASSF1A is methylated
along with PTEN mostly in FTC, suggesting a
possible role of RASSF1A in the same PI3K/Akt
pathway that PTEN would normally inhibit. On
the other hand, RASSF1A methylation is also
found (albeit uncommonly) in some papillary
thyroid cancers, independent of the presence of
BRAF mutations [96]. These findings illustrate
that epigenetic events can be varied and multiple,
and in combination with established thyroid
oncogenes can facilitate neoplastic progression
supporting the multihit model of carcinogenesis
as described by Knudson [97].
Considering the myriad ways in which DNA
methylation can potentially affect gene expression and progression of cancer cell development,
it is interesting that studies of global 5-methylcytosine content have actually shown an overall
decrease in genome-wide methylation [98]. This
phenomenon appears to hold true in the case
of thyroid cancer, based on recent quantitative
immunohistochemical studies that show decreased DNA methylation in PTC and FTC samples compared with benign controls [99]. This
occurs despite evidence of correlation between
undifferentiated thyroid carcinoma and hypermethylation at certain distinct tumor-related
CpG island promoter regions [100].The mechanism by which local hypermethylation leads to a
global hypomethylation across the cancer genome remains poorly understood as does the specific regulators of genome-wide methylation.
Other Epigenetic Mechanisms
in Thyroid Tumorigenesis
The covalent modification of histones via acetylation and deacetylation plays another key role
in the epigenetic regulation of gene expression.
Histone deacetylase (HDAC) is responsible for
freeing the histone’s positively charged lysine
residues at the N terminus, causing the histone
to more strongly bind its associated negatively-
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charged DNA. This in turn results in tighter
chromatin compaction and inhibition of gene
expression via blockage of DNA transcription.
The importance of HDAC in gene expression has
become more apparent in the last decade, especially because of its close association with DNA
methylation [89]. However, the role of histone
modification specifically in thyroid tumorigenesis has only recently begun to be characterized.
Most prior investigations have studied the effects
of HDAC inhibitors on cell-cycle regulation and
thyroid-specific gene expression in thyroid cancer cell lines, suggesting that HDAC-mediated
histone modification inhibits apoptosis via increased p53 and decreased p27 activity, and leads
to loss of expression of thyroid-specific genes
such as NIS, TPO, Tg, and RAR [101, 102].
Nucleosomal remodeling via noncovalent
modifications in the SWI/SNF chromatin-remodeling complex and the nucleosomal remodeling
complex (NuRD) has been shown to play a key
role in epigenetic gene silencing in various models of tumorigenesis, such as malignant rhabdoid
tumors (MRT) and cancers of the lung, breast,
prostate, and pancreas [89]. To our knowledge,
there have been no studies that have specifically
examined the role of nucleosomal remodeling in
thyroid cancer. Further investigations regarding
this possible mechanism in thyroid carcinogenesis are of interest.
Summary
Our understanding of the genetic and epigenetic
changes associated with thyroid cancer pathogenesis continues to increase. Many of these
genetic and epigenetic changes will have important clinical applications concerning the diagnosis, prognosis, and treatment of patients with
thyroid cancer.
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