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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 493-496
Copyright © 1997 by The Endocrine Society

Endocrinological Oncology

G Protein and Thyrotropin Receptor Mutations in Thyroid Neoplasia1

Christopher Esapa, Sally Foster, Sarah Johnson, J. Larry Jameson, Patricia Kendall-Taylor and Philip E. Harris

Department of Medicine (C.E., P.E.H.), King’s College School of Medicine and Dentistry, London SE5 9PJ, United Kingdom; Departments of Medicine (S.F., P.K.-T.) and Pathology (S.J.), Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, United Kingdom; and Division of Endocrinology (J.L.J.), Northwestern University Medical School, Chicago, Illinois 60611


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The cAMP pathway plays a central role in thyroid follicular cell growth and function. Mutations of the TSH receptor (TSHR) or G proteins (gsp) that activate adenylyl cyclase have been identified in autonomously functioning thyroid nodules. Gsp mutations have been identified also in other forms of thyroid neoplasia, but their reported prevalence has been extremely variable. We have studied the prevalence of gsp mutations and activating mutations of Gi2{alpha} (gip) in a series of 66 benign and 34 malignant thyroid tumors. Thirty-six tumors were from Boston and 64 from the UK. In addition, we examined the 64 UK tumors for mutations of the TSHR gene. DNA extracted from fresh-frozen or paraffin-embedded tissue was amplified by PCR and examined for mutations using oligonucleotide-specific hybridization and single-strand conformation polymorphism analysis. No G protein gene mutations were identified in the Boston tumors. One gsp mutation, R201C, in a Hürthle cell adenoma and 1 gip mutation, R179C, in a follicular adenoma were demonstrated in tumors from the UK. Oligonucleotide-specific hybridization and single-strand conformation polymorphism analysis of the UK tumors did not demonstrate any mutations of the TSHR gene. Eleven normal thyroid tissue samples were wild-type for Gs{alpha}, Gi2{alpha}, and the TSHR gene.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE ADENYLYL cyclase (AC)-cAMP system is a major regulator of thyroid follicular cell function and growth (1). AC is under stimulatory control by Gs and inhibitory control by Gi. TSH exerts its trophic effect on thyroid function by interacting with a seven-transmembrane receptor [TSH receptor (TSHR)] coupled to Gs. Gs activates AC with the production of cAMP (2) and consequent activation of protein kinase A (3). With such a central role in TSH signal transduction, abnormalities in several of the G protein-cAMP pathway components can be expected to have profound effects on thyroid follicular cell function and proliferation.

Activating mutations of the TSHR gene have been reported in up to 80% of autonomously functioning thyroid adenomas (4). In addition, germline mutations have been described in a number of pedigrees with toxic thyroid hyperplasia (5, 6) and in congenital hyperthyroidism (7, 8). In differentiated thyroid carcinomas with enhanced AC activity, activating mutations (3/6) of the TSHR have been described (9). However, no TSHR gene mutations were identified in one large series of thyroid tumors (10). Activating mutations of Gs{alpha} that inhibit the intrinsic GTPase activity result in constitutive activation of the {alpha}-subunit. These mutations have been described in about 25% of autonomously functioning thyroid adenomas. There is, however, a great variability in the reported prevalences of gsp mutations in other forms of thyroid neoplasia (10, 11, 12, 13, 14, 15, 16, 17). The small sample size in some of these studies probably accounts partly for some of the disparate prevalences and thus makes it difficult to draw any consistent conclusions about the prevalence of G protein gene mutations in general. Activating mutations of the inhibitory G protein (gip) for AC have been described in adrenal and ovarian tumors (13) and in small numbers of pituitary adenomas (18, 19). We are not aware of any reports of gip mutations in thyroid neoplasia.

Overall, there seem to be considerable discrepancies among different studies regarding the involvement of G proteins in thyroid neoplasia. We therefore set out to examine in detail the role of the AC system in thyroid tumor development. Thyroid tumors derived from two different populations (UK and USA) were screened for known activating mutations of Gs{alpha} and Gi2{alpha}. The TSHR gene was screened for known activating mutations by oligonucleotide-specific hybridization. In addition, the fifth to seventh transmembrane domains were screened (codons 582–654) using single-strand conformation polymorphism (SSCP) analysis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects

Ethical approval for the study was obtained from the Hospital Ethics Committee. One hundred tissue samples were analyzed, 64 from the UK and 36 from the USA. These comprised 35 nodular goiters, 2 autonomously functioning nodules, 25 follicular adenomas, 14 follicular carcinomas, 4 Hürthle cell adenomas, 13 papillary carcinomas, and 7 medullary cell carcinomas. In addition, for comparative purposes, 11 normal thyroids were analyzed (Table 1Go).


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  		Table 1. Tissues analyzed for TSHR and G protein gene mutations

 
DNA extraction

Genomic DNA was extracted from frozen tissue and from leukocytes using standard proteinase K-SDS digestion and phenol-chloroform extraction (20). Paraffin-embedded tissue was digested at 55 C overnight with 1 mg/mL proteinase K in a buffer containing 10 mmol/L Tris-HCl (pH8.3), 50 mmol/L KCl, 2.5 mmol/L MgCl2, and 0.45% Tween 20. The mixture was then heated at 100 C for 15 min and microcentrifuged at 13,000 x g for 20 sec and the supernatant stored at 4 C.

PCR

PCR was carried out (Techne, UK) in 100 µL vol containing 1 µg genomic DNA, 2.5 U Taq polymerase (Bioline, UK), 20 pmol of each primer, 0.2 mmol/L each dNTP, 10 mmol/L Tris-HCl (pH8.8 ), 50 mmol/L KCl, 1.5 mmol/L MgCl2, 0.1% Triton X-100.

Gs{alpha}, Gi2{alpha}

DNA was PCR-amplified for both Gs{alpha} (encompassing codons 201 & 227) and Gi2{alpha} (encompassing codons 179 & 205) as previously described (19). The primers used for Gs{alpha} were: forward 5'-CCC CTC CCC ACC AGA GGA CTC TGA-3', reverse 5'-AGA GCG TGA GCA GCG ACC CTG ATC-3'; and Gi2{alpha} primers were: forward 5'-ATT GCA CAG AGT GAC TAC ATC CCC-3', reverse 5'-GGC GCT CAA GGC TAC GCA GAA-3'.

TSHR gene

Two fragments of the TSHR gene (encompassing most of exon 10) were amplified by PCR (5, 10) using the following primers: fragment A (positions 942-1960), forward 5'-T GTG AAT GCC TTG AAT AGC C-3', reverse 5'-T GAG AGG CTT GTT CAG AAT T-3'; fragment B (positions 1746–2257), forward 5'-T ATT GTT TTT GTT CTG ACG CT-3', reverse 5'-TA CTC TTC TGA GAT TTG GCC-3'. PCR conditions were as follows: denaturation at 93 C for 3 min, 30 cycles (93 C for 1 min, 54 C for 1 min, 72 C for 1 min) and a final elongation step of 7 min at 72 C.

Oligonucleotide-specific hybridization

Oligonucleotide-specific hybridization of PCR-amplified DNA was carried out as previously described (21). Synthetic oligonucleotide probes (20-mers), degenerate or specific for single-base mutations, were used to screen the different codons of Gs{alpha}, Gi2{alpha}, and the TSHR genes. The temperature required for stringent washing was optimized for each probe in the presence of both positive (mutant) and negative (wild-type) control sequences. The membranes were autoradiographed for 4–24 h at -70 C.

SSCP analysis

A smaller PCR product (primer positions 1746–1960) was used for SSCP analysis.

Ten microliters of the PCR reaction mixture was added to 9 µL sequencing stop buffer (95% formamide, 10 mmol/L NaOH, 0.05% bromophenol blue, 0.05% xylene cyanol) and heated at 95 C for 5 min. The denatured DNA was chilled on ice and loaded onto 0.5 x mutation detection enhancement gel (Flowgen, UK) containing 5% glycerol. Electrophoresis was performed at 8 watts for 15 h, and the gel was stained with 0.1% silver nitrate. These conditions have been used to identify a novel TSHR mutation in a separate study (data not shown).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
G protein gene mutations were identified in 2 of 100 thyroid samples examined. One Hürthle cell adenoma was found to have a gsp mutation at codon 201 (CGC to TGC) encoding an amino acid change from arginine to cysteine (Fig. 1Go). One follicular adenoma was found to possess a gip mutation at codon 179 (CGC to TGC), also encoding an amino acid change from arginine to cysteine (Fig. 2Go). Both mutations were identified in the UK cohort. PCR products from the G2 and G3 regions encompassing codons 201, 227 of Gs{alpha} and codons 179, 205 of Gi2{alpha}, were also screened by SSCP analysis. No band shifts were identified (data not shown) when compared with PCR-amplified DNA obtained from paired normal tissue.



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  		Figure 1. Slot-blot of DNA from a Hürthle cell adenoma demonstrating a gsp mutation, Arg to Cys (CGT to TGT) at codon 201.

 


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  		Figure 2. Slot-blot of DNA from a follicular adenoma demonstrating a gip mutation, Arg to Cys (CGC to TGC) at codon 179.

 
Sixty-four samples from the UK population were analyzed for TSHR gene mutations at codons 509, 619, 623, 631, 632, 633, and 672. No mutations were detected using oligonucleotide-specific hybridization. In addition, SSCP analysis between codons 582 and 654 did not show any band shifts (Fig. 3Go). There was not sufficient DNA from the Boston thyroid samples to analyze for TSHR gene mutations. No Gs{alpha}, Gi2{alpha}, or TSHR mutations were identified in 11 normal thyroid tissue samples.



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  		Figure 3. SSCP analysis of PCR-amplified genomic DNA for mutations of the TSHR gene (codons 582–654). Amplified DNA was denatured at 95 C for 5 min and electrophoresed through a 0.5x mutation detection enhancement gel containing 5% glycerol. Representative sample list with no abnormal banding pattern. Lanes: 1, 3, 4, 9, 10, nodular goiters; 2, Hürthle cell adenoma; 8, treated Grave’s; 11, 12, normal controls.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the thyroid, the cAMP pathway plays a key role in mediating the effects of TSH on thyrotroph cell growth and function. In view of this, alterations in cAMP signal transduction may be expected to contribute to thyroid tumor development. In fact, gsp mutations and activating mutations of the TSHR seem to play a major role in the pathogenesis and functioning of autonomously functioning thyroid nodules. A number of studies have reported wide ranging prevalences of between 2% and 13% gsp mutations in follicular and papillary tumors (9, 10, 13, 14, 15, 16, 17) (Table 2Go), with the most plausible explanation for the discrepancies being the small sample numbers in most of the studies. In an attempt to resolve this controversy, we have investigated a large collection of samples from two different populations (UK and the USA) for the presence of G protein and TSHR gene mutations.


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  		Table 2. Prevalence of G protein gene mutations in thyroid neoplasia

 
Screening of the Gs{alpha} gene at known hot spots by specific oligonucleotide hybridization demonstrated the presence of one gsp mutation at codon 201 in a Hürthle cell adenoma, which encoded an amino acid change from arginine to cysteine. In addition, one gip mutation was detected at codon 179 in a follicular adenoma, encoding a change in amino acid from arginine to cysteine. Evidence for an oncogenic role for gsp has come from both in vivo and in vitro studies. Activation of the AC system in mice transgenic for the A2 adenosine receptor (22) and in mice transgenic for the gsp mutation (23) resulted in thyrotroph cell growth and thyrotoxicosis. Transient transfection of FRTL5 cells with mutant Gs{alpha} has demonstrated activation of the phosphodiesterase (PDE) system, suggesting that long-term activation of the AC system in vivo will be subject to counterregulatory effects (24, 25). We have demonstrated that, apart from autonomously functioning thyroid nodules, gsp mutations are uncommon in thyroid tumors. It is possible that, when present, gsp mutations occur at an early stage as an initiating event. The occurrence of a gsp mutation simultaneously with another predisposing oncogenic mutation may have an additive effect on tumor progression. Such a scenario, though rare, has been described in a papillary carcinoma bearing both N-ras and gsp mutations (11) and also in a follicular carcinoma with both TSHR and N-ras mutations (9).

Activating mutations of the TSHR have been well characterized in autonomously functioning thyroid nodules (4, 12, 26, 27, 28, 29) and in thyroid carcinomas with constitutively enhanced AC activity (9). In addition, germline mutations have been described in familial (5, 6) and neonatal (7, 8) toxic thyroid hyperplasia, mainly within the membrane spanning regions. Most activating mutations (Table 3Go) result in increased AC activity. The I486F, I486 M and I568T mutants also have been shown to stimulate the phospholipase C-dependent cascade in vitro (4). In the current study, no alterations were detected in the third, sixth, and seventh transmembrane domains, consistent with the study by Matsuo et al. Neither of these studies, however, has examined the tissues for AC activity. In addition, we have not excluded the possible presence of mutations at other sites of the TSHR gene.


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  		Table 3. Prevalence of TSHR gene mutations in thyroid disease

 
In conclusion, we have demonstrated that, apart from autonomously functioning thyroid adenomas, gsp, gip, and TSHR mutations are infrequent in thyroid neoplasia. Further studies are necessary to determine whether activation of the pathway downstream of AC occurs in the development of these tumors.


   Acknowledgments
 
We would like to thank A. Thor and A. Vickery for their help in classifying the Boston tumors and E. Williamson for her help with the Newcastle tumors.


   Footnotes
 
Address all requests for reprints to: Christopher Esapa, Kings College School of Medicine and Dentistry, Bessemer Road, London, England SE5 9PJ.

1 This study was supported by a grant from the Medical Research Council. Back

Received July 9, 1996.

Revised October 17, 1996.

Accepted October 23, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  3. Thomis DC, Floyd-Smith G, Samuel CE. 1992 Mechanisms of interferon action: cDNA structure and regulation of a novel splice-site variant of the catalytic subunit of human protein kinase A from interferon-treated human cells. J Biol Chem. 267:10723–10728.[Abstract/Free Full Text]
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  19. Williamson EA, Johnson SJ, Foster S, Kendall-Taylor P, Harris PE. 1995 G protein gene mutations in patients with multiple endocrinopathies. J Clin Endocrinol Metab. 80:1702–1705.[Abstract/Free Full Text]
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