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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 7 3521-3526
Copyright © 2004 by The Endocrine Society

A Novel Point Mutation of the RET Protooncogene Involving the Second Intracellular Tyrosine Kinase Domain in a Family with Medullary Thyroid Carcinoma

Camilo Jimenez, Gerald T. Dang, Pamela N. Schultz, Adel El-Naggar, Suzanne Shapiro, Elizabeth A. Barnes, Douglas B. Evans, Rena Vassilopoulou-Sellin, Robert F. Gagel, Gilbert J. Cote and Ana O. Hoff

Department of Endocrine Neoplasia and Hormonal Disorders (C.J., G.T.D., P.N.S, E.A.B., R.V.-S., R.F.G., G.J.C, A.O.H.), Division of Internal Medicine, Department of Surgical Oncology (S.S., D.B.E.), and Department of Pathology (A.E.-N.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Ana O. Hoff, The University of Texas M. D. Anderson Cancer Center, Department of Endocrine Neoplasia and Hormonal Disorders, 1515 Holcombe Boulevard, Unit 435, Houston, Texas 77030. E-mail: aohoff{at}mdanderson.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Hereditary medullary thyroid carcinoma, a tumor that arises from the parafollicular cells of the thyroid gland, occurs in isolation (as in familial medullary thyroid carcinoma), in association with hyperparathyroidism and pheochromocytoma (as in multiple endocrine neoplasia type 2A), or in association with pheochromocytoma, marfanoid habitus, and mucosal neuromas (as in multiple endocrine neoplasia type 2B). These genetic syndromes are associated with germline-activating mutations of the RET protooncogene, a cell surface tyrosine kinase receptor, which is believed to modulate specific intracellular signaling pathways involved in the regulation of C cell proliferation and apoptosis. RET-activating mutations involve two important functional areas of the receptor: the cysteine-rich extracellular domain and the intracellular tyrosine kinase domain. Multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma are more commonly associated with mutations in the cysteine-rich extracellular domain, whereas multiple endocrine neoplasia type 2B is exclusively associated with mutations involving the second intracellular tyrosine kinase domain. Here, we describe a novel missense mutation of the RET protooncogene that substitutes arginine for proline at codon 912 of the intracellular tyrosine kinase domain in a family with medullary thyroid carcinoma.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MEDULLARY THYROID CANCER (MTC), first described by Hazard et al.(1) in 1959, arises from the C cells of the thyroid gland and has the unique diagnostic characteristic of amyloid in its stroma. Most cases of MTC are sporadic; only approximately 30–35% are familial (2, 3, 4, 5, 6). The familial types include familial MTC (FMTC), which has MTC as its only manifestation, or MTC in association with multiple endocrine neoplasia types 2A (MEN2A) or 2B (MEN2B) (7). MEN2A is a genetic syndrome characterized by MTC, pheochromocytoma, and hyperparathyroidism. MEN2B is characterized by MTC, pheochromocytoma, marfanoid habitus, and neuromas of the lips, tongue, and gastrointestinal tract. Unlike sporadic MTC, hereditary MTC develops earlier in life, is typically multicentric and bilateral, and is preceded by C cell hyperplasia. Nearly 100% of hereditary forms of MTC are associated with a germline mutation of the RET protooncogene (7, 8). Among the hereditary forms of MTC, MEN2B generally develops earlier and is more aggressive than MEN2A, with FMTC typically having a later age of onset and exhibiting less aggressive behavior (8, 9, 10).

The RET protooncogene encodes a cell surface tyrosine kinase (TK) receptor that has a large extracellular domain, a single transmembrane region, and two cytoplasmic TK domains (11, 12). The extracellular domain includes a cadherin ligand-binding site and a cysteine-rich extracellular region, which is important for receptor dimerization. Mutations of the RET protooncogene in patients with MEN2A and FMTC were identified in 1993 and were localized to the cysteine-rich domain of the receptor encoded by exons 10 and 11 (13, 14). Since then, several germline mutations involving other exons including 8, 13, 14, 15, and 16 have been identified in these syndromes (12, 15, 16, 17, 18, 19, 20, 21).

Here we describe a patient who presented with MTC at age 14 yr and in whom initial analysis of the RET protooncogene failed to reveal a mutation. However, the early presentation of a multifocal MTC associated with C cell hyperplasia led us to suspect hereditary disease. Further analysis of the RET protooncogene revealed a novel mutation of codon 912 in exon 16 that tracked with MTC in an additional family member.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Index case

The family pedigree is shown in Fig. 1Go. The index patient (II-8) presented with a palpable thyroid nodule at age 14 yr. She was then referred to our institution, where she underwent a total thyroidectomy and left modified radical neck dissection in 1967. The pathological findings were consistent with lymphocytic thyroiditis and multifocal MTC involving the left lobe, isthmus, and right lobe of the thyroid and the connective tissue of the pretracheal region. A total of 44 lymph nodes were removed, and 39 showed evidence of metastatic disease. Postoperatively, the patient received external-beam radiation therapy (60 Gy) to the cervical and superior mediastinal areas. Slit-lamp examination showed no corneal nerve thickening suggestive of MEN2B. On her last follow-up visit, 30 yr after her initial diagnosis, there was no radiological evidence of recurrent or metastatic disease, despite an elevated serum calcitonin level of 509 ng/liter [509 pg/ml; normal range, <17 ng/liter (<17 pg/ml)]. There was no evidence of primary hyperparathyroidism [serum calcium, 2.225 mmol/liter (8.9 mg/dl); normal range, 2.1–2.55 mmol/liter (8.4–10.2 mg/dl)]; she had normal urinary excretion of catecholamines and metanephrines, and she had no symptoms suggestive of excessive catecholamine production. In addition to MTC, this patient had skeletal abnormalities that included congenital bowing of the tibia, narrowed and laterally displaced femoral necks, and scoliosis.



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  		FIG. 1. Pedigree of the family with the arg912pro RET mutation.

 
Before detection of the arg912pro mutation, there was no family history of MTC, pheochromocytoma, primary hyperparathyroidism, or skeletal abnormalities. Genetic analysis of the family revealed that two gene carriers had abnormal thyroid glands. They are described in Results.

Mutation detection

After written informed consent was obtained, blood was collected from the index patient according to an institutional review board protocol. DNA was extracted from peripheral blood leukocytes using the Promega Wizard Genomic DNA Purification kit (Promega, Madison, WI). Sequence analysis of RET protooncogene exons 10, 11, 13, 14, 15, and 16 was performed as previously described (22) but using the Thermo Sequenase Radiolabeled Terminator Cycle Sequencing kit (U.S. Biochemicals, Cleveland, OH). DNA sequence analysis of exon 16 was performed on 100 unrelated individuals. Informed consent was obtained from family members who participated in this study after identification of the RET protooncogene mutation in the index patient.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
An initial analysis of the RET protooncogene was negative for mutations of codons 609, 611, 618, and 620 on exon 10 and codon 634 on exon 11. Further analysis of the DNA sample by direct DNA sequencing revealed a novel mutation involving codon 912 within exon 16 that substitutes arginine for proline (CGG to CCG) (Fig. 2Go). This mutation was confirmed by digestion of the PCR product with AvaII (data not shown). The mutation was not observed in 100 unrelated individuals.



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  		FIG. 2. DNA sequence analysis showing the replacement of a guanosine nucleotide with a cytosine. The position of this change is indicated with an arrow and is heterozygous because of the presence of both normal and mutant alleles.

 
Since identifying the germline RET protooncogene mutation in our index patient, we have attempted to identify the origin of the mutant allele. Unfortunately, both of the patient’s parents are deceased, and DNA samples were unavailable. Her mother died in 1969 at age 49 yr because of congestive heart failure, and her father died at age 76 yr because of prostate carcinoma and diabetes mellitus. Therefore, we performed extensive genetic testing on both sides of the family. Unfortunately, to date we have no evidence linking the mutation to either the maternal or paternal side of the family. On the maternal side, 15 of 42 first cousins from 10 families were negative for the mutation (data not shown). Similarly, 10 of 20 paternal first cousins from four families were also negative (data not shown). However, germline transmission of the arg912pro mutation was observed in the immediate family. Eleven family members were found to harbor the arg912pro mutation: six siblings, three nephews, and two nieces (Fig. 1Go).

Despite the presence of the mutation in six of the index patient’s siblings, none had presented with MTC at the outset of this investigation. The youngest sibling was 35 yr old (II-15) at the time of evaluation. Two of the 14 siblings (II-10 and II-13) had enlarged and firm thyroid glands. The sister (II-13) underwent an ultrasound examination, which revealed an enlarged inhomogeneous thyroid gland with no discrete nodules. The baseline serum calcitonin was less than 0.7 ng/liter, and the peak calcitonin level after a calcium infusion test was 28 ng/liter [28 pg/ml; normal range, <25 ng/liter (<25 pg/ml)]. Her serum calcium, PTH, and urinary catecholamine levels were normal. She has declined thyroidectomy. The brother (II-10) presented at age 45 yr with an enlarged thyroid gland and a palpable nodule in the right thyroid lobe. Fine-needle aspiration of this nodule was consistent with a colloid adenoma. He underwent a right thyroid lobectomy at another hospital, where the histopathological studies showed autoimmune thyroiditis. He then presented to our institution for further evaluation. On clinical evaluation he had none of the skeletal findings observed in the index patient. His postsurgical calcitonin level was 4 ng/liter [4 pg/ml; reference range, <8 ng/liter (<8 pg/ml)]. He had a normal serum calcium level of 2.175 mmol/liter [8.7 mg/dl; reference range, 2.1–2.55 mmol/liter (8.4–10.2 mg/dl)], a normal intact PTH level of 31 ng/liter [31 pg/ml; reference range, 10–65 ng/liter (10–65 pg/ml)], and a normal 24-h urine collection for catecholamines and metanephrines. Review of his outside pathology slides, which included immunohistochemical staining for calcitonin, showed multiple foci of MTC. He underwent a completion thyroidectomy and central compartment (level VI) lymphadenectomy. Pathological examination of the residual thyroid gland showed two foci of microscopic MTC and extensive C cell hyperplasia in the background of Hashimoto’s thyroiditis (Fig. 3Go). Thirteen lymph nodes were removed and found to be negative for metastatic MTC.



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  		FIG. 3. Focus of MTC found in the thyroid specimen from patient II-10.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We report the finding of a novel germline RET mutation in a patient who presented with an apparently sporadic MTC. Although the initial routine analysis of commonly mutated codons failed to reveal a germline mutation of the RET protooncogene, the early onset of disease (age 14 yr) and the multifocality of the tumor led us to further analysis. We therefore performed direct DNA sequencing of exons 13, 14, 15, and 16, which revealed that the patient had a missense mutation that substituted arginine for proline at codon 912 within exon 16 of the RET protooncogene (Fig. 2Go).

After identifying the germline arg912pro mutation in the index patient, we performed extensive genetic analysis of her family members (Fig. 1Go and data not shown). Eleven of 68 family members tested were found to carry the same heterozygous germline mutation. Interestingly, the mutation was limited to the index patient’s immediate family. None of the 25 paternal or maternal first-degree cousins tested were found to carry the arg912pro mutation of the RET protooncogene. Her parents and most paternal uncles and aunts are deceased, and there was no DNA available for analysis. The only paternal aunt alive was not found to carry the arg912pro mutation.

After the family genetic testing, only the two gene carriers with enlarged thyroid glands chose to undergo further evaluation. Patient II-10 (age 45 yr) has undergone a total thyroidectomy with central lymph node dissection and was found to have multifocal microscopic MTC, extensive C cell hyperplasia, and no lymph node metastases. On ultrasonographic examination, patient II-13 (age 37 yr) was found to have an enlarged thyroid gland with no discrete nodules and a borderline abnormal calcitonin level after calcium stimulation. Because of the lack of clinically apparent disease in the known gene carriers (except for the index patient), patient II-13 has been reluctant to undergo thyroidectomy.

Approximately 95% of MEN2A families have mutations involving exons 10 (codons 609, 611, 618, and 620) and 11 (codon 634) of the RET protooncogene, which encodes the cysteine-rich domain of the RET receptor (13, 14, 16), with only rare mutations involving the intracellular TK domain. Mutations that involve the cysteine-rich extracellular domain of the RET receptor are thought to cause disease through constitutive dimerization and activation of the receptor. The FMTC phenotype is associated with mutations involving both the extracellular cysteine-rich and intracellular tyrosine kinase domains. These mutations are located in exons 10 (codons 618 and 620), 11 (codons 630, 631, and 634), 13 (codons 768, 790, and 791), 14 (codons 804 and 844), and 15 (codon 891) (13, 17, 18, 19, 23, 24, 25, 26).

The mutation identified in this kindred (arg912pro) is located in exon 16 of the RET protooncogene, a region that encodes the second intracellular TK domain of the RET receptor (Fig. 4Go). Most mutations involving the second TK domain cause MEN2B, with the most common and best characterized mutation involving codon 918 (met918tyr). The 918 mutation is responsible for more than 95% of MEN2B cases and is thought to induce tumor formation by altering the substrate specificity of the kinase domain, thereby activating growth-stimulating pathways (16, 27, 28, 29, 30, 31). A mutation that involves codon 891 is the only reported mutation involving the second TK domain that is not associated with MEN2B. This mutation has been associated with FMTC in several families (10, 23, 24, 32, 33). In these families, as observed in the codon 912 mutation carrier family, MTC has exhibited a slower growth rate than in families with higher-risk mutations of the second TK domain and has been diagnosed at a later age (48 yr) (23). However, an earlier age of presentation has been reported in a 13-yr-old patient with the 891 mutation (10). This mutation has also been associated with the presence of corneal nerve thickening in at least one of its carriers (24). Skeletal abnormalities, similar to those seen in the index patient with the arg912pro mutation, have not been reported with the codon 891 RET mutation.



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  		FIG. 4. The mutation replaces the normal arginine with proline at codon 912 of the RET protooncogene second TK domain.

 
Our kindred lacks the typical MEN2B phenotype and the aggressive biological behavior of MTC that is seen in patients with MEN2B. The MEN2A phenotype was not observed in any of the three gene carriers who were evaluated, which suggests that the arg912pro mutation is associated with the FMTC phenotype. However, the available data are not sufficient to exclude the MEN2A phenotype, and longer follow-up and further evaluation of additional gene carriers will be needed to define the specific phenotype associated with this novel RET mutation.

At the time of the international RET mutation consortium analysis in 1996, most of the RET mutations associated with FMTC were found to be located in exons 10 and 11, which encode the cysteine-rich region of the RET receptor (cysteine mutations), whereas only a few families were found to have RET mutations within exons 13, 14, and 15 (noncysteine mutations) (16). The systematic search for mutations in these exons in all patients presenting with MTC in whom a RET mutation in exons 10 and 11 was not found has resulted in an increased frequency of finding the noncysteine RET mutations. In fact, the French Calcitonin Tumors Study Group analyzed 148 patients from 47 FMTC kindreds and showed that the noncysteine mutations are more frequently occurring than previously thought, with almost 60% of their FMTC kindreds having an intracellular noncysteine RET mutation. Their cohort of FMTC patients with noncysteine RET mutations presented at an older age (similar to those with sporadic MTC) and had a lower frequency of distant metastatic disease than patients with FMTC who had a cysteine mutation. However, because two deaths attributed to metastatic MTC were observed in patients with noncysteine RET mutations, the authors suggested that these mutations are probably related to a late onset of disease rather than a less aggressive phenotype (33). In agreement with these data, the European Multiple Endocrine Neoplasia Study Group analyzed 207 gene carriers of RET mutations who underwent early thyroidectomy based on the results of genetic testing and found that the onset of C cell hyperplasia and the progression to MTC in patients with noncysteine RET mutations occurred at a significantly later age than in carriers of cysteine mutations (10).

In the kindred that we have described here, we observed a wide spectrum of disease manifestation. The index patient is the only individual carrying this mutation that presented with clinically overt and metastatic disease in the second decade of life. The other known gene carrier with MTC was found to have minimal, nonmetastatic disease at age 45 yr. In addition, none of her siblings who are gene carriers ranging in age from 41 to 63 yr have presented so far with clinically evident disease. There are several potential explanations for this difference in the clinical manifestation of the disease. One possibility could be that the index patient harbors an additional mutation of the RET protooncogene causing this clinical picture. However, our sequence analysis included exons 10, 11, 13, 14, 15, and 16, which represents approximately 93–98% of the mutations observed in families with MEN2A and 80–96% in families with FMTC (33). This sequence analysis failed to identify additional mutations in these exons. Two other potential explanations include: 1) the presence of a germline mutation in another gene that regulates activation and the signal transduction of the RET receptor, which in conjunction with the arg912pro mutation would lead to a more severe phenotype, or 2) the presence of a somatic RET mutation in this patient’s tumor (22, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43). These possibilities have not yet been examined. Furthermore, there are a few reports indicating that disease penetrance, age at onset, and clinical manifestation of the disease can be quite variable within carriers of the same RET mutation. In a recent study, Robledo et al. (44) have investigated the presence of specific RET polymorphisms (G691S/S904S) that could act as genetic modifiers and could potentially explain why such variations in phenotypes occur. This group analyzed 35 MEN2A families and found that individuals who were homozygous for the G691S/S904S polymorphisms were, in fact, younger at diagnosis of MTC, thus indicating that genetic background can indeed modify disease phenotype.

In conclusion, here we have described a novel arg912pro mutation within exon 16 of the RET protooncogene present in one branch (two generations) of a large family that has most likely arisen as a de novo mutation in one of the index patient’s parents. This mutation is associated with a variable clinical presentation. The index patient presented early and with nodal metastasis, whereas the other gene carriers have not presented with clinically significant disease up to the fifth decade of life. Despite the early and severe onset of disease observed in the index patient, she remained alive and with no radiological evidence of disease almost 40 yr after initial presentation. So far, this mutation is associated with MTC only, and it most likely adds to the growing body of noncysteine RET protooncogene mutations that has been described and is associated with the FMTC phenotype.

This paper also highlights the importance of performing a more extensive genetic analysis in patients who present with features suggestive of hereditary disease. Physicians managing patients with MTC should be aware that negative findings from routine RET analyses do not completely exclude the existence of a germline mutation, especially in young patients with multifocal MTC and C cell hyperplasia and should maintain an elevated level of suspicion until hereditary disease is conclusively ruled out.


   Footnotes
 
C.J. holds joint Endocrinology, Diabetes, and Metabolism Fellowship at The University of Texas M.D. Anderson Cancer Center and Baylor College of Medicine (Houston, TX).

Abbreviations: MTC, Medullary thyroid carcinoma; FMTC, familial MTC; MEN, multiple endocrine neoplasia; TK, tyrosine kinase.

Received January 15, 2004.

Accepted March 29, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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