The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 3 1003-1006
Copyright © 1998 by The Endocrine Society
The ret/ptc1 Oncogene Is Activated in Familial Adenomatous Polyposis-Associated Thyroid Papillary Carcinomas1
Francesco Cetta,
Gennaro Chiappetta,
Rosa Marina Melillo,
Margherita Petracci,
Giulia Montalto,
Massimo Santoro and
Alfredo Fusco
Istituto di Clinica Chirurgica (F.C., G.M.) and Dipartimento di
Oftalmologia (M.P.), Università di Siena, Nuovo Policlinico,
53100 Siena; Istituto Nazionale dei Tumori di Napoli, Fondazione
Senatore Pascale (G.C.), and Centro di Endocrinologia ed Oncologia
Sperimentale del CNR, Dipartimento di Biologia e Patologia Cellulare e
Molecolare, Facoltà di Medicina e Chirurgia, Università di
Napoli Federico II (R.M.M., M.S.), 80131 Naples; and Dipartimento di
Medicina Sperimentale e Clinica, Facoltà di Medicina e Chirurgia
di Catanzaro, Università di Reggio Calabria (A.F.), 88100
Catanzaro, Italy
Address all correspondence and requests for reprints to: Dr. Alfredo Fusco, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli Federico II, via Pansini 5, 80131 Naples, Italy. E-mail: afusco{at}synapsis.it
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Abstract
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Familial adenomatous polyposis (FAP) is caused by germ-line
mutations of the apc gene, and it is associated with an
increased risk of developing papillary thyroid carcinomas. We have
previously reported that a significant fraction of sporadic human
papillary thyroid carcinomas is characterized by gene rearrangements
affecting the ret protooncogene. These rearrangements
generate chimeric transforming oncogenes designated
ret/ptc. By a combined immunohistochemical and RT-PCR
approach, we analyzed, for ret/ptc oncogene activation,
papillary thyroid carcinomas occurred in two FAP kindreds, both showing
typical apc gene mutations. Kindred 1 had seven members
affected by FAP, and among these, three patients showed papillary
thyroid carcinomas. Kindred 2 had two patients, mother and daughter,
affected by colonic polyposis; the 20-yr-old daughter showed also a
papillary carcinoma. Here we report that ret/ptc1
oncogene was activated in two of the three papillary carcinomas of FAP
kindred 1 and in the papillary carcinoma of FAP kindred 2. These
findings document that loss of function of apc coexists
with gain of function of ret in some papillary thyroid
carcinomas, suggesting that ret/ptc1 oncogene activation
could be a progression step in the development of FAP-associated
thyroid tumors.
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Introduction
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FAMILIAL adenomatous polyposis (FAP) is an
autosomal dominant precancerous condition of the colon that is caused
by mutations of the tumor suppressor apc gene (1, 2, 3). FAP
patients often develop extracolonic manifestations, including osteomas
and brain tumors, and a review of the world literature indicated that a
total of 63 FAP patients showed the development of thyroid carcinomas
(4). Moreover, an analysis of the largest existing FAP register
indicated that about 1% of patients with FAP showed thyroid
differentiated carcinomas (5, 6). FAP-associated thyroid carcinomas are
currently considered a distinct type of follicular cell neoplasms
because of the age of these patients, which is relatively young (range,
16–40 yr) (7), the morphological features, and the excellent prognosis
(4, 8).
Thyroid differentiated cancer comprises follicular and papillary
histotypes, which greatly differ in terms of risk factors, pathogenetic
mechanisms, and biological behaviors (9, 10, 11). In fact, the
former is more frequent in areas with iodine deficiency and frequently
shows activation of ras family oncogenes; the latter is more
frequent after exposure to fall-out radiation and frequently shows
ret/ptc oncogene activation (between 25–40% of the cases)
(12, 13, 14, 15). Three ret/ptc isoforms are known and are
designated ret/ptc1, ret/ptc2, and
ret/ptc3. These oncogenes derive from gene rearrangements
affecting the RET gene, which encodes a receptor-type
tyrosine kinase for neurotropic molecules belonging to the glial
cell-line derived neurotropic factor (GDNF) family (16, 17). A gene
named H4 (or D10S170) is rearranged with
ret in the case of ret/ptc1 (18). The 5'-portion
of ret/ptc2 is represented by the gene encoding the
regulatory subunit RI of the protein kinase A (19). Finally, in the
case of ret/ptc3, the fusion of ret occurs with
the rfg gene (20).
We have recently described the pedigree and clinical data
of a FAP family in which three patients (two sisters and one maternal
aunt), in addition to adenomatous polyposis, developed thyroid
papillary carcinomas (21). Subsequently, we identified another FAP
kindred, a member of which also developed a papillary thyroid
carcinoma. Here we report that three of these four papillary carcinomas
are characterized by activation of the ret/ptc1
oncogene.
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Subjects and Methods
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Patients
Fifteen FAP families had intensive screening for associated
extracolonic manifestations (Cetta, F., et al., unpublished
results). All patients underwent ultrasound examination of the thyroid
gland; ultrasound-guided fine needle agobiopsy of all of the nodules
larger than 5 mm was performed, followed by cytological examination of
the specimen. Two families showed at least 1 member affected by thyroid
carcinoma. Kindred 1 consisted of 23 members throughout 4 generations.
Seven members of the last 2 generations were affected by FAP. Three
patients of this kindred, 2 daughters, aged 22 and 20 yr, and 1 aunt,
aged 36 yr, showed papillary thyroid carcinomas. The thyroid tumors
were unique in 2 patients and multiple in the 22-yr-old woman. They
were encapsulated and showed a predominant papillary architecture, with
ground-glass nuclei and nuclear inclusions and grooves. One case (aged
20 yr) also had widespread follicular areas. Kindred 2 showed 2
patients, mother and daughter, affected by FAP. The 22-yr-old daughter,
in addition to colonic polyposis, also had an 11-mm papillary thyroid
carcinoma. apc mutations were demonstrated by direct
sequencing of the PCR products. A 5-bp deletion around codon 1061 (A
CAA A; position 3183–3187), creating a stop codon at position
3189–3191, was observed in all of the affected patients of kindred 1,
including the 3 patients carrying papillary thyroid carcinomas. In
kindred 2, the apc mutation of the 2 affected members was at
codon 1309 (22, 23, 24).
Immunohistochemistry
Three- to 4-µm paraffin sections were deparaffinized, placed
in a solution of absolute methanol and 0.3% hydrogen peroxide for 30
min, and then treated with blocking serum for 20 min. The slides were
incubated overnight at 4 C with affinity-purified antibodies specific
for the ret tyrosine kinase domain (25, 26), diluted 1:100,
and subsequently incubated with biotinylated goat antirabbit IgG
(Vectostain ABC kits, Vector Laboratories, Burlingame, CA) and with the
premixed reagent, avidin-biotin-peroxidase complex (Vector) for 20 min.
Immunostaining was performed with a diaminobenzidine (DAB; Dako,
Carpenteria, CA) solution containing 0.06 mmol/L DAB and 2 mmol/L
hydrogen peroxide. After chromogen development, the slides were
counterstained with hematoxylin.
RT-PCR for ret/ptc expression
Ribonucleic acid (RNA) extraction from paraffin-embedded samples
was performed as previously described (27). Briefly, single 6- to
8-µm tissue sections, cut from paraffin blocks, were stirred for 20
min in 1.5-mL tubes with 1 mL xylene. After centrifugation, the pellet
was washed with 0.5 mL ethanol and air-dried. The dried pellet was
resuspended in 200 µL 6 mg/mL proteinase K (Sigma Chemical Co., St.
Louis, MO), 1 mol/L guanidinium thiocyanate, 25 mmol/L
2-mercaptoethanol, 0.5% Sarkosyl, and 20 mmol/L Tris-HCl, pH 7.5, and
incubated at 45 C for 6 h. RNA was then extracted with one sample
equivalent volume of 70% phenol-30% chloroform, and the aqueous
supernatant was transferred to a 0.5-mL tube containing 2 µg
glycogen. After adding 1 vol isopropanol, the supernatant was
precipitated at -20 C overnight. After centrifugation for 15 min at
12,000 x g in an Eppendorf (Barkhausenweg, Hamburg,
Germany) microcentrifuge, the pellet was washed with 70% ethanol and
air-dried. RT-PCR amplification was performed as previously reported
(15). The sequences of the forward primers used were:
ret/ptc1, 5'-ATTGTCATCTCGCCGTTC-3' (nucleotides 196–214)
(18); ret/ptc2, 5'-TATCGCAGGAGAGACTGTGAT-3' (nucleotides
483–503) (19); and ret/ptc3, 5'-AAGCAAACCTGCCAGTGG-3'
(nucleotides 697–714) (20). The sequence of the reverse primer
(synthesized according to the ret tyrosine kinase sequence)
was 5'-TGCTTCAGGACGTTGAAC-3' (nucleotides 543–561) (18). One fifth of
the RNA was reverse transcribed using the reverse primer and, after
addition of the forward primer, subjected to 40 cycles of PCR with a
thermal cycler (Perkin-Elmer/Cetus, Norwalk, CT; 94 C for 30 min, 55 C
for 2 min, and 72 C for 2 min ). The product of the reaction was
analyzed on a 2% agarose gel and hybridized with a ret
probe covering the tyrosine kinase domain. The human phosphoribosyl
transferase gene (hprt)-specific primers were
5'-CCTGCTGGATTACATCAAAGCACTG-3' (forward), corresponding to nucleotides
316–340 of the third exon of the human gene; and
5'-CCTGAAGTATTCATTATAGTCTCAAGG-3' (reverse), corresponding to
nucleotides 685–661 of the eighth exon of the human gene (28).
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Results
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Three patients belonging to FAP kindred 1 (two 22-
and 20-yr-old sisters, patients 1 and 2, and one 36-yr-old aunt,
patient 3) and one patient (patient 4) of FAP kindred 2 had thyroid
papillary carcinomas. Histological examination of these thyroid
carcinomas was described in detail previously (22). The families live
in a region without iodine deficiency, and the patients had never had
head or neck irradiation. To investigate ret/ptc activation
in these tumors, we took advantage of the fact that ret
expression is restricted to tissues and cell lines of neural crest
origin. However, after the rearrangements generating ret/ptc
oncogenes, ret regulatory sequences are replaced by those
belonging to the genes fused to its tyrosine kinase domain. These genes
(H4, RI, and RFG) are ubiquitously
expressed, and thus, their promoters drive the expression of the
truncated ret forms in thyroid cells. Indeed, we have
previously demonstrated that the presence of Ret protein, detected by
immunohistochemistry, correlates with ret/ptc activation in
thyroid carcinomas found by RT-PCR analysis (29, 30). We used this
combined immunohistochemical and RT-PCR approach to analyze the four
FAP-associated thyroid carcinomas for ret/ptc activation.
The results of the immunohistochemical analysis, reported in Fig. 1
, demonstrated that the papillary
carcinomas from the two sisters belonging to the FAP family (cases 1
and 2) were positive for ret/ptc expression; in contrast,
the tumor of patient 3, was negative (Fig. 1D). The papillary carcinoma
in FAP patient 4 (kindred 2) also scored positive for
ret/ptc expression (data not shown). Normal thyroid samples
(no. 10), used as negative controls, did not show any
ret/ptc expression (an example is shown in Fig. 1A).
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Figure 1. Immunohistochemical detection of the Ret/Ptc
protein in FAP-associated human thyroid papillary carcinomas. A, Normal
thyroid (magnification, x100). No staining was observed. B and C,
Papillary carcinomas of patients 1 and 2, respectively (magnification,
x100). A strong cytoplasmic staining was observed in the neoplastic
cells. D, Papillary carcinoma of patient 3 (magnification, x100). No
cytoplasmic staining was observed in the neoplastic cells. Three- to
4-µm paraffin sections were deparaffinized, treated with diluted
blocking serum for 20 min, and incubated overnight with
affinity-purified antibodies specific for the ret
tyrosine kinase domain (23). The slides were subsequently incubated
with biotinylated goat anti-rabbit IgG and then with the premixed
reagent, avidin-biotin-peroxidase complex. Immunostaining was performed
by incubating the slides in DAB solution. After chromogen development,
the slides were washed, counterstained with hematoxylin, dehydrated
with alcohol and xylene, and mounted with coverslips using a permanent
mounting medium (Permount, Fisher Scientific, Fairlawn, NJ).
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To confirm the expression of the rearranged ret
version in the positive samples and to discriminate among the different
forms of rearranged ret, the tumor samples were analyzed by
RT-PCR using primers specific for ret/ptc1, -2,
and -3 oncogenes. The three cases (patients 1, 2, and 4),
which scored positive at the immunohistochemistry, showed a specific
amplified fragment of 365 bp when ret/ptc1-specific primers
were used (Fig. 2A, lanes 5 and 6, and
data not shown). The sample (patient 3) negative at the
immunohistochemistry was also negative at the RT-PCR (Fig. 2, lane 4).
As negative controls, RNA from normal thyroid (lane 1) and from a human
papillary carcinoma previously scored negative for ret/ptc
activation (lane 3) (15) were used. The positive control (lane 2) was
represented by RNA extracted from the TPC cell line, which carries a
ret/ptc1 oncogene (31). The quality of extracted RNA was
confirmed by amplification with HPRT-specific primers (Fig. 2B). No
positivity was found in the examined samples for the other two
ret/ptc isoforms (ret/ptc2 and
ret/ptc3; data not shown). When the same RNAs were not
reverse transcribed before PCR amplification, no amplified products
were observed; this was used as a control to insure that the results
were due to amplification of RNA and not to contaminating DNA (not
shown).
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Figure 2. RT-PCR identification of
ret/ptc1 expression. A, RNAs were amplified with
ret/ptc1-specific primers, as indicated in the schematic
diagram, subjected to electrophoretic separation on a 2% agarose gel,
and hybridized with a ret probe covering its TK domain.
Lane 1, A negative control represented by normal thyroid RNA; lane 2, a
positive control represented by RNA extracted from the TPC cell line
(31); lane 3, another negative control represented by RNA extracted
from a thyroid tumor previously scored negative for
ret/ptc1 activation (15); lanes 4–6, RNAs extracted
from FAP patients 3, 1, and 2, respectively. B, The same RNAs as those
in A were subjected to RT-PCR amplification using HPRT-specific
primers. The products of the amplification were run on a 2% agarose
gel and hybridized to a HPRT-specific probe.
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Discussion
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A predisposition to develop thyroid carcinomas has been
observed in several kindreds affected by adenomatous polyposis coli
(FAP). This suggests that mutations of the apc gene, when
occurring in the germline (32, 33), have the potential to predispose to
development of thyroid carcinomas. Data reported in this manuscript
demonstrate that ret/ptc1 activation is a genetic alteration
that occurs in thyroid papillary carcinomas in some FAP patients.
Germ-line apc mutations associate with at least other seven
genetic alterations, including ras and p53 gene
mutations in the development of colonic cancer (3). Sporadic papillary
thyroid carcinomas are often characterized by ret activation
(between 25–40% of the cases) (13), and the group of FAP patients
examined in this manuscript is not large enough to draw any firm
statistical conclusion on the association between apc and
ret gene mutations. However, to date, apc
mutation is the first genetic alteration found in thyroid tumors in
association with ret activation. One possibility to explain
this association is that, in analogy to the scheme proposed for colon
cancer progression, the two mutations may sequentially act in the
establishment of some FAP-associated thyroid carcinomas. Although the
frequent occurrence of ret/ptc in thyroid microcarcinomas
might suggest that the rearrangement is an early event in thyroid
tumorigenesis, the initiating or progressional nature of this genetic
event is still unclear. The finding of somatic ret/ptc
rearrangements in patients carrying a germ-line apc mutation
suggests that they could be a progression event in neoplastic processes
initiated by apc mutation. It will be worthwhile to
investigate whether the two alterations cooperate in the neoplastic
transformation of thyroid follicular cells. It is known that the
ret/ptc oncoprotein has a constitutively activated kinase
function, and thus, it is able to couple with mitogenic pathways (34).
On the other side, recent evidence indicates that apc
product interacts with ß-catenins and may modulate cellular adhesion
and signaling pathways initiated by ß-catenins (3). Experiments
conducted with cultured thyroid cell lines or with transgenic mice will
help to clarify this issue. Whatever the case, the excellent clinical
behavior of FAP-associated thyroid carcinomas (4) (Cetta, F., in
preparation) correlates with findings indicating that
ret/ptc activation characterizes tumors that do not have a
tendency to progress to an aggressive phenotype (Tallini, G., Santoro,
M., Fusco, A., in preparation).
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Footnotes
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1 This work was supported by the Progetto Finalizzato Applicazioni
Cliniche della Ricerca Oncologica ACRO of the CNR, the Associazione
Italiana per la Ricerca sul Cancro, European Community Grant
FI4C-CT96–0003, MURST 40%-MURST 60%, Regione Toscana Grant 358/C
1995, and Telethon Italy Grant E-611. 
Received August 5, 1997.
Revised November 13, 1997.
Accepted November 18, 1997.
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J. Clin. Endocrinol. Metab.,
June 1, 1999;
84(6):
2257a - 2258.
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F. Cetta
Comment on Carney Complex and Related Syndromes and their Genetic Loci
J. Clin. Endocrinol. Metab.,
April 1, 1999;
84(4):
1491 - 1491.
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C. Soravia, S. L. Sugg, T. Berk, A. Mitri, H. Cheng, S. Gallinger, Z. Cohen, S. L. Asa, and B. V. Bapat
Familial Adenomatous Polyposis-Associated Thyroid Cancer : A Clinical, Pathological, and Molecular Genetics Study
Am. J. Pathol.,
January 1, 1999;
154(1):
127 - 135.
[Abstract]
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Top
Abstract
Introduction
