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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_53_библиотеки_им_акад_М_И_Перельмана
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An elevated risk was also reported in women who used estrogens for gynecologi-
cal problems. In some studies higher levels of estrogen receptors (ERs) were found
in neoplastic than in normal thyroid tissues (Yane et al. 1994). Classically, ERs are
intracellular receptors that serve as transcription factors. The ligand-bound dimer ER
can interact with an estrogen-responsive element, resulting in transcriptional activa-
tion of the target gene (Carson-Jurica et al. 1990). However, various studies have
provided evidence that estrogen may also affect growth factor-dependent signaling
pathways (Auricchio et al. 1996). One of the targets of estrogen action is the mitogen
activated protein (MAP) kinase (MAPK) whose activity is regulated by growth
factors (Migliaccio et al. 1996). 17 ß-Estradiol stimulates cell cycle progression
early in G1 phase by induction of cyclin D1 gene expression (Foster and
Wimalasena 1996). In different cell lines, the induction of cell growth was found
to correlate with increased expression of cyclin D1 protein levels (Diana et al. 2001).
8.2.3.9 Smoking Status
Although relatively little is known about the etiology of TC beyond its association
with radiation exposure and some previous thyroid disorders (Ron 1996), data is
slowly accumulating as to the protective effect of cigarette smoking on this disease.
TC has been negatively associated with cigarette smoking in a number of studies,
possibly consistent with the greater occurrence of the disease in women than in men
(Kreiger and Parkes 2000). There are at least five distinct proposed mechanisms for
the effect of tobacco smoke on thyroid function. The first one relates to a smoking
related reduction in TSH secretion, as it has long been hypothesized that elevated
levels of TSH may increase the risk of TC (Mack et al. 2003). The low er body weight
among smokers compared to non-smoker s is a second proposed explanation, as
increased body weight was associated with a slightly increased TC risk in the above-
mentioned pooled analysis (Mack et al. 2003). A third possible biological pathway
lies in the potential anti-estrogenic effect of cigarette smoke; a role for estrogen in the
etiology of TC is hypothesized because of the higher incidence of this cancer in
females relative to males (Mack et al. 2003). The fourth is higher levels of thyroxine-
binding globulin and testosterone among smokers compared to non-smokers and the
fifth is the higher levels of thyrotoxins in tobacco smoke in heavy smokers compared
to light and moderate smokers (Konstantinos and Faidon 2004).
8.2.3.10 Oxidative Stress (OS)
OS is an imbalance between free radicals and antioxidants in body. In essence, OS
represents an imbalance between the production of oxidants and their elimination by
anti-oxidative systems in the body. Many studies have linked OS to TC by showing
its association with abnormally regulated oxidative or anti-oxidative molecules
(Lassoued et al. 2010).
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8.3 Genetic Basis of Thyroid Cancer
TC is the most common malignancy of the endocrine system, and a disease whose
incidence has been increasing over the past 20 years (Jennifer and Manisha 2009).
Thyroid tumors represent an appropriate model for the study of epithelial neoplastic
transformation. The roles of somatic mutations, gene rearrangement(s), and level of
gene expression in carcinogenesis are now well established. The application of
molecular techniques to thyroid tumors has focused particular attention on the role
of point mutations activating (or inhibiting) the genes for the TSH receptor (TSHR),
RAS, BRAF, Gsp, P53, etc. (Yashimoto et al. 1992), specific rearrangements of the
oncogenes RET and TRK (Bounacer et al. 1997), and alterations in the pattern of
expression of the oncogene BRAF, MET, etc. (Horacio 1998).
The theory of sequential progression of well-differentiated thyroid carcinoma
through the spectrum of poorly differentiated to undifferentiated thyroid carcinoma
is supported by the presence of pre- or co-existing well-differentiated thyroid
carcinoma with less differentiated types, and the common core of genetic loci with
identical allelic imbalances in co-existing well-differentiated components (Tetsuo
et al. 2006). Figure 8.1 depicts the model of multi-step carcinogenesis of thyroid
neoplasms.
8.3.1 Genetic Alterations in Signaling Pathways in TC
The principal cell-surface receptors that are involved in the regulation of thyroid
follicular cell growth and function are shown in Fig. 8.2. Alterations in key signaling
effectors seem to be the hallmark of distinct forms of thyroid neoplasia.
8.3.1.1 Cyclic AMP (cAMP) Cascade
Thyroid-stimulating hormone (TSH) activates the GSα–adenylyl cyclase–cyclic
AMP (cAMP) cascade on binding to the TSH receptor (TSHR) (Fig. 8.2), thereby
regulating thyroid hormone synthesis and the growth of follicular cells (Kimura et al.
2001). Gain-of-function mutations of TSHR (which is located on chromosome
14q31) and GNAS1 (which encodes GSα and is located on chromosome 20q13),
both of which activate cAMP, occur in hyper-functioning thyroid adenomas (Krohn
et al. 2005). By contrast, activating mutations of TSHR and GNAS1 in thyroid
malignancies are rare—this is consistent with the clinical observation that hyper-
functioning thyroid nodules are unlikely to be malignant (Matsuo et al. 1993).
8.3.1.2 MAP Kinase Signaling Pathway
In well-differentiated thyroid c arcinoma, which is the most common form of TC,
mutations or rearrangements in genes that encode MAPK pathway effectors seem to
be required for transformation. Indeed, exclusive, non-overlapping, activating events
that involve the genes RET, NTRK1 (neurotrophic tyrosine kinase receptor 1), BRAF,
or RAS are detect able in nearly 70% of all cases (Xing 2005). Gain-of-function
mutations of RET are involved in sporadic and familial C-cell-derived medullary
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thyroid carcinoma, including multiple endocrine neoplasia 2A (MEN2A), MEN2B,
and familial medullary thyroid carci noma. By contrast, chimeric oncogenes,
designated RET/PTC, are implicated in the development of papillary carcinoma
(Tallini and Asa 2001) (Fig. 8.2).
Mutations in BRAF were the most recently identified MAPK effector in
TC. BRAF mutation provides an alternative route for the aberrant activation of
ERK signaling that is implicated in the tumorigenesis of several human cancers—
Fig. 8.1 Model of multi-step carcinogenesis of thyroid neoplasms. The proposed model of thyroid
carcinogenesis is based on general concepts and specific pathways. (a) Risk factors, such as
exposure to radiation, induce genomic instability through direct and indirect mechanisms, resulting
in early genetic alterations (b) Scheme of step-wise dedifferentiation of follicular cell-derived TC
along with genetic alterations
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for example, melanoma and colon carcinoma (Davies et al. 2002). BRAF V600E is
the most common alteration in sporadic papillary carcinoma (Xing et al., 2005).
Instead, a chromosomal rearrangement (AKAP9–BRAF) that represents yet another
form of paracentric inversion has been identified in radiation-associated TC (Ciampi
et al. 2005). Unlike other solid neoplasms, RAS, a member of MAP kinase pathway,
is the least prominent participant in thyroid carcinogenesis. Three RAS
protooncogenes (NRAS, HRAS, and KRAS) are implicated in human tumorigenesis
(Downward 2003). Mutations involving codon 61 of HRAS and NRAS have been
reported with variable frequency in thyroid neoplasms (Lemoine et al. 1989). RAS
mutations are more common in iodine-deficient than iodine-sufficient areas and in
lesions with follicular architecture (including follicular carcinoma and follicular
variant papillary thyroid carcinoma) than in typical papillary thyroid carcinoma
(Zhu et al. 2003).
Fig. 8.2 Cell signaling pathways in follicular cells. TSHR signaling operate through cAMP as
secondary messenger; MAP kinase signaling operates through RAS family and BRAF
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8.4 Genetic Polymorphisms in Thyroid Cancer
One of the most important tools underlying the revolution in medical genetics is the
ability to visualize sequence differences directly in DNA. When studied in the
context of a population, these differences in DNA sequences are called
polymorphisms; they may occur in coding regions (exons) or noncoding regions
of genes. The ability to visualize thousands of DNA polymorphisms has made
possible family studies for tracking genes of medical importance.
Classically, polymorphisms represent sequence variations, which are present in
the general population, and confer no deleterious effects. However, as the human
genome project evolved and molecular epidemiological studies were performed, it
became clear that some “polymorphisms” were not entirely harmless. This technique
has located and identified genes for many disorders with a clear pattern of Mendelian
inheritance, such as cystic fibrosis, the inherited muscular dystrophies, and neurode-
generative disorders such as Huntington’s disease. Methods that exploit genetic
polymorphism will also be essential for finding genes that predispose people to
more common conditions in which inheritance patterns are complex, such as diabe-
tes, atherosclerosis, and hypertension.
DNA polymorphisms are also playing a crucial part in unraveling the genetic
basis of tumor formation and progression in cancer. They provide markers for the
loss of specific chromosomal segments during the evolution of a tumor. DNA
polymorphisms have already been crucial in the identification of genes important
for susceptibility to common forms of cancer, such as colon cancer, as well as
susceptibility to less common childhood tumors, such as retinoblastoma and
Wilms’ tumor (David et al. 1995). As is true of the human genome as a whole–in
which over 3.1 million sequence variations have been mapped, which represent
25–35% of the total estimated SNPs (The International HapMap Consortium 2003;
Frazer et al. 2007).
Differentiated TC is characterized by a strong hereditability, and individual
susceptibility is likely due to genetic factors modulating the environmental risk.
Identification of genetic polymorphisms is important for understanding the potential
mechanisms involved in thyroid carcinogenesis. In TC many single nucleotide
polymorphisms have been reported in different genes and functional analysis of
many single nucleotide polymorphisms have been carried out. It has been reported
that these DNA polymorphisms in various genes predispose a person to higher risk
of TC and also has a marked effect on various clinicopathological characteristics of
TC patients (David et al. 1995).
8.4.1 HRAS (Harvey Rat Sarcoma)
In mammalian cells, the ras protooncogenes consist of three highly homologous
members, KRAS, HRAS, and NRAS. Each gene has the capacity to become
oncogenic as a consequence of a somatic mutation (Esteban et al. 2001). The word
Ras comes from a contraction of Rat sarcoma, the tumor where the first gene of the
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family was identified, as part of the genome of a retrovirus isolated from a carcino-
genesis protocol. It is located at 11p15.5, which is the short (p) arm of chromosome
11 at position 15.5 spanning base pairs 532,242 to 535,576.
8.4.1.1 Structure and Function of HRAS
The HRAS protooncogenes encode a family of evolutionarily conserved, 21-kDa
intracellular guanosine triphosphate (GTP) binding proteins (189 amino acids in
length) that are integral for cellular signal transduction and that ultimately regulate
cellular differentiation, proliferation, and function in a wide diversity of cell types
(Scott 2002) called HRAS. Through a process known as signal transduction, the
HRAS protein relays signals from outside the cell to the cell’s nucleus. These signals
instruct the cell to grow or divide. The HRAS protein is a GTPase, which means it
converts a molecule called GTP into another molecule called GDP. The H-Ras
protein acts like a switch, and it is turned on and off by GTP and GDP molecules.
To transmit signals, the protein must be turned on by attaching (binding) to a
molecule of GTP. The HRAS protein is turned off (inactivated) when it converts
GTP to GDP. When the protein is bound to GDP, it does not relay signals to the
cell’s nucleus. Mutations at affected codo ns result in oncogenic proteins containing
single amino acid substitutions at those corresponding positions. In a functional
sense, such ras proteins are aberrant as they become constitutively GTP-bound due
to a loss both in intrinsic GTPase activity and responsiveness to GAPs (GTPase-
activating proteins), which ordinarily help to facilitate the hydrolysis or dephosphor-
ylation of GTP to GDP. Hence, ras oncoproteins in the activated form appear to be in
a constitutively “on” state or signal transmitting mode, which has been proposed to
represent an early event in the initiation of the neoplastic process. This is most
notable, for example, in the pathogenesis and progression of human colorectal and
pancreatic adenocarcinoma. Mutations of ras have been found in, and associated
with, benign adenomas/polyps and pancreatic intraductal lesions (PILs) of colorectal
and pancreatic tumorigenesis, respectively, suggesting that the mutation precedes
the development of malignancy (Scott 2002).
8.4.1.2 Reported SNPs in HRAS Gene
Besides the mutation hotspots, inher ited polymorphisms in the HRAS sequence
were described (Sol-Church et al. 2006; Sanyal et al. 2004). A single nucleotide
polymorphism at HRAS cDNA position T81C (rs12628), originally described by
Catela et al., was shown to be associated with the risk of human cancers (Catela et al.
2009). It is present in codon 27 of exon 1 of HRAS, which is located in a wobble
base position. To the author’s knowledge, three relative meta-analyses were
performed previously. In 2008, Zhang et al. performed a meta-analysis of four
case–control studies with 388 cases and 391 controls and found that HRAS
rs12628 seems to be associated with the susceptibility to cancers, including bladder,
thyroid, and oral cancer (Zhang et al. 2008). In 2012, Traczyk, M. et al. assessed the
association between HRAS rs12628 and urinary bladder cancer in the Polish
patients, and conducted another meta-analysis of eight case–control studies (Traczyk
et al. 2012). Their meta-analysis resul ts showed that CC genotype of HRAS rs12628
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is likely to have implications in the overall cancer risk (Traczyk et al. 2012). In 2013,
Pandith et al. evaluated the relationship between HRAS rs12628 and urinary bladder
cancer in ethnic Kashmiri population, and also performed a meta-analysis with five
case–control studies, which suggested that HRAS rs12628 may act as a kind of risk
factor for cancer (Pandith et al. 2013). Another polymorphic site that could be
involved in the development of cancer disease is a hexanucl eotide repeat (Kotsinas
et al. 2001).
8.4.1.3 HRAS T81C Gene Polymorphism in TC
Follicular tumors of the thyroid are often aneuploid (Castro et al. 2006). Although
the presence of aneuploidy is not by itself an indicator of malignancy (Castro et al.
2006), aneuploid carcinomas tend to carry a worse prognosis than diploid
(or neardiploid) carcinomas of the thyroid (Schelfhout et al. 1990). Castro et al.
have first time investigated HRAS T81C polymorphism in thyroid tumors and has
associated it with aneuploidy in follicular tumors of the thyroid (Castro et al. 2006).
Although HRAS T81C polymorphism does not alter the amino acid sequence of the
protein, it may affect the expression of the gene inducing overexpression. It is
possible that it is linked to another polymorph ic locus inside regulatory intronic
region. HRAS T81C SNP has been found to moderately incre ase TC risk with variant
alleles implicated more in follicular thyroid tumors. Interestingly, it is also observed
that HRAS T81C variant allele shows reduced risk for the smokers with TC (Mosin
et al. 2013).
8.4.2 RET (Rearranged During Transfection)
The RET gene is located on chromo some 10q11.2 near the centromere and includes
21 exons. Takahashi et al. first identified RET in 1985 as a proto-oncogene that can
undergo activation by cytogenic rearrangement (Takahashi et al. 1985). Three years
later, the RET gene was cloned by the same investigators (Takahashi et al. 1988).
The RET gene encodes a plasma membrane-bound tyrosine kinase enzyme, the RET
receptor, which is expressed by neuroendocrine and neural cells, including thyroid C
cells, adrenal medullary cells, parasympathetic, sympathetic, and colonic ganglia,
cells of the urogenital tract, and parathyroid cells derived from branchial arches
(Tsuzuki et al. 1995).
8.4.2.1 Structure and Biology of RET Receptor
The RET protein consists of an N-terminal signal peptide, an extracellular region
(four cadherin-like repeats, a calcium binding site, and a cysteine-rich domain), a
transmembrane domain, and two intracellular tyrosine kinase domains. The extra-
cellular cadherin-like domains are important for cell–cell signaling, whereas the
cysteine-rich extracellular domain is importan t for receptor dimerization. The
C-terminal tail of RET shows three different splicing variants that produce three
protein isoforms with 9 (RET9; short isoform), 43 (RET43; middle isoform), or
51 (RET51; long isoform) distinct amino acids at their C termini (Myers et al. 1995)
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(Fig. 8.3). To date, four liga nds for the RET receptor have been identified (Treanor
et al. 1996). These ligands are the glial cell line-derived neurotrophic factor
(GDNF), neurturin, artemin, and persephin (Milbrandt et al. 1998). Various RET
mutations identified and correlated with disease phenotype are shown in Fig. 8.4.
8.4.2.2 Polymorphisms and Haplotypes in RET
Not only do high penetrant germline RET mutations have a key role in disease
development, but also RET polymorphisms exist that are believed to be genetic
modifiers and might be associated with an increased relative risk for the development
of disorders derived from neural crest cells. RET polymorphisms have a relatively
strong association with various disease phenotypes.
The most frequent RET polymorphisms; the nonsynonymous variant G691S
(G2071A) in exon 11 and the synonymous variants L767L (T2307G) in exon
13, S836S (C2508T) in exon 14, and S904S (C2712G) in exon 15, are being referred
Fig. 8.3 The RET protein, its functional domains, ligands, and co-receptors. Left, functional
domains of the three RET isoforms. Right, canonical (unbroken lines), and noncanonical (broken
lines) interactions of the RET ligands GDNF, neurturin (NRTN), persephin (PSPN), and artemin
(ARTN) with their GFRa co-receptors. Lipid rafts are depicted as a purple box in the plasma
membrane
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HSCR
MEN2A
FMTC
MEN2B
HSCR-
MEN2A-FMTC
Exon
Cadherindomain
Cysteine-rich domain
Tyrosine kinasedomain
918
891
883
804
791
790
768
10
11
13
14
15
16
634
630
620
618
611
609
Mutations all
over the gene
mRNA
Loss of function
Gain of function
Protein
Codon
Fig. 8.4 Germline missense mutations in RET associated with MEN2 and Hirschsprung disease. Shown are the structure of the RET mRNA and protein. The
codons mutated, the associated clinical entities, and the location of these mutations in relation to the exons and structural domains are indicated
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to as disease modifiers owing to the observation that they were found more often in
patients with sporadic MTC and DTC (“cases”) than controls [104] (Andreas et al.
2012). These polymorphisms might interact with other genetic variants or with
disease-associated germline mutations, modulating the disease phenotype or age of
onset. Because polymorphisms are comparatively common in the population, they
could bestow a much higher attributable risk on the general population as compared
with rare mutations in high-penetrance disease susceptibility genes such as RET.It
has been suggested that the RET polymorphisms G691S and S904S have a modifier
effect on the age of onset of MEN2A (Robledo et al. 2003). Several RET
polymorphisms have been described in association with sporadic MTC. Both
G691S and S904S had been previously associated with sporadic MTC and
MEN2A (Elisei et al. 2004). A low-penetrance RET haplotype compr ising the
wild-type allele at IVS1–126 and IVS1–1463 and a 16-basepair intron-1 deletion
of these SNPs is strongly associated with and over-represented in sporadic pheo-
chromocytoma (McWhinney et al. 2003). Several groups have characterized candi-
date disease-associated polymorphisms in Hirschsprung disease (Garcia-Barcelo
et al. 2005). Two groups have described two closely located SNPs, rs2435357 and
rs2506004, in intron 1 as disease-causing candidates on the basis of association
studies, functional assays, and comparative genomics (Ivan et al. 1997). Linkage
between G691S and S904S has been suggested previously (Borrego et al. 1999).
8.4.2.3 RET Polymorphisms and Haplotypes in TC
In recent years, it has been shown that there are some interconnections between
follicular and parafollicular-type C cells. The microenvironment provided by MTC
cells has the capacity to stimulate the proliferation of follicular cells, resulting in
hyperplastic and adenomatous follicles, and as suggested recently, the latter can
ultimately acquire a fully developed neoplastic phenotype (either follicular or
papillary). The opposite situation has also been described: C-cell hyperplasia was
recognized in some patients with Hashimoto thyroiditis as well as in thyroid adjacent
to follicular and papillary neoplasms (Tsui-Pierchala et al. 2002). Giuseppe et al in
their combination of in vivo and in vitro results have shown that the thyroid follicular
component can express a functional RET receptor, which may be activated in the
presence of specific ligands in the thyroid microenvironment (Giuseppe et al. 2000).
Because C cells express the RET receptor, the concept that RET ligands are
present in this microenvironment is highly plausible. They have report ed presence of
RET mRNA in follicular cell-derived TCs which may be activated in the presence of
specific ligands in the thyroid microenvironment (Giuseppe et al. 2000). So the role
of RET gene polymorphism in differentiated TCs came into being. Some variants
within RET could represent low penetrant alleles for the PTC phenotype. A study
conducted by Lesueur et al. found the strongest association with PTC with A45A
(G135A) polymorphism in exon 2 and L769L (T2307G) in exon 13 (Lesueur et al.
2002). The seven most frequent haplotypes have been described by Borrego et al. in
controls of Spanish and German origin (Borrego et al. 2000). Distribution of some of
these haplotypes differed between cases and controls. The G G C C haplotype is
over-represented in both Italian and French sporadic PTC and this over-
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