European Journal of Endocrinology (2006) 155 645653 ISSN 0804-4643

INVITED REVIEW

RET/PTC activation in papillary thyroid carcinoma: European

Journal of Endocrinology Prize Lecture
Massimo Santoro1, Rosa Marina Melillo1 and Alfredo Fusco1,2
1
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR G. Salvatore, c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, University
Federico II, Via S. Pansini, 5, 80131 Naples, Italy and 2NOGEC (Naples Oncogenomic Center)CEINGE, Biotecnologie Avanzate & SEMM, European
School of Molecular Medicine, Naples, Italy
(Correspondence should be addressed to M Santoro; Email: masantor@unina.it)

Abstract
Papillary thyroid carcinoma (PTC) is frequently associated with RET gene rearrangements that
generate the so-called RET/PTC oncogenes. In this review, we examine the data about the mechanisms
of thyroid cell transformation, activation of downstream signal transduction pathways and
modulation of gene expression induced by RET/PTC. These findings have advanced our understanding
of the processes underlying PTC formation and provide the basis for novel therapeutic approaches to
this disease.

European Journal of Endocrinology 155 645653

RET/PTC rearrangements in papillary
thyroid carcinoma
The rearranged during tansfection (RET) proto-onco-
gene, located on chromosome 10q11.2, was isolated in
1985 and shown to be activated by a DNA rearrange-
ment (rearranged during transfection) (1). As
illustrated in Fig. 1, it encodes a single-pass trans-
membrane tyrosine kinase that functions as the
receptor (receptor tyrosine kinase, RTK) for the growth
factors of the glial cell line-derived neurotropic factor
family (2). RET is essential for the development of the
sympathetic, parasympathetic, and enteric nervous
systems, the kidney and the testis (2). Germline point
mutations in RET lead to multiple endocrine neoplasia
type 2 syndromes thereby predisposing to thyroid C-cell-
derived medullary thyroid carcinoma (3).
With an incidence ranging between 0.5 and 10 cases
per 100 000 population, thyroid cancer is the most
frequent endocrine malignancy (4). Papillary thyroid
carcinoma (PTC), which accounts for approximately
80% of cases, is the most frequent of all thyroid
malignancies (4). In PTC, genomic rearrangements
juxtapose the RET kinase and COOH-terminus encoding
domains (exons 1121) to unrelated genes, thereby
creating dominantly transforming oncogenes called
RET/PTC (5, 6). Similar rearrangements of another
neurotropic RTK, namely the neurotropic tyrosine
receptor kinase type 1 (NTRK1), the receptor for nerve
Presented at the 7th European Congress of Endocrinology,
Gothenburg, Sweden, 2005.
growth factor, have been described in a fraction of PTC
patients (7). As illustrated in figure 1, many different
genes have been found to be rearranged with RET in
individual PTC patients. RET/PTC1 and 3 account for
more than 90% of all rearrangements and are hence, by
far, the most frequent variants (811). They result from
the fusion of RET to the coiled-coil domain containing
gene 6 (CCDC6, formerly called H4/D10S170) or to the
nuclear receptor co-activator gene 4 (NcoA4, formerly
called RET fused gene (RFG)/ELE1/androgen receptor
activator 70(ARA70)) (811).
Prevalence of RET/PTC rearrangements
For a detailed discussion of the prevalence of RET/PTC
rearrangements and their correlation with clinico-
pathological features of thyroid carcinomas, we refer
the reader to three excellent reviews (810). The
prevalence of RET/PTC rearrangements in thyroid
cancer varies widely among studies. In an adult
population from the United States, the prevalence of
rearrangements was approximately 35% (9). Preva-
lences between 3 and 85% have been reported for other
regions (810). This wide range of values probably
reflects not only the geographic variation but also the
different procedures used to identify RET/PTC
rearrangements, i.e. various reverse transcriptase
(RT)-PCR methods, Southern blot, and fluorescence
in situ hybridization. An exhaustive study by Zhu and
co-workers (12) demonstrated that the method used has
a striking effect on the efficacy of RET/PTC detection,
and hence on the prevalence reported. Tumor

q 2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02289

Online version via www.eje-online.org
646 M Santoro and others
heterogeneity is another factor that can affect the
evaluation of RET/PTC prevalence. In addition to PTC
samples with clonal RET/PTC rearrangements (those
affecting the majority of tumor cells), there are samples
with non-clonal rearrangements (those affecting a
small portion of tumor cells) (12, 13). Whereas RET/
PTC is likely to be important for tumor formation in
samples with clonal rearrangements, RET/PTC could
not be a driver mutation in PTC samples with non-
clonal rearrangements (13). This distinction has
important implications for the stratification of patients
who could potentially benefit from novel therapeutic
approaches based on the use of RET kinase inhibitors
(see below). It is still controversial the presence of RET/
PTC rearrangements in non-neoplastic cells in Hashi-
motos thyroiditis. It is possible that a heterogeneous
presence of the rearrangement may account, at least in
part, for such a controversy (8, 9, 13). Tumor
heterogeneity and multiclonality is also indicated by
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155
Figure 1 Schematic drawing of the RET
protein with the four extracellular cadherin-like
domains, the cysteine-rich box adjacent to the
plasma membrane, the juxtamembrane
domain and the split tyrosine kinase domain
(TK). In PTCs, RET is rearranged with diverse
genes, encoding protein dimerization motifs
(highlighted) that mediate ligand-independent
RET dimerization. The arrowheads indicate
RET breakpoints.
the presence of multiple RET/PTC variants in individ-
ual PTC samples (14).
RET/PTC rearrangements have so far been identified
only in thyroid lesions, and in particular in PTC (810).
Most studies concur that RET/PTC rearrangements are
rare or absent in benign follicular adenomas, and absent
in follicular and medullary carcinomas (810). Various
PTC histological variants have been identified, namely
classic, follicular, diffuse-sclerosing, columnar-cell,
Hurthle-cell, cribriform, solid and tall-cell variants (4).
Classic (w45%) and follicular (w18%) variants are the
most prevalent (4). RET/PTCs are more frequent in
tumors that have a classic architecture (15) and in
microcarcinomas (!1 cm) (16). They are rare in the
follicular variant of PTC (15). RET/PTCs have been
reported in the cribriform variant, which is typically
associated with familial adenomatous polyposis (17), in
the Hurthle-cell variant (18, 19), and in hyalinizing
trabecular adenoma, a rare tumor that can be
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155
morphologically similar to PTC (20, 21). The solid
variant, which is an aggressive PTC subtype, is closely
associated with the RET/PTC3 oncogene, whereas the
classic variant is associated with RET/PTC1 (22).
Clinical, epidemiologic, and pathologic evidence
supports the possibility of a stepwise progression from
well-differentiated carcinoma, including PTC, to poorly
differentiated and anaplastic carcinoma (23). Accor-
dingly, some anaplastic carcinomas are associated with
genetic lesions (rat sarcoma viral oncogene homolog
(RAS) and BRAF mutations) that overlap those present
in PTC and in other well-differentiated carcinomas (23).
Conflicting results have been reported about the
presence of RET/PTC in poorly-differentiated and
anaplastic carcinomas and, therefore about whether
or not RET/PTC predisposes to thyroid tumor pro-
gression (2328). Again, methodological differences
and tumor heterogeneity may account for these
controversies. A large multicenter study in which all
centers use the same methodology should resolve this
issue. It is also important to study the different RET/PTC
variants individually, because, as mentioned above, they
could confer different degrees of aggressiveness on PTC.
It should be noted that intercross of RET/PTC transgenic
mice with p53null mice induced the formation of
anaplastic carcinomas, suggesting that at least in a
specific genetic background RET/PTC is able to induce
thyroid tumor progression (29).
Chromosomal basis for RET/PTC
rearrangements
CCDC6 (the RET fusion partner in RET/PTC1) and
NcoA4 (the RET fusion partner in RET/PTC3 and 4)
map together with RET on chromosome 10, whereas
the other RET fusion partners are located on different
chromosomes. Therefore, RET/PTC recombination
events are caused either by a paracentric inversion of
chromosome 10 (in the case of RET/PTC1 and
RET/PTC3) or balanced chromosomal translocations
involving chromosome 10 and other chromosomes
(in the case of the other RET/PTC subtypes). It is well
known that ionizing radiations promote DNA double-
strand breaks and that PTC is the most common form of
solid neoplasm associated with radiation exposure.
These findings prompted the notion that there is a
direct link between radiations, RET/PTC rearrange-
ments, and PTC formation. At least two observations
support this concept. First, X-ray irradiation induces the
formation of RET/PTC1 (3032). Second, RET/PTC
rearrangements are very frequent in PTC samples from
patients, who had received external radiations (3335)
and in post-Chernobyl PTCs (22, 3639). The Cherno-
byl nuclear power plant accident in April 1986 resulted
in the release of large amounts of iodine isotopes,
mainly 131I, and, therefore, there was widespread
radiation exposure to the thyroid (36). A high incidence
RET/PTC in thyroid cancer 647
of childhood PTC was reported in contaminated areas.
Post-Chernobyl PTC featured a high prevalence (over
60%) of RET/PTC rearrangements (22, 3639).
RET/PTC3 was more prevalent among short latency
solid PTCs, whereas RET/PTC1 was more frequently
found after a long latency period (9, 22, 3639). Rapid
thyroid cell proliferation may account for the particu-
larly high sensitivity to radiation-induced RET/PTC
rearrangements among children (40). However, also in
cases of PTC in non-exposed populations, the prevalence
of RET/PTC was higher in children than in adults,
which suggests that in general RET/PTC recombina-
tions occur more frequently in young thyroids (41, 42).
RET/PTC rearrangements are not the only intrachro-
mosomal aberration found in radiation-associated PTC.
Also NTRK1 rearrangements, caused by paracentric
inversions of chromosome 1q, have been reported in
post-Chernobyl PTC (7, 38). Moreover, in 11% of the post-
Chernobyl PTCs there was a paracentric inversion of
chromosome 7q that resulted in the A-kinase anchor
protein (AKAP)9BRAF fusion oncogene (43). Differently,
point mutations in BRAF, which are very frequent in
sporadic PTC (see below) are rare in Chernobyl cancers
affecting children (44). This suggests that young age and
radiation exposure are specifically linked to gene
rearrangements in PTC.
The reason for the high frequency of chromosomal
rearrangements, and particularly paracentric inver-
sions, in thyroid cancer after radiation exposure is not
clear. Nikiforova and co-workers (45) shed new light on
this issue when they demonstrated that, although the
two loci participating in the formation of the RET/PTC1
fusion are about 30 megabases apart, they frequently
juxtapose within the interfase nuclei of thyroid cells.
This spatial contiguity can provide a structural basis for
radiation-induced illegitimate recombination of the two
genes. More recently, the same group showed that
NcoA4 is also in close proximity to RET in thyroid cell
chromatin (46). A similar mechanism was proposed for
NTRK1 fusions in PTC (47). Taken together, these
findings suggest that tissue-specific chromatin folding is
the genomic basis underlying the high prevalence of
gene rearrangements in PTC.
Molecular mechanisms of activation of
RET/PTC oncoproteins
Adoptive expression of RET/PTC transforms murine
fibroblasts (5, 6). Chronic RET/PTC expression causes
thyrotropin-independent proliferation and impairs the
expression of the thyroid differentiation markers of rat
thyroid follicular PC Cl 3 cells (4850). On the other
hand, acute expression of RET/PTC oncogenes induces
apoptosis of PC Cl 3 cells (49, 51), a phenomenon that is
often seen when dominant oncogenes are acutely
introduced in normal cells. RET/PTC expression in
primary cultures of human thyrocytes results in changes
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648 M Santoro and others
of nuclear morphology (irregular nuclear contours and
euchromasia) resembling those characterizing human
PTC (52). Finally, thyroid targeting of RET/PTC1 (53, 54)
or RET/PTC3 (55) in transgenic mice leads to the
development of tumors that histologically and cytologi-
cally resemble human PTC. Interestingly, mice carrying
RET/PTC3 develop thyroid tumors, whose solid pheno-
type resembles those associated with activation of this
RET/PTC variant in humans (22, 55). RET/PTC3 is more
potently transforming than RET/PTC1 also when tested
in cultured thyrocytes in vitro (56).
RET/PTC can exert oncogenic activity via various
mechanisms (schematically illustrated in Fig. 2); altered
expression, ligand-independent kinase activation, sub-
cellular relocalization and functional alteration of the
RET fusion partner. Whereas wild-type RET expression
is tightly regulated (2), its fusion partners are
ubiquitously expressed (57, 58). Therefore, RET/PTC
rearrangements may lead to the unscheduled
expression of RET in the thyroid cell (mechanism no.
1 in Fig. 2). However, also unrearranged RET is
expressed in thyroid follicular cells and in tumors that
derive from them (59), and therefore the rearrangement
might be not essential for RET expression in the thyroid.
The mechanisms driving the ligand-independent kinase
activity of RET/PTC oncoproteins have been partially
elucidated. The rearrangement deletes the signal
sequence, the extracellular ligand-binding domain and
the intracellular juxtamembrane domains of the
receptor (mechanism no. 2 in Fig. 2). As in the case of
Figure 2 Mechanisms for RET/PTC activation. The wild-type RET protein, the PTPRJ tyrosine phosphatase, and the rearranged
RET/PTC1 oncoproteins are depicted.
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155
other receptors, the juxtamembrane domain negatively
affects RET mitogenic signaling although the molecular
mechanisms governing this process are not clear (60).
On the other hand, all the translocated amino termini
fused to RET are predicted to fold into coiled-coils (Figs 1
and 2 mechanism no. 3). Coiled-coils are protein
protein interaction domains able to mediate dimeri-
zation and activation of the kinase. Accordingly, RET/
PTC proteins form dimers that are essential for
oncogenic activation (58, 61). Whereas wild-type RET
is a transmembrane protein, as a further consequence of
the deletion (mechanism no. 4 in Fig. 2), RET/PTC
oncoproteins are re-localized to the cytosolic compart-
ment. This could prevent RET/PTC from interacting
with negative regulators located at plasma membrane
level, for instance, the tyrosine phosphatase protein
tyrosine phosphatase receptor type-J (PTPRJ) (62)
(Fig. 2). However, it should be noted that by interacting
with proteins resident at the plasma membrane, e.g.
Enigma (63) or FRS2 (64), RET/PTC proteins may be
re-directed to the membrane compartment. Finally
(mechanism no. 5 in Fig. 2), RET/PTC rearrangements,
besides activating RET, can also alter the function of
RET-fused genes. This could explain why the RET/PTC
variants constituted by different fusion partners might
have, at least in part, non-overlapping biological effects.
Perhaps, the best example of a RET fusion partner,
whose altered function may contribute to neoplastic
transformation is the regulatory subunit type I-a of
protein kinase A (PRKAR1A) that is involved in RET/
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155 RET/PTC in thyroid cancer 649

PTC2. PRKAR1A is, indeed, a bona fide tumor

suppressor (65) and its ablation in the mouse induced
the formation of thyroid tumors (66). The knowledge
about the function of the other RET fusion partners is
limited. Some of them are involved in transcriptional
regulation, such as Ncoa4, tripartite motif-containing
(TRIM)24 (formerly called HTIF1, human transcrip-
tional intermediary factor I), methyl-CpG binding
domain protein 1 (MBD1) (formerly called PCM1,
pericentriolar material 1), and RET finger protein
(RFP) (formerly called TRIM27) (www.ncbi.nlm.nih.
gov/entrez/), or in cell fate determination, such as
TRIM33 (formerly called RFG7/Ectodermin/HTIFg)
(67). Ncoa4 functions as a co-activator of several
nuclear receptors. It interacts with and promotes
androgen receptor activity via the consensus FXXLF
motif (located at amino acids 328332) (68), and
interacts with and promotes peroxisome-proliferator-
activated receptor-g via the LXXLL motif located at
amino acids 9296 (69). Therefore, its rearrangement
may affect the function of these steroid hormone
receptors. Surprisingly, we still know very little about
CCDC6, the first isolated RET fusion partner (6, 57).
According to the conserved domain database (www.
ncbi.nlm.nih.gov/Structure/cdd/), this protein, like
golgi autoantigen glogin subfamily A (GOLGA)5
(formerly called RFG5) and KTN1 (kinectin; the fusion
partners in RET/PTC5 and 8 respectively) contains the
signature sequence of the ATP-binding cassette family of
ATPases, which are proteins involved in DNA mainten-
ance and repair. It is still unknown whether such a
function is altered consequent to the RET/PTC1
rearrangement. Of note, CCDC6 overexpression induces
apoptosis, suggesting that abrogation of its function
may promote PTC cell survival (57). Intriguingly, some
of the RET fusion partners are found rearranged in
tumors other than PTC; CCDC6 rearranges with the
kinase domain of the platelet-derived growth factor Figure 3 RET/PTC binds adaptor proteins such as growth factor
receptor-b in myeloproliferative disorders (70), TRIM24 receptor-bound protein 2 (GRB2) that, in cooperation with the
guanine nucleotide exchange factor SOS, activates RAS. In its
with BRAF in mouse hepatocellular carcinomas (71), GTP-bound form, RAS activates RAF kinases (such as BRAF), and
and PCM1 with JAK2 in chronic myeloid leukemia (72). its downstream signaling cascade (MEK and ERK). There are
several negative regulators of this pathway but the possible role of
these mediators in RET/PTC signaling has not been studied yet.
These proteins include the sprouty family of proteins (SPRY), which
RET/PTC and the MAPK signaling can inhibit the pathway at various levels; RAF kinase inhibitor
protein (RKIP); RAS and RAB interactor 1 (RIN1); IMP (impedes
cascade mitogenic signal propagation); and the MKP (dual specificity
phosphatase) family of MAPK phosphatases.
The most common genetic alteration found in PTC (up to
45% of cases) is the activating point mutation (most often
V600E) in BRAF (73). Together with the other onco- adaptors, IRS1/2, FRS2, and DOK1/4/5 (2, 11, 75).
proteins implicated in PTC (RET, NTRK1 and RAS), BRAF Binding to Shc and FRS2 mediates recruitment of growth
functions in the mitogen-activated protein kinase (MAPK) factor receptor-bound protein 2 (GRB2)/son of sevenless
pathway. By promoting GTP loading on RAS, RET and (SOS) complexes, thereby leading to RAS and, in turn,
NTRK1 stimulate RAF family kinases, which leads to the BRAF/MAPK stimulation (48, 50).
phosphorylation of MEK (MAP kinase or ERK) and ERK A wealth of experimental evidence supports the role
(extracellular signal-regulated kinases or MAPK) (74) of this signaling cascade in thyroid cell transformation:
(Fig. 3). One tyrosine residue (tyrosine 1062) in RET (i) RET/PTC-mediated transformation requires BRAF
mediates the firing of this cascade. This tyrosine is the (48, 50, 76); (ii) PTC formation in transgenic mice
binding site for several proteins including Shc family requires the integrity of the RET/PTC tyrosine

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650 M Santoro and others
corresponding to Y1062 in wild-type RET (77); and (iii)
transcriptional responses to RET/PTC and BRAF
partially overlap (see also below) (48, 76, 78). Such
an assembly of oncogenic proteins in one signaling
cascade has numerous implications; one is that other
genes implicated in PTC formations may encode
proteins functioning in the same cascade. Many
proteins (schematically represented in Fig. 3) are
potentially able to modulate the RET/PTC-BRAF-
MAPK axis (79); it would be well worth investigating
their activity in thyroid cell transformation.
Not all the biological activities of the RET/PTC and
BRAF oncoproteins overlap. Indeed, activated BRAF but
not RET/PTC induces genomic instability in cultured
thyroid cells (80); BRAF (but not RET/PTC) transgenic
mice develop PTCs that progress to undifferentiated
carcinomas (81); and RET/PTC and BRAF regulate the
expression of specific sets of genes as well as the
expression of common genes (48, 78, 82, 83). Thus,
although functioning on the same pathway, RET/PTC
and BRAF are endowed with differential signaling
abilities. This could explain the different clinico-
pathologic features of PTCs associated with the two
oncogenes. In fact, whereas most RET/PTC-positive
PTCs belong to the classic variant and are associated
with a young age and an early stage at presentation,
BRAF-positive PTCs belong to the classic and tall cell
variants and are associated with old age and an
advanced tumor stage (15, 73).
The pro-inflammatory transcriptional
program regulated by RET/PTC
The transcriptional response to RET/PTC has been
evaluated both in rat thyroid PC Cl 3 cells, either stably
(48, 84) or conditionally (76, 78, 85) expressing RET/
PTC3, and in human thyrocytes expressing RET/PTC1
(86). Although some differences were noted (perhaps
linked to the different model systems used), these studies
reached two conclusions. First, as anticipated above,
tyrosine 1062 and the downstream signaling cascade is
particularly important for RET/PTC-mediated effects
(48, 76, 84, 86). Second, RET/PTC induced the
expression of a pro-inflammatory transcriptional
program. Such a program included the up-regulation
of various cytokines (OPN/SPP1, GM-CSF, M-CSF,
G-CSF, IL1A, IL1B, IL6, and IL24) (8487), chemokines
(CCL2, CCL20, CXCL8, CXCL1, CXCL10, and CXCL12)
(48, 8486), chemokine receptors (CXCR4) (48, 86,
88), pro-inflammatory enzymes (cyclooxygenase-2, and
microsomal prostaglandin E2 synthase) (84, 85, 89),
and interferon-dependent genes (85). Many of these
mediators were also upregulated in the thyroids of RET/
PTC3 transgenics (90). Moreover, injection of RET/PTC-
transformed PC Cl 3 cells induced angiogenesis and
inflammatory responses in SCID mice (84). These
findings suggest that induction of an inflammatory-type
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155
reaction might be part of the oncogenic effect of RET/
PTC on thyroid cancer and may explain the chronic
inflammatory reaction that is characteristic of this
tumor type.
Concluding remarks
Since the RET/PTC oncogene was isolated almost three
decades ago (5), much progress has been made in our
understanding of the effect exerted by this oncogene. Its
relationship with radiation exposure has been estab-
lished, the chromosomal basis for its activation has been
clarified, its transforming and signaling properties have
been characterized, and finally we now know that RET/
PTC triggers a pro-inflammatory response. Over the
last few years, it has become clear that cancers
characterized by activating mutations in dominant
oncogenes can be treated by directly targeting the
disease-causing oncoprotein. In this framework, RET
and the downstream signaling cascade are promising
therapeutic targets. Several inhibitors of RET, BRAF, and
MEK kinases have been isolated (11, 91) and hopefully,
their clinical use will lead to novel therapeutic options
for patients afflicted by thyroid cancer.
Acknowledgements
We thank members of our laboratory for scientific
advice and Jean A Gilder for text editing. We apologize
to many of our colleagues for failure to cite their work
owing to space limitations.
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Received 4 August 2006
Accepted 4 September 2006
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