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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 3 754-759
Copyright © 2006 by The Endocrine Society

CLINICAL CASE SEMINAR

In Vivo and in Vitro Characterization of a Novel Germline RET Mutation Associated with Low-Penetrant Nonaggressive Familial Medullary Thyroid Carcinoma

Leonardo D’Aloiso, Francesca Carlomagno, Michele Bisceglia, Suresh Anaganti, Elisabetta Ferretti, Antonella Verrienti, Franco Arturi, Daniela Scarpelli, Diego Russo, Massimo Santoro and Sebastiano Filetti

Unit of Endocrinology and Division of Anatomic Pathology (L.D., M.B.), Instituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza Hospital, S. Giovanni Rotondo, 71013 Foggia, Italy; Dipartimento di Biologia e Patologia Cellulare e Molecolare (F.C., S.A., M.S), University Federico II c/o Istituto di Endocrinologia ed Oncologia Sperimentale Consiglio Nazionale delle Ricerche, 80131 Naples, Italy; Dipartimento di Scienze Cliniche e Dipartimento di Medicina Sperimentale e Patologia (E.F., A.V., S.F.), Università di Roma La Sapienza, Viale del Policlinico 155-00161 Rome, Italy; and Dipartimento di Medicina Sperimentale e Clinica Gaetano Salvatore and Dipartimento di Scienze Farmacobiologiche (F.A., D.S., D.R.), University of Catanzaro Magna Graecia, 88100 Catanzaro, Italy

Address all correspondence and requests for reprints to: Sebastiano Filetti, M.D., Dipartimento di Scienze Cliniche Università di Roma La Sapienza, Viale del Policlinico 155-00100 Rome, Italy. E-mail: sebastiano.filetti{at}uniroma1.it.


   Abstract
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 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: RET mutation analysis provides useful information on the clinical outcome of medullary thyroid carcinomas (MTCs) and the risk of disease in the family members.

Objective: The objective of this study was to document genotype-phenotype relationships in an Italian family with a novel RET mutation.

Design/Setting: RET gene alterations were investigated in a patient with unifocal MTC and her relatives. The identified mutation was subjected to in vitro functional testing.

Patients: Patients included a female proband who developed MTC at age 60, her five children, and three grandchildren.

Main Outcome Measures: DNA extracted from the blood and the proband’s tumor were analyzed for RET alterations. The transforming potential and mitogenic properties of the identified mutation were investigated.

Results: A novel heterozygous germline RET mutation at codon 777 (AAC->AGC, N->S) (RET/N777S) was identified in the proband and three of her relatives. Two of the latter presented thyroid nodules, but none had MTC or C cell hyperplasia. The proband’s MTC was characterized by late onset and limited aggressiveness, with no evidence of regional lymph node or distant metastases 10 yr after total thyroidectomy. This phenotype is consistent with the RET/N777S mutant’s low-grade transforming potential and limited activation of RET tyrosine kinase.

Conclusion: Our findings indicate that the newly identified RET/N777S mutation is a low-penetrant cause of MTC disease. This phenotype might be less aggressive than that associated with MEN2A of familial MTC, although close clinical follow-up of carriers is essential.


   Introduction
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 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
RET PROTOONCOGENE MUTATION analysis plays a central role in the management of medullary thyroid cancer (MTC) disease. It can distinguish between sporadic and hereditary forms of the disease [familial MTC (FMTC)], reveal risks for other types of cancer, i.e. those associated with multiple endocrine disease (MEN) type 2 (2A or 2B) (1, 2), and identify family members who are also at risk for MTC. The increasing use of this type of genetic testing can also expand our knowledge of genetic-phenotypic relationships in MTC.

In patients with MEN2A or FMTC, RET mutations usually affect the cysteine-rich receptor domain encoded by exons 10 and 11, but mutations involving exons 8, 13, 14, 15, and 16 have also been described. In contrast, almost all the RET mutations detected in MEN 2B involve codon 918 of exon 16 (3).

Here, we describe a novel germline RET mutation in an Italian woman who underwent thyroidectomy for unifocal MTC at age 60. She currently has no evidence of recurrent or metastatic disease, but 10 yr after surgery, she was diagnosed with Mibelli’s porokeratosis. Genetic testing revealed mutation of codon 777 (AAC/AGC) in exon 13 resulting in a serine-for-asparagine substitution in the intracellular region of the RET protein. The same mutation was found in three of the proband’s relatives, none of whom have developed MTC thus far. Our clinical analysis and functional studies indicate that the N777S alteration is characterized by low penetrance and associated disease that is relatively nonaggressive.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The study protocol was approved by the local ethics committee, and informed consent was obtained from all subjects.

Family history

The family pedigree is shown in Fig. 1Go. The index patient (II.4) was referred to our institution in 1993 at the age of 60, when she underwent total thyroidectomy for a solitary 3.5-cm nodule in the left lobe of the gland, which was histologically diagnosed as MTC with stromal amyloid and no sign of C cell hyperplasia. A normal intrathyroidal parathyroid gland was found in the right lobe. All seven regional lymph nodes removed during surgery were negative for metastases. Ten years after surgery, atrophic skin lesions with keratotic borders were noted on both legs and histologically diagnosed as Mibelli’s porokeratosis (Fig. 2Go). There was no clinical or imaging-based evidence of tumor recurrence or metastatic disease. Serum levels of calcitonin (CT) levels (basal and pentagastrin-stimulated), calcium, and PTH and urinary levels of catecholamines and metanephrines were all within normal ranges. The patient never had any symptoms suggestive of excessive catecholamine production.


Figure 1
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  		FIG. 1. Pedigree of the family with the RET/N777S mutation.

 

Figure 2
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  		FIG. 2. Histological features of the atrophic skin lesions, 3–4 mm in diameter, located on the proband’s legs were consistent with Mibelli’s porokeratosis. A, Two keratin-filled invaginations of the epidermis, each containing a partially parakeratotic column (the so-called cornoid lamella). A small mononuclear cell infiltrate is also visible in the upper dermis. B, Detail of the porokeratotic furrow illustrating the cornoid lamella. The underlying granular cell layer is diminished or absent, an important clue to diagnosis.

 
Complete clinical work-ups and RET mutation analysis were performed on the proband, her five children (age range, 31–47 yr), and two of her three grandchildren, ages 5 and 15 (Fig. 1Go). All seven had normal serum levels of CT (basal and pentagastrin-stimulated), PTH, and calcium. The proband’s 47-yr-old son (III.2) had a thyroid nodule (1.6 cm in diameter) with no cervical lymphadenopathy. In 1991, 2 yr before the proband’s thyroidectomy, her eldest daughter (III.3), then 25 yr old, had undergone a subtotal thyroidectomy for a nodular goiter. The pathology report contained no information on the parafollicular C cell status. The proband’s youngest daughters are monozygotic twins, one of whom (III.5) was found to have Graves’ disease with diffuse nonnodular goiter.

Paraffin-embedded thyroid tissue specimens taken during the proband’s thyroidectomy and that of her daughter (III.3) were retrieved and reexamined to definitively exclude occult C cell hyperplasia.

RET gene analysis

Genomic DNA was extracted from peripheral blood leukocytes with a commercial kit (Nucleon, Amersham Pharmacia Biotech, Milan, Italy). Exons 10, 11, and 13–16, including the exon-intron-flanking regions, were screened for ret mutations with a denaturing HPLC assay developed by our group (4). Sequences were compared with that of human RET cDNA (GenBank accession no. X12949), and each alteration noted was confirmed by sequencing both DNA strands of two independent PCR products.

Protein studies

Previously described (5) polyclonal rabbit antibodies against the RET tyrosine kinase domain (amino acids 738-1058) [anti-RET(TK)] were affinity-purified by sequential chromatography on RET-coupled agarose columns. Monoclonal anti-phosphotyrosine (4G10) antibody was purchased from Upstate Biotechnology, Inc. (Lake Placid, NY), and horseradish peroxidase-coupled secondary antibodies were from Amersham Pharmacia Biotech (Little Chalfont, UK). Immunoprecipitation and immunoblotting were performed according to standard protocols. Briefly, cells were lysed in a buffer containing 50 mM HEPES (pH 7.5), 1% (vol/vol) Triton X-100, 50 mM NaCl, 5 mM EGTA, 50 mM NaF, 20 mM sodium pyrophosphate, 1 mM sodium vanadate, 2 mM phenylmethylsulfonyl fluoride, and 1 µg/ml aprotinin. After 15 min centrifugation at 10,000 x g, lysates containing comparable amounts of proteins, estimated by a modified Bradford assay (Bio-Rad, Munich, Germany), were immunoprecipitated with the required antibody or subjected to direct western blotting. Immune complexes were detected with an enhanced chemiluminescence kit (Amersham Pharmacia Biotech).

Molecular constructs

All the constructs used encode the short RET-9 isoform and were cloned in pCDNA3(Myc-His) (Invitrogen, Groningen, The Netherlands). The wild-type RET and RET/C634R constructs have been described previously (5). RET/N777S (AAC{Rightarrow}AGC) was generated by site-directed mutagenesis using the QuikChange kit (Stratagene, La Jolla, CA), and the mutation was confirmed by DNA sequencing.

Cell culture and transfection experiments

NIH 3T3 fibroblasts grown in DMEM (Invitrogen, Groningen, The Netherlands) with 5% calf serum (Invitrogen) were transfected using the calcium phosphate precipitation method, as described elsewhere (5). Transformed foci were scored at 3 wk. Transforming efficiency was assessed at 3 wk and expressed as focus-forming units per picomole of added DNA (5).

Histological and immunohistochemical investigations

Four paraffin blocks containing tissue sections ranging in size from 1.5 x 1.5 cm to 2.0 x 2.0 cm were retrieved for subject III.3; nine blocks (slices ranging from 1.2 x 1.2 cm to 2.5 x 2.0 cm) were available for the proband. Four-micron-thick sections newly cut from these blocks were examined after routine staining with hematoxylin and eosin, and sections from all blocks were immunohistochemically probed with prediluted polyclonal antibodies to chromogranin-A and CT (both from Dakocytomation, Glostrup, Denmark) using a standard avidin-biotin peroxidase technique. The MTC tissue from the proband, which was present along with adjacent normal thyroid tissue in four of the nine blocks, was also evaluated as a positive control.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The denaturing HPLC-based analysis of the proband’s peripheral leukocyte DNA excluded known RET mutations involving exons 10 (codons 609, 611, 618, and 620), 11 (codon 634), and 14–16, but the elution profile for exon 13 was abnormal. Direct DNA sequence analysis revealed a heterozygotic transition at codon 777 (AAC>AGC) causing a serine-for-asparagine substitution (Fig. 3Go). This abnormality has not been found in the DNA obtained from about 150 healthy control subjects, suggesting that it is not a benign polymorphism. The same mutation was also found in DNA from the proband’s MTC tissue and lesional skin biopsy specimen.


Figure 3
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  		FIG. 3. Sequence analysis of RET codon 777 reveals a heterozygous AAC>AGC mutation in subject II.4.

 
All of the proband’s available relatives were then screened for RET mutations (Fig. 1Go). None had any symptoms suggestive of hereditary MTC or skin lesions consistent with Mibelli’s porokeratosis. The N777S mutation was found in two of the proband’s children (III.2 and III.3) and one granddaughter (IV.1). Although MTC was excluded in all three cases, subjects III.2 and III.3 did have benign thyroid nodules. The latter had undergone nodule resection, and the pathology report confirmed the benign nature of the lesion but made no mention of C cell hyperplasia. Her CT levels (basal and pentagastrin-stimulated) are currently normal. Polymorphism at codon 769 was also detected in the proband, the three RET-N777S carriers, and the proband’s eldest daughter (subject III.1), who also presented a second polymorphism involving codon 836.

To determine whether the N777S mutation was capable of converting RET into a dominantly transforming oncogene, we transfected NIH 3T3 cells with wild-type RET, RET/N777S, or RET/C634R (a strong RET oncogene associated with MEN 2A). As reported by others (6), RET/C634R colonies contained numerous transformed foci, whereas the transforming capacity of wild-type RET was negligible. The number of transformed foci induced by RET/N777S was roughly one tenth of that produced by RET/C634R (Fig. 4BGo).


Figure 4
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  		FIG. 4. A, Expression levels and phosphorylation status of the various RET proteins in mass populations of transfected NIH 3T3 cells. Equal amounts (100 µg) of extracted proteins were immunoprecipitated with anti-RET and blotted with anti-RET or phosphorylation-specific antibodies. The results are representative of at least three independent assays. B, Focus-forming activity of the three RET constructs. Results are the average from three independent assays, each performed in duplicate. C, Growth curves of the three cell lines under different serum conditions. Cells (n = 10,000) were plated and counted at different time points. Results are the average ± SD of three independent determinations. CS, Calf serum.

 
The expression level of each of the three RET constructs was evaluated in mass populations of neomycin-selected transfected NIH 3T3 cells (>50 colonies for each construct). RET/N777S protein products were correctly synthesized as molecular weight 145,000 and 160,000 isoforms, the former representing a mature glycosylated protein present on the cell surface and the latter, its immature precursor (7). Oncogenic activation of RET causes constitutive activation of tyrosine kinase, which triggers autophosphorylation of RET, recruitment of intracellular substrates, and activation of several signaling pathways (8). Therefore, to determine the activation status of the three RET proteins, we measured in vivo tyrosine phosphorylation levels in RET immunoprecipitates using immunoblotting with phosphotyrosine-specific monoclonal antibodies. As shown in Fig. 4AGo, wild-type RET protein had no detectable phosphotyrosine content, whereas phosphorylation of RET/N777S was significantly (approximately 7-fold) less intense that that of RET/C634R.

Because oncogenic RET mutants are mitogenic for NIH 3T3 fibroblasts, we measured proliferation rates in untransfected cells and those expressing RET/N777S during growth in complete medium (containing 5% calf serum) or under conditions of serum deprivation (1% calf serum). RET/N777S stimulated NIH 3T3 mitogenesis under both growth conditions (Fig. 3CGo), although once again its effect was less potent than that of RET/C634R (data not shown).

Collectively, these findings indicate that the N777S mutation has unequivocal transforming potential, which is, however, clearly weaker than that exerted by RET/C634R, and this picture is fully consistent with the mutation’s phenotype.

The results of our reexamination of the pathology specimens of the proband and her daughter are fully consistent with the results of our molecular and in vitro studies. No foci of definite parafollicular C cell hyperplasia were detected by routine histology or immunohistochemistry. C cells were absent in all but one of the sections from the four tissue blocks from subject III.3 and all but two of the sections from five blocks containing nonneoplastic thyroid tissue from the proband. C cell positivity was noted, however, in one section from subject III.3 and two sections from the proband. In each case, the cells were confined to a single roundish area 0.4 cm in diameter located within the follicular basal lamina (intrafollicular position). Each cluster contained around 100 immunostained C cells, isolated or in small groups of five to six cells. In familial forms of C cell hyperplasia, there are usually numerous C cells randomly distributed through both lobes and in various patterns of growth. They are often associated with early multifocal medullary neoplasia. Therefore, the distribution patterns noted in the specimens we examined are probably representative of normal tissue in the lateral thyroid lobes, where C cells are normally restricted.


   Discussion
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Most RET mutations detected in MEN2A and FMTC patients affect a region of the gene (involving exons 10 and 11) that encodes RET’s cysteine-rich extracellular domain, although several novel noncysteine mutations have recently been associated with FMTC disease (1, 9). The novel exon-13 RET mutation documented in this Italian family is associated with a seemingly mild phenotype. The proband’s MTC was characterized by late-onset and low-grade biological behavior. At diagnosis, the cancer was confined to the thyroid, and 12 yr after surgery, the patient is alive and well with no evidence of disease. Moreover, at ages ranging from 15–47 yr, the three family members who carried the same mutation presented no signs of MTC or any of the other tumors seen in MEN disease. The presence of C cell hyperplasia was also excluded in subject III.3, who had already had surgery for a benign thyroid nodule.

These characteristics are typical of FMTC related to RET mutations involving the tyrosine kinase domain 1 (10), including those affecting codon 804 (11, 12). The disease documented in this family can probably be considered low-risk. However, it is presently unclear whether FMTCs related to cysteine and noncysteine RET mutations have different clinical courses. The latter alterations are relatively rare, and more data are needed to establish their actual risk level.

Remarkably, a specific RET codon mutation can be related to a specific phenotype of hereditary MTC (13). Germline mutations in the cysteine domain of exon 11 (codon 634) cause dimerization of RET monomers via disulfide bond formation. The result is ligand-independent constitutive activation of tyrosine kinase, which is associated with extremely strong in vitro transforming activity (5) that might explain the aggressivity of MEN2A disease. Like other exon 13 alterations identified in FMTC patients (14), the N777S mutation displayed a low transforming potential and limited constitutive tyrosine-kinase activity, although it did stimulate the growth of 3T3 cells.

For optimal management and follow-up of the N777S mutation carriers (and all individuals with rare FMTC mutations), careful surveillance is clearly indicated. The absence of C cell hyperplasia is consistent with the low transforming potential of the mutation and may partly explain both the late onset of MTC in the proband and the normal serum CT levels found in her kindred.

There are conflicting views on the roles of RET polymorphisms as predisposing factors for MTC (15). The two polymorphisms identified in our family, which involved codons 769 and 836, do not appear to increase the risk for MTC (16). Their distribution is not suggestive of any causative association with the disease.

Associated abnormalities, such as pheochromocytomas and/or hyperparathyroidism, have been detected in MEN 2A patients, but they were generally restricted to individuals with mutations in the cysteine-rich domain of RET. Familial diseases other than FMTC have never been described in association with noncysteine mutations. However, both MEN2A and FMTC are reportedly associated with cutaneous lichen amyloidosis (17). The significance of the Mibelli-type porokeratotic lesion diagnosed in our proband is unclear. This prototypical form of porokeratosis is characterized by variable clinical expression. However, it is considered to be a preneoplastic process due to the increased incidence of squamous cell carcinoma within these lesions. Although it was originally regarded as a familial disorder with an autosomal dominant inheritance pattern, numerous nonfamilial cases have recently been reported (OMIM 175800). Similar skin lesions have not been detected in any of our proband’s relatives, and the association between this rare cutaneous disorder and her hereditary MTC may be purely casual.


   Footnotes
 
This work was supported by the Italian Association for Cancer Research and by grants from the Italian Ministry of Education, Universities, and Scientific Research and the Ministry of Health.

First Published Online December 29, 2005

Abbreviations: CT, Calcitonin; FMTC, familial medullary thyroid carcinoma; MEN, multiple endocrine disease; MTC, medullary thyroid carcinoma.

Received October 25, 2005.

Accepted December 20, 2005.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Leboulleux S, Baudin E, Travagli JP, Schlumberger M 2004 Medullary thyroid carcinoma. Clin Endocrinol (Oxf) 61:299–310[CrossRef][Medline]
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  6. Carlomagno F, Salvatore G, Cirafici AM, De Vita G, Melillo RM, de Franciscis V, Billaud M, Fusco A, Santoro M 1997 The different RET-activating capability of mutations of cysteine 620 or cysteine 634 correlates with the multiple endocrine neoplasia type 2 disease phenotype. Cancer Res 57:391–395[Abstract/Free Full Text]
  7. Carlomagno F, De Vita G, Berlingieri MT, de Franciscis V, Melillo RM, Colantuoni V, Kraus MH, Di Fiore PP, Fusco A, Santoro M 1996 Molecular heterogeneity of RET loss of function in Hirschsprung’s disease. EMBO J 15:2717–2725[Medline]
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