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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 5 1700-1704
Copyright © 1999 by The Endocrine Society

Original Studies

A Novel 9-Base Pair Duplication in RET Exon 8 in Familial Medullary Thyroid Carcinoma1

Pascal Pigny, Catherine Bauters, Jean-Louis Wemeau, Martine Lecomte Houcke, Michel Crepin, Philippe Caron, Sophie Giraud, Alain Calender, Marie-Pierre Buisine, Jean-Pierre Kerckaert and Nicole Porchet

Laboratoire de Biochimie-Secteur commun de Biologie Moléculaire de l’Hôpital Huriez (P.P., M.C., M.P.B., J.P.K., N.P.), Service d’Endocrinologie & Médecine Interne (C.B., J.L.W.), Service d’Anatomie Pathologique A (M.L.H.), Centre Hospitalier Régional Universitaire, 59037 Lille Cedex; Laboratoire de Génétique Moléculaire, Hôpital Edouard Herriot (S.G., A.C.), F-69437 Lyon Cedex; and Service d’Endocrinologie, Hôpital de Rangueil, Centre Hospitalier Universitaire (P.C.), F-31403 Toulouse Cedex 4, France

Address all correspondence and requests for reprints to: Pascal Pigny, Pharm.D., Ph.D., Laboratoire de Biochimie, Bâtiment USN-A, Clinique Marc Linquette, Centre Hospitalier Régionale Universitaire, F-59037 Lille Cedex, France. E-mail: p-pigny{at}chru-lille.fr


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia type 2A syndromes are dominantly inherited diseases caused by activating germline mutations of the RET protooncogene. The majority of these patients carry a germline point mutation affecting one of five cysteine residues encoded by exon 10 (codon 609, 611, 618, or 620) or 11 (codon 634). In a few FMTC families, point mutations involving noncysteine codons in exon 13 (codons 768, 790, and 791), 14 (codon 804), or 15 (codon 891) have been reported. Hirschsprung’s disease is a nonneoplastic disorder associated with RET mutations leading to a loss of function effect. Mutations are identified in 50% of the familial cases and are scattered along the gene. We now report the study of a FMTC family with four affected members and a history of fatal neonatal intestinal obstruction in the sister of the proband. Genetic analysis demonstrated the absence of an usual FMTC mutation and the presence of a germline 9-bp duplication in RET exon 8 in the heterozygous state in all patients with MTC. This new mutation creates an additional cysteine residue in the extracellular cysteine-rich domain of RET. Further studies are warranted to confirm whether this new mutation is causing MTC only or could be associated with Hirschsprung’s disease.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MEDULLARY thyroid carcinoma (MTC) occurs either sporadically or, more rarely, in a context of dominantly inherited cancer (20–25% of the cases). In familial forms, MTC is the only disease feature in familial MTC (FMTC) or exists as part of multiple endocrine neoplasia type 2 syndromes (MEN 2A and 2B). In MEN 2A, 50% of patients have a pheochromocytoma, whereas parathyroid hyperplasia or adenoma is observed in 10–30% of the cases. The rarer MEN 2B syndrome is characterized by MTC, PC, and developmental abnormalities such as marfanoid habitus, mucosal neuromas, and ganglioneuromatosis of the gastrointestinal tract. Parathyroid disease is not observed.

The RET protooncogene encodes a membrane-bound tyrosine kinase receptor characterized by a cadherin-like domain and a cysteine-rich domain, both in its extracellular region (1). Recently, glial cell-derived neurotropic factor (GDNF) and neurturin, which belong to the transforming growth factor-ß superfamily, were found to be RET ligands (2, 3). GDNF and neurturin can activate RET receptor through different coreceptors linked to the cell surface, designated GDNF family receptors. The RET receptor seems to play a central role in the development and survival of neural crest cells (4).

Germline mutations of the RET protooncogene are associated with hereditary MTC as well as familial Hirschsprung ’s disease (HD), a congenital disorder characterized by intestinal obstruction due to the absence of enteric innervation which affects about 1 in 5000 live births (5). However, MEN 2 mutations convert RET into a dominantly acting oncogene (6, 7), whereas most HD mutations have a loss of function effect (8, 9). In nearly all MEN 2A families, mutations involve one of five cysteines in the extracellular domain of RET encoded by exon 11 (codon 634) or 10 (codons 609, 611, 618, and 620). In MEN 2B patients, the mutation involves a methionine codon in the tyrosine kinase domain of RET encoded by exon 16 and, rarely, codon 883 in exon 15 (10). In FMTC families, RET mutations, which are characterized in about 75–88% of the cases (11, 12), affect either one cysteine codon in exon 10 or exon 11 or, less often, codon 768, 790, or 791 (exon 13), codon 804 (exon 14), or codon 891 (exon 15) in the tyrosine kinase domain (13, 14, 15, 16). In the present report, we describe the RET mutations screening in a large FMTC family in whom HD may coexist. A novel germline mutation consisting in a 9-bp duplication in RET exon 8 was observed in all patients with MTC. This duplication creates an additional cysteine codon in the extracellular cysteine-rich domain of RET.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Family history

The pedigree of the family is shown in Fig. 1Go. A total of 12 individuals from 3 generations were studied. Informed consent was obtained from each patient before genetic analysis was performed. The index case was a 39-yr-old woman (II.1) who underwent total thyroidectomy in 1995 for an isolated thyroid nodule. Histological examination showed the presence of a MTC in one lobe and an atypic microvesicular adenoma in the controlateral lobe. Four weeks after surgery, the basal serum calcitonin (CT) level was undetectable; it was within the normal range (13 pg/mL) after pentagastrin (Pg) stimulation.



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  		Figure 1. Pedigree of the investigated FMTC family. Circles, Females; squares, males.

 
One sister of the proband (II.3) was admitted in a pediatric surgical unit in 1961 at the age of 8 days for a colonic obstruction on a microcolon, suggesting HD. A transverse colostomy was performed, but the child died 1 day later. No data concerning an histological confirmation of HD on the surgical resected specimen was available.

Her father (I.1), 61 yr old, had a basal CT level of 1474 pg/mL and a basal carcinoembryonic antigen (CEA) level of 21 ng/mL (normal range, <5 ng/mL) at the time of the initial diagnosis. He underwent total thyroidectomy and cercivocentral lymph node dissection in 1997; the pathological examination demonstrated the presence of bilateral MTC and bilateral node metastasis. After surgery, the serum CT level after Pg stimulation test was increased to 120 pg/mL.

Among the children, the oldest one (III.1), born in 1978, exhibited an increased serum CT level in response to Pg stimulation (basal CT, 4 pg/mL; stimulated CT, 42 pg/mL). He underwent total thyroidectomy in 1997; histological examination confirmed the presence of two micro-MTC (0.4 and 2 mm in diameter) accompanied by diffuse C cell hyperplasia. The other three children (III.2 born in 1979, III.3 born in 1984, and III.4 born in 1988) showed no CT response to Pg stimulation. However, the youngest (III.4) was recently shown to be a gene carrier.

During the genetic screening of the other members of this family, subject II.4, 35 yr old, was identified as gene carrier. The Pg stimulation test produced the following results: basal CT, 328 pg/mL; T3-stimulated CT, 8000 pg/mL. Interestingly, this patient exhibited a thickening of corneal nerves. She underwent total thyroidectomy in January 1998. Histological examination showed the presence of an invasive bilateral MTC associated with C cell hyperplasia in the right lobe. Three months after surgery the serum CT level remained elevated at 87 pg/mL.

In each patient there was no evidence of hyperparathyroidism (serum calcium, phosphate, and PTH levels and urinary calcium levels in the normal range) or pheochromocytoma (by assessment of plasma and urinary catecholamines and by thoracic and abdominal computed tomography scan).

Pg test and CT assay

The Pg stimulation test consisted of a pulse administration of 0.5 mg/kg Pg (Peptavlon, Zeneca Pherme, Cergy, France). Blood was collected before and 3 and 5 min after injection. Serum CT levels were determined by an immunoradiometric assay using the ELSA-hCT kit provided by CIS-Bio International (Gif-sur-Yvette, France). CT levels were considered normal with reference to the data from the Groupe d’Etude des Tumeurs à Calcitonine (basal CT, <10 pg/mL; Pg-stimulated CT, <30 pg/mL) (17).

DNA analysis

Genomic DNA was prepared from peripheral blood samples collected on ethylenediamine tetraacetate according to standard protocols. High mol wt DNA was isolated from one 10-µm thick section of the tumor tissue block using standard protocols (18). Sequencing analysis was performed on PCR-amplified RET exons. The sequences of primers and PCR protocols were obtained from previously published sources (19, 20). For exon 8, 300 ng DNA were amplified in a 100-µL reaction volume containing 25 pmol of each primer (8F, 5'-TGGTGCTGTTCCCTGTCC-3'; 8R, 5'-CCACCGGTGCCATCGCCCCT-3'; annealing temperature, 63 C), 200 mmol/L deoxy-NTPs, 1.5 mmol/L MgCl2, and 2.5 U Taq Gold DNA polymerase (Perkin Elmer, France) on a PE 2400 thermocycler. For RET exon 21, the sequence of the primers were as follows: 21F, 5'-TCTTGTCATTCTTCATTGCTTG-3'; and 21R, 5'-GCCTCACAAAATGCCACAAT-3' (Eng, C., personal communication). PCR products were purified on Wizard PCR preps columns (Promega Corp., Madison, WI) before sequencing. Both strands were sequenced by PCR using either the fmol DNA sequencing system (Promega Corp.) according to the [{gamma}-32P]deoxy-ATP end-labeled primers protocol or with an automated DNA sequencer (ABI310 at Lille INSERM U-124 and ABI377 at Lyon) and the dRhodamine cycle sequencing ready reaction (Perkin Elmer). To confirm the nature of the insertion, the PCR products of RET exon 8 of both the index case (II-1) and a healthy control were cloned in pCR2.1 (Invitrogen, Leek, The Netherlands). Two positive clones were obtained for the index case, designated C1 and C2. Both strands of these two clones were sequenced with the ABI 310 automatic sequencer together with the control clone.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Germinal DNA from the two first affected patients (I.1 and II.1) was studied simultaneously in the two laboratories to ascertain the familial nature of the tumors. According to the literature data (11), we first looked for RET mutations in exons 10, 11, 13, 14, and 15. No molecular abnormalities were characterized in these two patients. We then focused on RET exons 8 and 9 that, together with exons 10 and 11, encode the extracellular cysteine-rich domain of the protooncogene. PCR amplification of exon 8 of the index case did not result in a single sharp band of 262 bp as routinely seen in healthy controls. As shown in Fig. 2Go, an additional band larger than the wild-type allele was observed. The same profile was observed for patients III.1 (Fig. 2Go) and I.1 (not shown). RET exon 8 PCR products of the index case II.1 were cloned in pCR2.1 vector, and the two positive clones obtained were subjected to DNA sequencing. One clone, C1, contains a 262-bp insert whose sequence was strictly normal. On the contrary, the C2 clone sequencing reaction showed that after codon 531, the previous 9-bp AGGAGTGTG are repeated, and then the normal sequence is continued (Fig. 3Go). The mutated allele is then 9 bp larger than the wild-type one. The insertion of this 9-bp sequence leads to the introduction of a new cysteine codon. Direct sequencing of exon 8 PCR products showed that the other affected members of the family (I.1 and III.1) were positive for this duplication. Another child of the index case (III.4) whose CT response to the Pg stimulation test was normal was shown to carry the mutated allele. Moreover, one sister of the proband (individual II.4) was identified as a mutated gene carrier, a status confirmed by the explosive response of CT to Pg administration.



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  		Figure 2. Characterization of the PCR-amplified RET exon 8 on a 3.5% agarose gel. Lane 1, 100-bp ladder; lane 2, healthy control; lane 3, index case II.1; lane 4, III.2; lane 5, III.3; lane 6, III.4; lane 7, III.1; lane 8, healthy control.

 


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  		Figure 3. A, Direct sequencing of the PCR-amplified RET exon 8 of the index case (II.1) showing the presence of a double population after codon 531. B and C, Sequence analysis of the two alleles of RET exon 8 of the index case (II.1) after PCR and cloning. The upper sequence (B) corresponds to the mutated-type allele (clone C2); the lower sequence (C) corresponds to the wild-type allele (clone C1). The boxed bases correspond to the duplicated sequence. The sequencing reaction was performed with the dRhodamine cycle sequencing reaction (Perkin Elmer) and then run on an ABI310 automated sequencer.

 
To demonstrate that this novel mutation is underlying the tumoral process, the nucleotide sequence of RET, encoded by exons 2–21, was determined on the germinal DNA of the index case (II.1). Except for a polymorphism at codon 45 in RET exon 2 (GCG->GCA), no other molecular abnormalities were observed. The exon 1 of RET, which contains a large untranslated region and a small coding part corresponding to the signal peptide (21), was not analyzed due to the lack of an efficient and easy to use PCR protocol. Mutation analysis was also carried out on the DNA extracted from the paraffin-embedded thyroid tissue of patient II.4. It revealed the presence of the exon 8 mutation and the absence of an additional somatic mutation in exons 16, 11, 13, and 15.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
According to the data collected by the international RET Mutation Consortium, mutations are identified in nearly 88% of FMTC families (11). In contrast to MEN 2A, in which codon 634 in exon 11 is by far the most frequently mutated (85% of the families), mutations affecting 1 of the 4 cysteine codons in exon 10 are most common in FMTC families (60% of the cases). Rare mutations involving noncysteine codons have been identified in FMTC. The first mutations described were at codon 768 in exon 13 and codon 804 in exon 14 (13, 14). Recently, Hofstra et al. described a novel mutation at codon 891 (exon 15) in 1 FMTC family (15), whereas Berndt et al. reported a new hot spot of mutations at codons 790 and 791 in exon 13 (16). Finally, a rare mutation affecting the cysteine codon 630 has also been reported (22). Therefore, the fact that no mutation at these 11 codons was characterized in our FMTC family was at least unusual. Two reasons prompt us to focus on other RET exons. First, the hereditary nature of MTC was for us well documented. Second, 1 sister (II.3) of the index case died during the neonatal period of an intestinal obstruction, suggesting HD. In familial HD forms, RET mutations, which are identified in 50% of the cases, are scattered along the length of the gene (23, 24). In the rare cases of association of MEN 2A/FMTC and HD, germline RET mutations most often involved exon 10 (25), especially codon 618 or 620 (11, 26). However, a coincident sporadic case of HD could not be excluded in this kindred because HD occurs frequently sporadically (~80% of the cases) (5), and the genetic status of patient II.3 could not be determined.

In the present report we describe a novel type of RET mutation underlying a syndrome of hereditary MTC. To the best of our knowledge and according to RET Mutation Consortium data, no molecular abnormalities of RET exon 8 have previously been reported in MEN 2 syndromes. In the same way, RET exon 8 is not frequently mutated in familial or sporadic HD (23, 24). However two different duplications in RET exon 11 creating an additional cysteine codon have recently been described in MEN 2A families (27, 28). Despite its rarity, the facts that 1) in the index case, no other germinal mutation was present in the entire coding sequence of RET (except exon 1); and 2) the mutation cosegregates with the MTC in at least four patients of this family [for the fifth gene carrier (patient III.4) the diagnostic of MTC awaits thyroidectomy] suggest that the exon 8 duplication is responsible for tumor development. The absence of an additional somatic mutation in exons 16, 11, 13, and 15 is another argument in favor of the pathogenicity of this mutation. Lastly, cysteine mutations detected in MEN 2A and FMTC families induce a ligand-independent dimerization of RET, leading to its constitutive activation (6, 7). The additional cysteine created by the exon 8 duplication in the cysteine-rich domain could lead to RET activation by the same mechanism, as proposed for RET exon 11 duplication (27).

Several questions remain to be answered. First, does this family correspond to a true FMTC one? Indeed, in combined MEN 2A (FMTC)/HD families, HD more often occurs in association with MEN 2A than FMTC (13 vs. 3 families) (29). Until now, gene carrier patients did not exhibit any biological or radiological features of pheochromocytoma or hyperparathyroidism. Another approach would be to evaluate in vitro the transforming capacity of the mutated RET protein and to compare it with those of mutations typically associated with FMTC to infer the phenotypic consequences of this mutation. Indeed, it has been demonstrated that RET carrying an usual FMTC mutation (in exons 10, 13, or 14) is severalfold less oncogenic than RET bearing a MEN 2A mutation, suggesting a correlation between tissue involvement and transformant activity in vitro (30, 31). Another leading question is to determine whether this novel mutation is characteristic of the rare families in whom HD coexists with heritable MTC. One way to answer this question would be to look for this 9-bp duplication in the 12% of FMTC families classified as RET negative by routine protocols. Another way would be to determine the pattern of the cellular expression of the mutated RET. Several groups have demonstrated that HD mutations affecting the extracellular domain led to a reduced level of RET expressed at the cell surface (32) by affecting either RET maturation and/or intracellular transport (33). Recently, Pelet et al. (9) showed that a FMTC/HD mutation involving the cysteine codon 609 (C609W) both decreased the amount of RET present at the cell surface and induced the formation of covalent dimers. Since then, similar functional consequences were reported for mutations affecting cysteine 618 or 620 (34), which are the most frequently found in combined families. Therefore, the demonstration that the RET exon 8 duplication induces such a dual effect in vitro would provide a molecular basis for our hypothesis of its implication in both MTC and HD.

In conclusion, we report a new germinal RET mutation in a FMTC kindred in whom HD may coexist. To improve genetic testing sensitivity, the analysis of RET exon 8 should be considered in FMTC families with no identified mutations.


   Acknowledgments
 
We thank Mrs. A. Leclercq, C. Mouton, and J. Jacques for their expert technical assistance, and Mrs. Y. Descamps for determination of serum CT concentrations. We are grateful to Prof. A. Boersma for his continual support and helpful discussion, and to Dr. C. Eng for discussions and expert advice about all aspects of RET.


   Footnotes
 
1 This work was supported by a Projet de Recherche Clinique referenced PHRC 97-048 (Hospices Civil de Lyon). Back

Received July 16, 1998.

Revised September 15, 1998.

Revised January 25, 1999.

Accepted February 1, 1999.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Specific haplotypes of the RET proto-oncogene are over-represented in patients with sporadic papillary thyroid carcinoma
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J. R Hansford and L. M Mulligan
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