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Multiple Endocrine Neoplasia Type 2
Evaluation of the Genotype-Phenotype Relationship
Linwah Yip, MD;
Gilbert J. Cote, PhD;
Suzanne E. Shapiro, MS;
Gregory D. Ayers, MS;
Cynthia E. Herzog, MD;
Rena V. Sellin, MD;
Steven I. Sherman, MD;
Robert F. Gagel, MD;
Jeffrey E. Lee, MD;
Douglas B. Evans, MD
Arch Surg. 2003;138:409-416.
ABSTRACT
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Hypothesis Multiple endocrine neoplasia type 2 (MEN 2) is caused by RET proto-oncogene mutations and has a strong penetrance for medullary thyroid carcinoma (MTC). Subtypes are defined by the presence or absence of pheochromocytomas, hyperparathyroidism, and characteristic clinical stigmas. We hypothesize that specific RET mutations correlate with the MEN 2 phenotype and aggressiveness of MTC.
Design Review of endocrine surgery database from 1951 through 2002.
Setting Tertiary referral center.
Patients Eighty-six patients from 47 kindreds were identified with MEN 2A, MEN 2B, or familial MTC. Patients were classified into 3 RET mutation risk groups: level 1, low risk for MTC (codons 609, 768, 790, 791, 804, and 891); level 2, intermediate risk (codons 611, 618, 620, and 634); and level 3, highest risk (codons 883 and 918).
Main Outcome Measures Stage of MTC at diagnosis and at last follow-up and frequency of pheochromocytomas and hyperparathyroidism.
Results RET analysis was complete for 71 patients from 39 kindreds. Multivariate analysis identified an increased likelihood of stage III or IV MTC at diagnosis with increasing age (odds ratio, 1.12 per year of age at thyroidectomy; 95% confidence interval, 1.07-1.17; P<.001) and increasing risk group (odds ratio, 14.23 per incremental increase in MTC risk group from 1 to 3; 95% confidence interval, 3.05-66.55; P<.001). Pheochromocytomas were found in 21 patients from 12 kindreds; 20 of 21 patients had codon 634 or 918 mutations. Hyperparathyroidism was found in 10 patients from 7 kindreds; 7 of 10 patients had codon 634 mutations.
Conclusion Specific RET mutations predict the phenotypic expression of disease and the MTC aggressiveness in patients with MEN 2, guiding the timing of thyroidectomy and screening for pheochromocytoma.
INTRODUCTION
MULTIPLE endocrine neoplasia type 2 (MEN 2) is an autosomal dominant syndrome that is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT). MEN 2 is divided into subtypes depending on the presence or absence of tissue-specific tumors and phenotypic characteristics, and the number of affected family members (Table 1).1 Rare variants of MEN 2 have been associated with Hirschsprung disease (HSCR) and cutaneous lichen amyloidosis (CLA).2-3 Medullary thyroid carcinoma, which has a penetrance of greater than 90% and is usually the first manifestation of MEN 2,4-5 has been confirmed in thyroidectomy specimens from patients as young as 17 months.6 The prognosis of MEN 2 is related to the aggressiveness of the MTC, which can develop early lymph node metastases. These metastases have been found in patients as young as 3 years.7 Germline mutations in the RET proto-oncogene cause MEN 2.8-9 Analysis of the RET mutation status of at-risk patients allows for effective screening and improved clinical management.10
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Table 1. Classification of MEN 2 Subtypes
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The RET gene is located on chromosome 10 and includes 21 exons. It encodes a transmembrane tyrosine kinase, the ret receptor, which is primarily expressed by neuroendocrine and neural cells.11-14 Rearrangements of RET have been identified in papillary thyroid carcinomas, while inactivating RET mutations play a role in the development of HSCR.15-20 Missense mutations that result in a constitutively active receptor are responsible for MEN 2.21-23 These mutation hot spots are located in the extracellular cysteine-rich region involved in receptor dimerization that is encoded by exons 10 and 11, and in the intracellular tyrosine kinase domain encoded by exon 16.24-26
The specific RET codon mutation can be correlated with the phenotypic expression of MEN 2. For example, pheochromocytoma and HPT are most common in patients with codon 634 mutations, and HPT does not occur in patients with codon 918 mutations.27-32 Recently, it has been suggested that the biological aggressiveness of MTC can also be associated with the specific RET mutation.33 RET mutations have been stratified into 3 groups (levels 1-3) based on the biological aggressiveness of MTC observed in patients with different RET mutations. Patients with level 1 mutations (codons 609, 768, 790, 791, 804, and 891) have the lowest risk for the development and growth of MTC. Patients with level 2 mutations (codons 611, 618, 620, and 634) are at intermediate risk, and patients with level 3 mutations (codons 883 and 918) are at the highest risk for the early development and growth of MTC.34 In the present study, we examined the impact of both tumor biological characteristics and age at thyroidectomy on the staging of MTC at both diagnosis and last follow-up to confirm this risk-group stratification in our MEN 2 population. In addition, we examined the frequency and characteristics of pheochromocytoma and HPT to determine whether RET mutation–specific screening can be applied to this patient population.
METHODS
A review of the endocrine surgery database at The University of Texas M. D. Anderson Cancer Center, Houston, a tertiary referral center, covering 1951 to 2002 identified 86 individuals with MEN 2 in 47 kindreds who had been evaluated at the hospital (institutional review board protocols RCR01-485 and RCR01-096). The diagnosis and subtype of MEN 2 were confirmed according to previously published criteria.1 Briefly, kindreds with MTC and at least 1 family member presenting with pheochromocytoma and either with or without HPT were categorized as having MEN 2A. Kindreds with MTC and characteristic mucosal neuromas on the tongue, lips, subconjunctival areas, and gastrointestinal tract and either with or without pheochromocytoma were categorized as having MEN 2B. Kindreds with MTC in 4 or more members and with objective evidence against adrenal and parathyroid gland involvement were categorized as having familial MTC (FMTC). Kindreds with MTC in 3 or fewer members and with no evidence of pheochromocytoma, HPT, or MEN 2B were categorized as unclassified. Follow-up information was obtained during routine outpatient visits, telephone interviews, or written communication with the patient and/or family member.
For each patient, we determined the phenotypic characteristics of MEN 2 by reviewing the original laboratory results, radiographic imaging studies, and operative and pathology reports. Staging was based on the TNM classification.35 The stage of disease at diagnosis and at last follow-up was used as a measure of the biological aggressiveness of MTC; patients with advanced disease (stage III, IVA, IVB, or IVC) were assumed to have more aggressive disease than those with small, localized MTC (stage I or II). The diagnosis of MTC with or without local regional lymph node metastasis was made after the original histology reports of surgical specimens were reviewed. Distant metastases were confirmed by means of the original radiographic imaging studies and/or biopsy reports. A plasma basal calcitonin level above the upper limit of normal was considered evidence of persistent MTC. Transcutaneous cervical ultrasonography was used to exclude the presence of residual thyroid tissue (incomplete thyroidectomy) as a cause of post-thyroidectomy elevations in plasma calcitonin level.
The diagnosis of pheochromocytoma was made on the basis of the original histologic review of adrenalectomy specimens or biochemical evidence of elevated levels of serum or 24-hour urinary fractionated metanephrines or catecholamines. The diagnosis of HPT was made on the basis of the original histologic review of parathyroidectomy specimens or on biochemical evidence of hypercalcemia and inappropriate elevation of serum parathyroid hormone levels. Additional nonendocrine manifestations of MEN 2 were determined by clinical examination with or without histologic confirmation.
Mutation analyses of the RET proto-oncogene were performed on blood collected from affected and at-risk individuals before 1994 by manual DNA sequencing or allele-specific hybridization and confirmed by a secondary method as previously described.36 Informed consent was obtained at the time of blood collection. Mutation analyses for affected and at-risk individuals after 1994 were performed on phenol-chloroform–extracted DNA with a fluorescence sequence DNA analyzer (ABI Prism 3700; Applied Biosystems, Foster City, Calif). RET sequencing was limited to exons 10, 11, and 16 and, if necessary, expanded to include exons 13, 14, and 15. Patients were stratified to 1 of 3 risk groups (levels 1-3) on the basis of their genotype: level 1 mutations included codons 609, 768, 790, 791, 804, and 891; level 2 mutations included codons 611, 618, 620, and 634; and level 3 mutations included codons 883 and 918.
Statistical analyses were performed with SAS statistical software (SAS Institute Inc, Cary, NC). Logistic regression was used to estimate the likelihood of aggressive MTC disease with age at diagnosis and risk group as variables in univariate and multivariate models. Correlation among kindred members was accounted for by implementing logistic regression in the framework of generalized linear models with the use of generalized estimating equations for correlated outcomes. Variable effects were estimated as odds ratios with 95% confidence intervals. Results were considered statistically significant at P<.05.
RESULTS
Eighty-six patients from 47 kindreds were identified with MEN 2. Eighty-one (94%) were alive at the time of analysis and 5 (6%) had died. Two patients had died of progressive metastatic MTC, 1 patient had died after a probable hypertensive crisis attributed to bilateral pheochromocytomas, and 1 patient had died of metastatic bladder carcinoma; the cause of death in 1 patient was unknown. Among the 47 kindreds, 19 (40%) were categorized as having MEN 2A; 10 (21%), MEN 2B; and 6 (13%), FMTC. The remaining 12 kindreds (26%) were categorized as unclassified and included FMTC kindreds with 3 or fewer affected individuals and MEN 2A kindreds with affected individuals who had inconclusive or incomplete biochemical evidence of pheochromocytomas and HPT.
We completed the RET mutation analysis for 71 patients (83%) in 39 kindreds (83%). The distribution of the identified RET mutations is shown in Figure 1. Most of the mutations were in codons 609, 611, 618, 620, and 634, which encode the cysteine-rich domain. The most frequent mutation was a missense mutation at codon 634 resulting in an amino acid change from cysteine to arginine. There were 10 patients from 9 kindreds with level 3 (highest-risk) RET mutations, all involving codon 918. Fifty-three patients from 22 kindreds had level 2 (intermediate-risk) mutations involving codons 611, 618, 620, and 634. Fifteen patients from 9 kindreds had level 1 (lowest-risk) mutations involving codons 609, 804, and 891.
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Figure 1. Distribution of RET mutations (n = 86).
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The frequency and characteristics of MTC within each risk group are given in Table 2. In the level 1 risk group, 1 kindred (11%) was categorized as having MEN 2A and 3 kindreds (33%) were categorized as having FMTC. The remaining 5 kindreds (56%) were categorized as unclassified. All 15 patients were alive at last follow-up. Thyroidectomy was performed in 14 of the 15 patients. The median age at thyroidectomy was 40.7 years (range, 15.2-78.2 years). The median age at thyroidectomy for the 12 patients with MTC in the surgical specimen (patients with premalignant C-cell hyperplasia were excluded) was 41.5 years (range, 17.4-78.2 years). Lymph node metastases within the initial surgical specimen were found in 3 (25%) of the 12 patients. Three of the 9 remaining patients had no mention of lymph node status in the pathology report. At the time of diagnosis, 8 patients (53%) had stage 0, I, or II disease and 3 patients (20%) had stage III or IV disease. The stage at the time of diagnosis for 4 patients (27%) was unknown. Recurrent disease in the neck developed in 4 (33%) of the 12 patients at a median of 3.1 years after initial thyroid surgery. One (7%) of the 15 patients in this lowest-risk group developed distant metastases 6.5 years after thyroidectomy at age 29.3 years, and at last follow-up 9 patients (60%) had persistent disease, as evidenced by elevated basal calcitonin levels.
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Table 2. Patient Risk Group and MTC Characteristics
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In the level 2 intermediate-risk group, 15 (68%) of the 22 kindreds were categorized as having MEN 2A and 3 kindreds (14%) were categorized as having FMTC; the remaining 4 kindreds (18%) were categorized as unclassified. Two (4%) of 53 patients died: 1 at age 38 years of a probable hypertensive crisis due to bilateral pheochromocytomas and the other at age 57 years of metastatic MTC. Thyroidectomy was performed in 52 of the 53 patients. The median age at thyroidectomy was 21.8 years (range, 3.0-60.4 years). The median age at thyroidectomy for the 44 patients with MTC in the thyroid specimen (patients with premalignant C-cell hyperplasia were excluded) was 22.9 years (range, 5.2–60.4 years). Lymph node metastases were found within the initial surgical specimen in 16 (36%) of the 44 patients. Thirteen of the 28 remaining patients had no mention of lymph node status in the pathology report. At the time of diagnosis, 22 (42%) of the 53 patients had stage 0, I, or II disease and 16 patients (30%) had stage III or IV disease. The stage at the time of diagnosis for 15 patients (28%) was unknown. Recurrent disease in the neck developed in 9 (20%) of the 44 patients at a median of 5.9 years after initial thyroid surgery. Ten patients (19%) in this intermediate-risk group developed distant metastases at a median of 8.6 years after thyroidectomy and at a median age of 33.6 years (range, 18.9-57.1 years). At last follow-up, calcitonin levels were elevated in 37 (70%) of the 53 patients.
All 10 patients in the level 3 highest-risk group were classified as having MEN 2B. All patients were alive at last follow-up. Nine of the 10 patients had undergone thyroidectomy at a median age of 13.5 years (range, 5.0-25.5 years). All had MTC in the surgical specimen. Four (44%) of the 9 patients had lymph node metastases at the time of initial surgery. Four of the 5 remaining patients had no mention of lymph node status in the pathology report. At the time of diagnosis, 1 patient (10%) had stage 0, I, or II disease and 5 patients (50%) had stage III or IV disease. The stage at the time of diagnosis was unknown for 4 patients (40%). Recurrent disease in the neck developed in 4 (44%) of the 9 patients at a median of 5.7 years after initial thyroid surgery. Four (40%) of the 10 patients in this highest-risk group developed distant metastases at a median of 2.6 years after thyroidectomy and at a median age of 16.4 years (range, 9.6-22.6 years). At last follow-up, all 10 patients (100%) had evidence of residual MTC, as evidenced by an elevated basal level of serum calcitonin.
Univariate and multivariate logistic regression was used to correlate the age at thyroidectomy and risk group (levels 1-3) with the aggressiveness (stage) of MTC at diagnosis (Table 3). On the basis of the univariate analysis, older age at thyroidectomy was significantly associated with the likelihood of having stage III or IV MTC (odds ratio, 1.06 per year of age at thyroidectomy; 95% confidence interval, 1.02-1.10; P = .004). In addition, the likelihood of having stage III or IV MTC at the time of diagnosis increased 3-fold for each incremental increase in the MTC risk group from level 1 to level 3 (95% confidence interval, 1.01-9.28; P<.001). On the basis of the multivariate analysis, the relationship between advanced MTC (stage III or IV) at the time of diagnosis and age at thyroidectomy and risk group became more pronounced. The risk of having stage III or IV MTC at the time of diagnosis increased 12% per year of age at thyroidectomy (95% confidence interval, 1.07-1.17; P<.001). The likelihood of having stage III or IV MTC at the time of diagnosis increased 14-fold for each incremental increase in the MTC risk group from level 1 to level 3 (95% confidence interval, 3.05-66.55; P<.001). Figure 2 represents the multivariate model and depicts the estimated effects of age at thyroidectomy and MTC risk group on the likelihood of having advanced-stage MTC at diagnosis.
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Table 3. Univariate and Multivariate Odds Ratios for Advanced MTC (Stage III or IV) at Diagnosis
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Figure 2. Multivariate analysis of medullary thyroid carcinoma (MTC) stage at diagnosis and association with risk group and age at thyroidectomy. Lines are parametric splines of predicted values.
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The frequency of pheochromocytomas and HPT in kindreds categorized by the MEN 2 subtype and genotype is shown in Table 4. Pheochromocytomas were diagnosed in 21 patients (24%) from 12 kindreds (26%). One patient (5%) died of a catecholamine crisis attributed to bilateral pheochromocytomas. The median age at diagnosis was 33.1 years (range, 19.0-60.4 years). Sixteen patients (76%) had mutations in codon 634. Bilateral tumors were found at initial presentation in 11 (52%) of the 21 patients. Contralateral pheochromocytomas developed in 3 (30%) of the 10 patients with a unilateral tumor at initial presentation at a median of 2.6 years after their initial adrenalectomy. Fifteen cortical-sparing adrenalectomies were performed in 11 of the 21 patients. Four ipsilateral recurrences (27%) occurred, at a median of 5.1 years after the initial subtotal adrenalectomy. None of the patients who had undergone adrenalectomy developed a catecholamine crisis during the period of follow-up.
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Table 4. Frequency of Pheochromocytomas and Hyperparathyroidism With Associated MEN 2 Subtype and Genotype
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Hyperparathyroidism was diagnosed in 10 patients (12%) from 7 kindreds (15%). The median age at diagnosis was 36.2 years (range, 17.5-49.4 years). Seven patients (70%) had mutations in codon 634. In 4 (40%) of the 10 patients, recurrent HPT required at least 1 reoperation.
The frequency and genotype of other phenotypic characteristics of MEN 2 are shown in Table 5. Of the 10 patients from 5 kindreds with CLA, all had a codon 634 RET mutation. One member of an MEN 2A kindred had manifestations of both MEN 2A and HSCR. This patient had a RET mutation in codon 620. Enlarged corneal nerves were diagnosed in 9 patients from 9 kindreds. This characteristic was most common (6 patients [67%]) in patients with MEN 2B. Patients with codon 609 and 891 mutations were also identified with enlarged corneal nerves. However, not all patients were examined for this characteristic.
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Table 5. Frequency and Genotype of Other Phenotypic Characteristics of MEN 2
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COMMENT
Recently, it has been suggested that patients with MEN 2 can be stratified into 3 groups based on the risk for development and growth of MTC.33-34 We sought to determine whether the apparent difference in MTC phenotype between the different MTC risk groups was due to a difference in age at onset or in tumor biological characteristics. Our multivariate analyses estimated statistically significant and independent associations of both greater age at thyroidectomy and increasing MTC risk group and the likelihood of having advanced MTC (stage III or IV) at the time of diagnosis. These results confirm the hypothesis that MTC risk group is an independent predictor of MTC aggressiveness.
Our statistical modeling was supported by the clinical impression that patients with level 1 mutations are often older at presentation and have more indolent tumors than do patients with level 2 or 3 mutations. For example, 1 patient with a V804M (level 1) mutation presented at age 55 years with a palpable thyroid mass (MTC). After thyroidectomy and central and bilateral neck dissection, the patient was found to have multifocal, bilateral MTC yet no local regional metastases in the 60 lymph nodes examined. After surgery, calcitonin levels in this patient fell to less than 1 pg/mL. In contrast, a patient with an M918T (level 3) mutation presented at age 17 years with the mucosal neuromas that are characteristic of MEN 2B and with a normal thyroid by palpation. After thyroidectomy and neck dissection, however, this patient was found to have multifocal MTC with bilateral local regional metastases in 32 of 71 lymph nodes and within 5 years had developed bone and liver metastases. These examples suggest that patients with lowest-risk mutations develop MTC with a different metastatic potential and also have a delay in the neoplastic transformation of thyroid C cells.
Because age is an independent predictor of aggressive disease at thyroidectomy, early thyroidectomy in at-risk patients with level 2 and 3 mutations can potentially reduce the risk of MTC to that for patients with lower-risk mutations. The importance of early thyroidectomy cannot be overemphasized.34, 37-40 The data in Table 6, which lists all thyroidectomies performed in the pediatric subgroup of this study population, demonstrate that MTC can be found in young patients who have undergone prophylactic thyroidectomy. One patient with a C634R mutation had undergone prophylactic thyroidectomy at age 5 years and was found to have a 0.4-cm MTC in the right thyroid lobe.
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Table 6. Thyroidectomies in Pediatric Patients With MEN 2
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If thyroidectomy is delayed, patients with level 1 mutations can also develop lymph node and distant metastases. One patient with an S891A mutation presented with bone metastases at 29 years of age and within 6 years had developed metastases in the liver, lung, and breast. Although unusual for a carrier of a level 1 mutation, this case emphasizes the heterogeneity in biological behavior that may complicate the treatment of patients who postpone thyroidectomy.
Pheochromocytoma, which has been reported in all RET mutations except those in codons 768, V804M, and 891, is most frequently associated with mutations in codons 634 and 918.34, 40 These latter 2 mutations were found in most of the patients with pheochromocytomas in our study. Pheochromocytomas were unilateral at the time of diagnosis in 10 (48%) of 21 patients. Three (33%) of the 10 developed a contralateral recurrence within the first 3 years of follow-up. Previous reports suggested an increasing rate of contralateral recurrence as patients age.41-42 We currently screen all patients with MEN 2, except those in FMTC kindreds, by a yearly evaluation of either plasma or 24-hour urinary fractionated metanephrines and catecholamines.
At last follow-up, none of the patients in this study had been diagnosed as having metastatic pheochromocytoma. The absence of metastatic pheochromocytoma in patients with hereditary pheochromocytoma and the risk of morbidity and mortality from adrenal insufficiency in patients who undergo bilateral total adrenalectomy support the surgical practice of cortical-sparing adrenalectomy. In our study, 4 (27%) of 15 cortical-sparing adrenalectomies subsequently required reoperation because of ipsilateral recurrence. This rate of recurrence was consistent with those reported previously.43-45
Our current management of unilateral familial pheochromocytoma is to perform a laparoscopic adrenalectomy. For bilateral disease or a contralateral recurrence, the main surgical objective is to preserve a portion of the adrenal cortex in situ, which is often facilitated by an open surgical procedure.46
Hyperparathyroidism occurs in 10% to 35% of patients with MEN 2A.47 It is associated most commonly with codon 634 mutations and less frequently with codon 609, 611, 618, 620, 790, and 791 mutations. Ten (12%) of the patients with MEN 2 evaluated in this study received the diagnosis of HPT. Six of the 7 for whom the codon mutation analysis was complete had mutations in codon 634. None of the patients with codon 918 mutations were diagnosed as having HPT. This pattern was consistent with previous reports that patients with a mutation in codons 918, 883, or 922 have no risk of HPT.48
Other phenotypic characteristics of MEN 2 were rare. Twelve percent of our patients with MEN 2 had the diagnosis of CLA, and all had a mutation in codon 634. The pathophysiologic mechanism underlying the development of CLA may be related to a sensory abnormality in the C6 through T6 dermatomes and resulting pruritus and chronic irritation.49-50 In general, not all patients with codon 634 mutations developed CLA, and not all patients with CLA had RET mutations. One patient with a C620R mutation also had a history of HSCR, which is a rare variant of MEN 2. In the families with a history of both diseases, not all mutation carriers developed manifestations of HSCR, and HSCR has also been associated with germline mutations in other genes. The underlying molecular mechanisms causing HSCR are likely multifactorial as well as multigenic.51-52 Enlarged corneal nerves were identified in only 10% of our patients with MEN 2. However, not all patients were examined for this abnormality. Takai et al53 examined 22 patients in 10 families with MEN 2A and identified pathologic corneal nerve thickening in 60%. Although most common in families with MEN 2B, enlarged corneal nerves have also been reported in families with FMTC.54 It is likely that slitlamp examination of all patients with MEN 2 will increase the identification of this phenotypic characteristic.
The results of this study confirmed that the biological behavior of MTC can be stratified by the specific RET mutation in our MEN 2 population. Our findings also emphasize the importance of DNA-based mutation analysis of the RET proto-oncogene for at-risk patients. Current genetic-testing methods can detect 99% of RET mutations. Because of the importance of early intervention in the management of MTC and of screening for pheochromocytoma, the identification of mutation carriers can significantly affect clinical decision making in these patients. The comprehensive care of identified families and patients should also include appropriate genetic counseling and long-term surveillance.
AUTHOR INFORMATION
Corresponding author and reprints: Douglas B. Evans, MD, Department of Surgical Oncology, Unit 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail: devans{at}mdanderson.org).
Accepted for publication December 19, 2002.
This paper was presented at the Annual Meeting of the New England Surgical Society, Dixville Notch, NH, September 27, 2002, and is published after peer review and revision. The discussions that follow this article are based on the originally submitted manuscript and not the revised manuscript.
Patient population identification was facilitated by the Tumor Registry database maintained by the Department of Medical Informatics at The University of Texas M. D. Anderson Cancer Center.
From the Departments of Surgical Oncology (Drs Yip, Lee, and Evans and Ms Shapiro), Endocrine Neoplasia and Hormonal Disorders (Drs Cote, Sellin, Sherman, and Gagel), Biostatistics (Mr Ayers), and Pediatrics (Dr Herzog), The University of Texas M. D. Anderson Cancer Center, Houston.
REFERENCES
| |
1. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: international RET mutation consortium analysis. JAMA. 1996;276:1575-1579.
ABSTRACT
2. Verdy M, Weber AM, Roy CC, Morin CL, Cadotte M, Brochu P. Hirschsprung's disease in a family with multiple endocrine neoplasia type 2. J Pediatr Gastroenterol Nutr. 1982;1:603-607.
ISI
| PUBMED
3. Gagel RF, Levy ML, Donovan DT, Alford BR, Wheeler T, Tschen JA. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med. 1989;111:802-806.
4. Ponder BAJ, Ponder MA, Coffey R, et al. Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet. 1988;1:397-401.
ISI
| PUBMED
5. Easton DF, Ponder MA, Cummings T, et al. The clinical and screening age-at-onset distribution for the MEN-2 syndrome. Am J Hum Genet. 1989;44:208-215.
ISI
| PUBMED
6. Sanso GE, Domene HM, Garcia R, et al. Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers. Cancer. 2002;94:323-330.
FULL TEXT
|
ISI
| PUBMED
7. Kaufman FR, Roe TF, Isaacs H Jr, Weitzman JJ. Metastatic medullary thyroid carcinoma in young children with mucosal neuroma syndrome. Pediatrics. 1982;70:263-267.
FREE FULL TEXT
8. Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363:458-460.
FULL TEXT
| PUBMED
9. Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET proto-oncogene are associated with MEN2A and FMTC. Hum Mol Genet. 1993;2:851-856.
FREE FULL TEXT
10. Wohllk N, Cote GJ, Evans D, Goepfert H, Ordonez NG, Gagel RF. Application of genetic screening information to the management of medullary thyroid carcinoma and multiple endocrine neoplasia type 2. Endocrinol Metab Clin North Am. 1996;25:1-25.
FULL TEXT
|
ISI
| PUBMED
11. Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 1985;42:581-588.
FULL TEXT
|
ISI
| PUBMED
12. Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H. Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene. 1988;3:571-578.
ISI
| PUBMED
13. Pachnis V, Mankoo B, Costantini F. Expresssion of the c-ret proto-oncogene during mouse embryogenesis. Development. 1993;119:1005-1017.
ABSTRACT
14. Tsuzuki T, Takahashi M, Asai N, Iwashita T, Matsuyama M, Asai J. Spatial and temporal expression of the ret proto-oncogene product in embryonic, infant and adult rat tissues. Oncogene. 1995;10:191-198.
ISI
| PUBMED
15. Donghi R, Sozzi G, Pierotti MA, et al. The oncogene associated with human papillary thyroid carcinoma (PTC) is assigned to chromosome 10q11-q12 in the same region as multiple endocrine neoplasia type 2A (MEN2A). Oncogene. 1989;4:521-523.
ISI
| PUBMED
16. Grieco M, Santoro M, Berlingieri MT, et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell. 1990;60:557-563.
FULL TEXT
|
ISI
| PUBMED
17. Edery P, Lyonnet S, Mulligan LM, et al. Mutations of the RET proto-oncogene in Hirschsprung's disease. Nature. 1994;367:378-380.
FULL TEXT
| PUBMED
18. Romeo G, Ronchetto P, Luo Y, et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease. Nature. 1994;367:377-378.
FULL TEXT
| PUBMED
19. Angrist M, Bolk S, Thiel B, et al. Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. Hum Mol Genet. 1995;4:821-830.
FREE FULL TEXT
20. Attie T, Pelet A, Edery P, et al. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet. 1995;4:1381-1386.
FREE FULL TEXT
21. Asai N, Iwashita T, Matsuyama M, Takahashi M. Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol. 1995;15:1613-1619.
ABSTRACT
22. Santoro M, Carlomagno F, Romano A, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995;267:381-383.
FREE FULL TEXT
23. Xing S, Smanik PA, Oglesbee MJ, Trosko JE, Mazzaferri EL, Jhiang SM. Characterization of ret oncogenic activation in MEN2 inherited cancer syndromes. Endocrinology. 1996;137:1512-1519.
ABSTRACT
24. Akhand AA, Ikeyama T, Akazawa S, et al. Evidence of both extra- and intracellular cysteine targets of protein modification for activation of RET kinase. Biochem Biophys Res Commun. 2002;292:826-831.
FULL TEXT
|
ISI
| PUBMED
25. Hofstra RM, Landsvater RM, Ceccherini I, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994;367:375-376.
FULL TEXT
| PUBMED
26. Eng C, Smith DP, Mulligan LM, et al. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene. 1995;10:509-513.
ISI
| PUBMED
27. Berndt I, Reuter M, Saller B, et al. A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab. 1998;83:770-774.
FREE FULL TEXT
28. Mulligan LM, Eng C, Attie T, et al. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Hum Mol Genet. 1994;3:2163-2167.
FREE FULL TEXT
29. Carlson KM, Dou S, Chi D, et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A. 1994;91:1579-1583.
FREE FULL TEXT
30. Cote GJ, Wohllk N, Evans D, Goepfert H, Gagel RF. RET proto-oncogene mutations in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma. Baillieres Clin Endocrinol Metab. 1995;9:609-630.
FULL TEXT
|
ISI
| PUBMED
31. Eng C. Multiple endocrine neoplasia type 2 and the practice of molecular medicine. Rev Endocr Metab Disord. 2000;1:283-290.
FULL TEXT
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