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Endocrinological Oncology |
Genes as a Cause of Toxic Thyroid Adenomas1
Institut de Recherche Interdisciplinaire (J.P., L.D., J.V.S., S.C., P.R., J.E.D., G.V.); Department of Medical Genetics (J.P., G.V.), Université Libre de Bruxelles, Campus Erasme, 1070 Bruxelles; Centre Hospitalier de Jolimont (J.H.), Haine-Saint-Paul, Belgium; Service de Chirurgie Thoracique (P.R.), Hôpital Erasme, 1070 Bruxelles; Service d’Endocrinologie (G.V.V.), Hôpital Sainte-Justine, Montréal, H3T 1C5 Québec, Canada
Address all correspondence and requests for reprints to: G. Vassart, I.R.I.B.H.N, Faculty of Medicine, University of Brussels, Campus Erasme, Route de Lennik 808, 1070 Brussels, Belgium. E-mail: gvassart{at}ulb.ac.be
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genes. This
constitutes an extension of our previous study, including the first 11
nodules of the series. The complete coding sequence of the TSH receptor
gene and the segments of Gs known to harbor mutations
impairing guanosinetriphosphotase activity were studied by direct
sequencing of genomic DNA extracted from the nodules. DNA from the
juxtanodular tissue or peripheral white blood cells was analyzed in all
patients to confirm that the mutations identified were somatic.
Twenty-seven mutations (82%) were found in the TSH receptor gene,
affecting a total of 12 different residues or locations. All these
mutations but 2 (see below) have been identified previously as
activating mutations. Only 2 mutations were found in Gs
(6%). In 4 nodules, no mutation was detected. Five residues (Ser281,
Ile486, Ile568, Phe631, and Asp633) were found mutated in 3 or 4
different nodules, making them hot spots for activating mutations.
Phe631 and Asp633 belong to a cluster of 5 consecutive residues
(629–633) in the N-terminal half of transmembrane segment VI, which
harbor together 44% of the mutations identified in this cohort. Two
novel mutations were identified: a point mutation causing substitution
of Phe for Leu at position 629 (L629F); and a deletion of 12 bases
removing residues 658–661 at the C-terminal portion of exoloop 3
(del658–661). When tested by transfection in COS-7 cells, both mutant
receptors display increase in constitutive stimulation of basal cAMP
accumulation. Although it is still capable of binding TSH, the
del658–661 mutant has completely lost the ability to respond to the
stimulation by the hormone. Our results demonstrate that, in a cohort
of patients from a moderately iodine deficient area, somatic mutations
increasing the constitutive activity of the TSH receptor are the major
cause of autonomous hot nodules. |
Introduction |
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genes constitute a pathophysiological explanation for
a number of endocrine diseases (1). The known effects of TSH and cAMP
agonists on thyroid cell function and growth (2), and knowledge about
the structure-function relationships of G protein-coupled receptors (3)
and the G proteins themselves (4), had provided the rationale to look
for such mutations in autonomous thyroid adenomas (5, 6, 7).
In spite of rapid replication (8, 9, 10) of our initial observation of
activating mutations in the TSH receptor (5), some authors have failed
to identify similar mutations in a series of adenomas from Japan (9).
Together with earlier claims that the TSH receptor did not behave as a
proto-oncogene (11), this led to an uncertainty about the true
prevalence of TSH receptor and Gs mutations in toxic
adenomas.
In the present study, we have completed our initial survey (5, 12, 13)
by completely sequencing the coding portions of the TSH receptor gene
from a total of 33 adenomas. In addition, the known hot spots for
mutations affecting the GTPase activity of Gs (14)
were also sequenced. Twenty-seven mutations (82%) were found in a
total of 12 different locations within the TSH receptor. These include
2 novel mutations that have been studied functionally. Only 2 mutations
(6%) were identified in Gs. We conclude that in our
population, somatic mutations of the TSH receptor gene are, by far, the
most frequent cause of autonomous thyroid adenomas.
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Materials and Methods |
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Twenty-two adenomas were added to a series of 11 investigated
previously (12). In this earlier study, only the serpentine portion of
the TSH receptor had been sequenced, and the Gs gene was
not explored. Some characteristics of the patients and their adenomas
are summarized in Table 1
. All cases had a Tc-99 m
scintigraphy. After surgery, the nodular and surrounding tissues were
analyzed by standard pathology. A minority of cases presented with
multinodular goiter with multiple zones of autonomy devoid of capsule.
All patients had a suppressed plasma TSH.
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Genomic DNA was extracted from nodular and, when available, from
juxtanodular tissue (if not, DNA was extracted also from peripheral
white blood cells) (12). Care was taken to sample the zones identified
as hot on the scintiscan. In some cases, the status of the sampled
tissue was verified by 131I uptake of tissue slices
incubated in vitro (see Table 1
) (15).
TSH receptor gene. All coding portions of the TSH receptor gene were sequenced using a total of 14 fragments amplified by PCR (the list of primers is available upon request). Direct genomic DNA sequencing of both strands was realized with the Thermosequenase sequencing kit (RPN 2436, Amersham Gent, Belgium) and mutations identified using the Factura and Sequence Navigator Software running on an ABI 373 sequencer.
Gs gene.
The exons 8 and 9 were amplified by
PCR as previously described (16). The sequence reaction and analysis
were performed as described above.
Functional analysis of novel TSH receptor mutants by transient transfection in COS-7 cells
Preparation of expression constructs. pSVL-TSHr constructs harboring the two new mutations were obtained as previously described (5, 17).
Transfections. COS-7 cells were grown and transfected as described (12). In brief, cells were seeded at the density of 300,000 cells/3-cm dish and transfected 1 day later with 500 ng/dish of each construct. Two days after transfection, cells were used for flow cytofluorometry, cAMP, or inositolphosphate determinations and 125I-TSH-binding studies. Triplicate dishes were used for each measurement, except for inositolphosphate experiments, for which duplicates were used. Each experiment was repeated at least twice.
cAMP and inositolphosphate determinations. cAMP and inositolphosphate determinations were performed, essentially as described previously, by competitive binding assay and metabolic labeling, followed by ion exchange chromatography, respectively (12). For cAMP, results are expressed as picomoles per dish; for inositolphosphates, as the percentage of radioactivity incorporated from [3H]-inositol in inositolphosphates (IP1 + IP2 + IP3) over the sum of radioactivity incorporated in inositolphosphates and phosphatidylinositols.
Binding assays. Binding assays were performed on whole cells incubated at room temperature for 4 h in NaCl-free Hank’s buffer, supplemented with sucrose 280 (mmol/L), BSA (0.2%), and low fat milk (2.5%), exactly as described previously (18).
Flow cytofluorometry.
Cells were detached from the plates
with phosphate-buffered saline (PBS), supplemented with ethylenediamine
tetraacetate (EDTA) and ethyleneglycol-bis-(ß-aminoethyl
ether)-N,N,N'-tetraacetic acid (EGTA) (5 mmol/L each),
transferred into Falcon tubes (2052) and pelled by centrifugation at
500 x g for 3 min at 4 C. For the nonpermeabilized
cell assay, cells were incubated immediately with the antibody. For the
permeabilized cell assay, cells were first fixed in phosphate buffered
saline-paraformaldehyde (PBS-PAF) 1% (Paraformaldehyde, UCB, Leuven,
Belgium) for 10 min on ice and, thereafter, incubated with PBS-BSA
0.1%-Saponin 0.2% (Sigma Chemical Co., St. Louis, MO) for 30 min.
Saponin-supplemented PBS buffer was used in all subsequent incubations.
After incubation for 30 min at room temperature with 100 µL PBS-BSA
(0.1%) containing the 2C11 mAb (10 µg/mL), the cells were washed
with 4 mL PBS-BSA (0.1%), centrifuged as above, and incubated for 30
min on ice in the dark with fluorescein-conjugated 
chain-specific
goat antimouse IgG (Sigma) in the same buffer. The 2C11 mAb, kindly
provided by Dr. A.P. Johnstone (19), recognizes a linear epitope of the
extracellular aminoterminus of the TSH receptor (VFFEEQ, residues
354–359)(20). Propidium iodide (10 µg/mL) was used for detection of
damaged cells, which were excluded from the analysis. Cells were washed
once again and resuspended in 250 µL PBS-BSA (0.1%). The
fluorescence of 10,000 cells per tube was assayed by a FACScan Flow
Cytofluorometer (Beckton Dickinson, San Jose, CA).
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Results |
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mutations
In our initial studies (5, 12, 13), 11 patients were
investigated for the presence of somatic mutations within the
serpentine portion of the TSH receptor encoded by exon 10 of the gene.
We have now completed this series by studying 20 additional patients,
yielding a total of 33 adenomas (2 patients harbored 2 separate hot
nodules). To avoid the sampling bias of previous studies, the full
coding portion of the TSH receptor gene was sequenced, including the 9
exons encoding the aminoterminal extracellular domain (5, 8, 9, 12, 13, 21, 22). Also, the 2 hot spots for mutations in Gs were
explored (residues 201 and 227) (14). The results are illustrated in
Table 1, together with some characteristics of the patients and their
tumors. A somatic mutation of the TSH receptor gene was found in 27
adenomas (82%, confidence interval 95%: 65–93), whereas only 2 were
found in Gs (6%, confidence interval 95%: 1–20). In
all cases, the mutations were confined to the adenomatous tissue. As
reported previously, 1 patient with a multinodular goiter had 2 hot
nodules with a different mutation in each (23).
Spectrum of mutations in the TSH receptor
The 27 mutations identified involve a total of 12 different
locations in the TSH receptor gene (Fig. 1), some
regions or residues constituting convincing hot spots (Fig. 1). The 6th
transmembrane segment alone harbors 12 of the 27 mutations (44%).
Detailed inspection of the various mutations revealed no obvious bias
in base substitutions (Fig. 1). Specifically, no single mutation
affected CpG dinucleotides that are known as hot spots for mutations in
vertebrates. However, the diversity of mutations at different positions
vary considerably: whereas a variety of aminoacid substitutions are
observed at some positions (e.g. Asp633, Ser281), the same
substitutions are repeatedly observed at others (e.g.
Ile568, Phe631). This suggests strongly that selection of the mutations
is based essentially on functional criteria, i.e. their
aptitude to trigger proliferation of (hyper)functional thyrocytes (see
Discussion).
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Except for 2 (L629F and del658–661), all mutations have been
documented and analyzed functionally by transfection in COS-7 cells (5, 8, 12, 21, 22, 24, 25, 26). Whereas L629F is included in the major hot spot
area at the basis of transmembrane VI, del658–661 is unusual both in
its location (the border between the 3rd exoloop and transmembrane
segment VII) and its nature (a deletion of 12 bases, removing 4
aminoacids). The mutations are illustrated in Fig. 2.
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, panel a), does not affect the basal level of
inositolphosphates (Fig. 3, panel b), continues to respond to TSH for
both cAMP and inositolphosphate accumulation (Fig. 3 and Fig. 4, panel a), and binds TSH with slightly higher affinity
than the wild-type (Fig. 4, panel b). Expression of L629F mutant at the
cell surface is lower than the wild-type (Fig. 5).
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, panel a), its expression at the cell surface is much lower (Fig. 5).
Most of the mutated receptor molecules remain trapped intracellularly,
as revealed by flow immunocytometry of cells permeabilized with saponin
(Fig. 5). Similar to L629F, del658–661 has no effect on basal
inositolphosphate accumulation (Fig. 3, panel b), but contrary to
L629F, it has completely lost the ability to respond to TSH for
stimulation of both adenylyl-cyclase and phospholipase C (Fig. 3).
Binding of labeled TSH is clearly present (Fig. 4, panel b), but it is
difficult to analyze quantitatively, because of the low level of
expression at the plasma membrane. |
Discussion |
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account for a minority of cases only.
Considering the known role of cAMP agonists on thyrocyte growth and
function (27, 28), and in agreement with transgenic mice models (29, 30), these mutations that enhance the basal adenylyl-cyclase activity
in thyrocytes provide a convincing pathophysiological explanation for
the development of thyroid autonomy. It must be emphasized, however,
that additional mutational events might be implicated in the continuous
growth of toxic adenoma, as suggested by experimental data
demonstrating a limitation in the growth potential of normal thyrocytes
when stimulated continuously by TSH or cAMP agonists (31, 32).
The large excess of TSH receptor mutations (82%) over
Gs mutations (6%) may have more than one explanation:
first, as demonstrated by transgenic mice models, constitutive
activation of the adenylyl-cyclase/cAMP pathway is more efficient at
the receptor level than at Gs (29, 32); second, as our
results demonstrate, the number of effective targets for activating
mutations is much higher in the TSH receptor (at least 12 different
locations, see Table 1) than in Gs (2 residues)
(14).
Studies from other groups do not all agree with the prevalence of TSH
receptor mutations observed here. In a Japanese study, no activating
mutation could be found in 38 toxic nodules (9); in 1 Italian study,
activating mutations were observed in 7 of a series of 11 toxic
adenomas (8); in another, 37 hot nodules were found to harbor 3 and 9
mutations in the TSH receptor and Gs, respectively (22).
This may have methodological causes (direct sequencing was not always
used; only selected segments of the receptor gene were studied), but it
may reflect, in part, a true difference in the underlying
pathophysiological mechanism. The chronic low-grade stimulation of the
thyroid associated with the mild iodine deficiency of our population
may favor the accumulation of somatic mutations, as discussed in
reference to the case displaying different mutations in his 2 hot
nodules (Nr4 in Table 1) (23). That (an)other pathophysiological
mechanism(s) may be implicated is suggested by our observation that, in
4 nodules out of 33 (12%), we were unable to identify any mutation in
the 2 genes. This may reflect limitation in our methodology, pitfalls
in sampling, mutations in other genes or in regions controlling the
level expression of the TSH receptor gene (33), or nonmutational
epigenetic mechanisms.
The 27 mutations of the TSH receptor identified in this cohort involve 12 different locations or residues. Together with somatic mutations identified by other groups (8, 22) and germline mutations responsible for hereditary or sporadic toxic thyroid hyperplasia (18, 24, 25, 34), the total number of targets for activating mutations in the TSH receptor is currently 19. This surprising diversity of activating mutations tells us that activation of the TSH receptor is most likely a result of the release of an inhibitory structural constraint (35, 36). In the absence of the agonist, the equilibrium between inactive and active conformations of the receptor could thus be shifted toward active conformations by a wide spectrum of different alterations in the primary structure, having similar or equivalent effects on the tertiary structure. With this model in mind, it is interesting to explore the spectrum of amino acid substitutions at the different positions where activating mutations are observed. If one considers only the mutations observed in this cohort, residues can be classified into two categories: those, like Ile568 and Phe631, where the same aminoacid substitutions are repeatedly observed (Ile568Thr in 4/4 cases; Phe631Leu in 4/4 cases); others, like Asp633, which can be changed to a variety of aminoacids belonging to different classes (Glu, Tyr, His, Ala). This could mean that, depending on the residue, some mutations might destroy interactions stabilizing the inactive conformation of the receptor, whereas others would involve the establishment of new attractive or repulsive interactions. However, because we cannot predict which substitutions would prevent receptor expression at the plasma membrane (37, 38), it can simply be that the identical substitutions observed repeatedly at some residues would result from a selection bias (all other substitutions at these residues being either silent, or incompatible with correct receptor expression).
Two novel mutations have been identified: the first, L629F, can be
added to the list of mutations affecting the hot spot in transmembrane
VI. Their functional characteristics do not deviate from the average
mutations identified in this region. Transmembrane VI is considered to
play a key role in the transmission of an activation signal to the G
protein by altering the conformation or position of the third
cytoplasmic loop (39). The second mutation, del658–661, is more
interesting, both from its nature and functional characteristics. To
the best of our knowledge, it is the first natural activating mutation
caused by a deletion. Although it is poorly expressed at the surface of
COS-7 cells (Fig. 5), it is the first to display strong constitutive
activity while having lost completely the ability to respond to TSH
(Fig. 3). In keeping with the discussion above, it is likely that this
deletion would destroy an interaction and/or, from its location at the
C-terminal portion of the third exoloop, modify the position of
transmembrane segments VI or VII. It is tempting to explain the
functional characteristics of this mutant in the light of a model in
which interactions between the aminoterminal domain and the exoloops of
the receptor would be implicated in maintaining the unliganded receptor
in an inactive conformation (20).
Comparing the spectrum of somatic mutations found in toxic adenomas with germline mutations found in hereditary toxic thyroid hyperplasia, leads to the surprising observation that they do not overlap (18, 34, and the present report). A likely explanation is that this reflects a selection bias. Starting from a single cell, to produce a sizable tumor, the adenoma type must be more aggressive to be selected by the clinical screening. In comparison, mutations causing a milder stimulation are expected to cause hyperthyroidism when they are expressed in all thyrocytes, as in the familial diseases. When occurring in the germline, mutations of the adenoma type indeed cause severe congenital hyperthyroidism (24, 25) and are expected to significantly decrease reproductive fitness in the absence of treatment.
Apart from this gross subdivision between hereditary and somatic or neomutations, there is no obvious correlation between the nature of the mutations in toxic adenomas and the clinical picture. Even the TSH receptor mutations identified in rare cases of thyroid cancers all belong to the spectrum of mutations found also in benign toxic adenomas (40, 41).
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Acknowledgments |
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Footnotes |
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2 Contributed equally to this study.
3 Aspirant at the Belgian FNRS.
Received January 22, 1997.
Revised March 21, 1997.
Accepted April 29, 1997.
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References |
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in human thyroid cancers: low prevalence of mutations
predicts infrequent involvement in malignant transformation. J
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