Molecular genetics and clinical implications of medullary thyroid carcinoma and mutations of the RET protooncogene

Current Opinion in Endocrinology and Diabetes

Volumn 3, Issue 5, 1996, Pages 439-448

  Lips, Cees J M ^a   Höppener, Jo W M ^a  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0342561801     PISSN: 10683097     EISSN: None     Source Type: Journal    
DOI: 10.1097/00060793-199610000-00014     Document Type: Article

References (98)

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36. Mulligan LM, Marsh DJ, Robinson BG, Schuffenecker I, Zedenius J, Lips CJM, Gagel RF, Takai S-I, Noll WW, Fink M, Raue F, Lacroix A, Thibodeau SN, Frilling A, Ponder BAJ, Eng C, for the International RET Mutation Consortium: Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med 1995, 238:343-346. This paper reports that specific mutations of the ret protooncogene predict the nature of the disease (MEN 2A, FMTC, or MEN 2B) and even the risk of involvement of organs affected within the MEN 2A syndrome: cysteine codon 634 mutations are significantly correlated to adrenal and parathyroid lesions in MEN 2A. This finding may be of prognostic value.
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40. Marsh DJ, Robinson BG, Andrew S, Richardson AL, Pojer R, Schnitzler M, Mulligan LM, Hyland VJ: A rapid screening method for the detection of mutations in the RET proto-oncogene in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma families. Genomics 1994, 23:477-479.
41. Morita H, Daidoh H, Nagata K, Okano Y, Sudoh Y, Maruyama T, Sarui H, Ishizuka T, Akagi K, Nishisho I, Yasuda K: A family of multiple endocrine neoplasia type 2A: genetic analysis and clinical features. Endocr J 1996, 43:25-30. This paper describes a family with hereditary MTC associated with a cysteine codon 618 mutation in exon 10 of the RET gene. Among 11 affected family members, MTC was diagnosed in 10 but pheochromocytoma in only one and hyperparathyroidism in none. None of the patients died of the tumors, in accordance with the favorable prognosis in our two large families with a cysteine 618 mutation, in which pheochromocytoma was diagnosed in two of 60 and in one of 20 patients, respectively. We suggest that members of FMTC families in which the disease is associated with exon 10 RET gene mutations do have an increased risk for additional neoplasms and that they develop a subtype of MEN 2A that has a low frequency of pheochromocytoma and parathyroid involvement.
42. Eng C, Smith DP, Mulligan LM, Healy CS, Zvelebil MJ, Stonehouse TJ, Ponder MA, Jackson CE, Waterfield MD, Ponder BAJ: 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.
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45. Marsh DJ, Learoyd DL, Andrew SD, Krishnan L, Pojer R, Richardson AL, Delbridge L, Eng C, Robinson BG: Somatic mutations in the RET protooncogene in sporadic medullary thyroid carcinoma. Clin Endocrinol 1996, 44:249-257.
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48. Eng C, Mulligan LM, Smith DP, Healy CS, Frilling A, Raue F, Neumann HPH, Pfragner R, Behmel A, Lorenzo MJ, Stonehouse TJ, Ponder MA, Ponder BAJ: Mutation of the RET proto-oncogene in sporadic medullary thyroid carcinoma. Genes Chromosom Cancer 1995, 12:209-212.
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54. Chew SL, Lavender P, Jain A, Weber A, Ross RJ, Wass JA, Besser GM, Clark AJ: Absence of mutations in the MEN 2A region of the ret protooncogene in non-MEN 2A phaeochromocytomas. Clin Endocrinol 1995, 42:17-21.
55. Yoshimoto K, Kimura T, Tanaka C, Moritani M, Iwahana H, Itakuta M: Absence of mutations at codon 768 of the RET proto-oncogene in sporadic and hereditary pheochromocytomas. Endocr J 1996, 43:109-114.
56. Beldjord C, Desclaux-Arramond F, Raffin-Sanson M, Corvol JC, De Keyzer Y, Luton JP, Plouin PF, Bertagna X: The RET proto-oncogene in sporadic pheochromocytomas: frequent MEN 2-like mutations and new molecular defects. J Clin Endocrinol Metab 1995, 80:2063-2068. In this paper, an uncommon RET gene mutation is described in a sporadic pheochromocytoma: a deletion in the splice acceptor site of intron 9, leading to skipping of exon 10 in RET mRNA. Although a causal relation with the development of that tumor cannot be proven, this finding suggests that in MEN 2 families that do not harbor one of the common mutations, the whole RET cDNA and the RET gene may have to be analyzed in order to find the uncommon mutations that should segregate with the disease in such families.
57. Kimura T, Yoshimoto K, Tanaka C, Ohkura T, Iwahana H, Miyauchi A, Sano T, Itakura M: Obvious mRNA and protein expression but absence of mutations of the RET proto-oncogene in parathyroid tumours. Eur J Endocrinol 1996, 134:314-319.
58. Padberg BC, Schroder S, Jochum W, Kastendieck H, Roth J, Heitz PU, Komminoth P: Absence of RET proto-oncogene point mutations in sporadic hyperplastic and neoplastic lesions of the parathyroid gland. Am J Pathol 1995, 147:1539-1544. This paper describes the absence of MEN 2-specific RET gene mutations in sporadically occurring benign or malignant neoplasms of the parathyroid glands, as opposed to sporadic tumors of the other two main tissues involved in MEN 2 tumorigenesis: thyroid C cells (MTC) and adrenal medulla (pheochromocytoma). Because parathyroid hyperplasia or adenoma occurs in more than 90% of patients with MEN 1, patients with apparently sporadic parathyroid lesions may have a mutation in the MEN 1 gene (which is on chromosome 11q13 but has not yet been identified). These patients would not have a greatly increased risk for MTC, in contrast to patients with apparently sporadic pheochromocytoma, who appear to have a germline RET gene mutation and thus are in fact MEN 2 patients.
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62. Songyang Z, Carraway KL, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, Schlessinger J, Hubbard SR, Smith DP, Eng C, Lorenzo MJ, Ponder BAJ, Mayer BJ, Cantley LC: Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature 1995, 373:536-539.
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65. Carlomagno F, Salvatore D, Santoro M, De Franciscis V, Quadro L, Pananello L, Colantuoni V, Fusco A: Point mutation of the RET protooncogene in the TT human medullary thyroid carcinoma cell line. Biochem Biophys Res Commun 1995, 207:1022-1028.
66. Wada M, Asai N, Tsuzuki T, Maruyama S, Ohiwa M, Imai T, Funahashi H, Takagi H, Takahashi M: Detection of ret homodimers in MEN 2A-associated pheochromocytomas. Biochem Biophys Res Commun 1996, 218:606-609.
67. Marsh DJ, Andrew SD, Eng C, Learoyd DL, Capes AG, Pojer R, Richardson AL, Houghton C, Mulligan LM, Ponder BAJ, Robinson BG: Germline and somatic mutations in an oncogene: RET mutations In inherited medullary thyroid carcinoma. Cancer Res 1996, 56:1241-1243. In vitro studies had shown that the MEN 2A and MEN 2B RET genes act as dominantly transforming oncogenes, in contrast to the involvement of tumor suppressor genes in other hereditary cancer syndromes, in which both alleles of the predisposing gene are mutated in tumor tissue. This paper describes the detection of a somatic codon 918 RET mutation, in addition to a germline codon 618, 620, or 634 cysteine mutation, in three of 14 MEN 2A or FMTC MTCs investigated. Because both the codon 918 and the codon 634 mutations are activating, these data do not contradict the notion that MEN 2 is the first hereditary cancer syndrome that has been shown to be caused by activating germline mutations in a protooncogene.
68. Lips CJM, Landsvater RM, Höppener JWM, Geerdink RA, Blijham GH, Jansen-Schillhorn van Veen JM, van Gils APG, de Wit MJ, Zewald RA, Berends MJH, Beemer FA, Brouwers-Smalbraak J, Jansen RPM, Ploos van Amstel H-K, van Vroonhoven TJMV, Vroom TM: Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994, 331:825-835.
69. Wundrack I, Reichert J, Langer HJ, Leicht E, Hermann M, Subke F, Meese E, Blin N: Molecular screening for RET proto-oncogene mutations in a German MEN 2A pedigree. Endocr Pathol 1996, 7:71-76.
70. Marsh DJ, McDowall D, Hyland VJ, Andrew SD, Schnitzler M, Gaskin EL, Nevell DF, Diamond T, Delbridge L, Clifton-Bligh P, Robinson BG: The identification of false positive responses to the pentagastrin stimulation test in RET mutation negative members of MEN 2A families. Clin Endocrinol 1996, 44:213-220. This paper confirms earlier important data (eg, Lips et al., N Engl J Med 1994, 331:825-835) that clinical C-cell test results can lead to false-positive diagnoses of MTC and unnecessary thyroidectomy in RET mutation-negative family members. Therefore, DNA analysis should always be performed prior to thyroidectomy in family members with elevated C-cell test results. The DNA test is the gold standard for assessment of disease gene carriership in families with a known disease gene mutation.
71. Marsh DJ, McDowall D, Hyland VJ, Andrew SD, Schnitzler M, Gaskin EL, Nevell DF, Diamond T, Delbridge L, Clifton-Bligh P, Robinson BG: The identification of false positive responses to the pentagastrin stimulation test in RET mutation negative members of MEN 2A families. Clin Endocrinol 1996, 44:213-220. This paper confirms earlier important data (eg, Lips et al., N Engl J Med 1994, 331:825-835) that clinical C-cell test results can lead to false-positive diagnoses of MTC and unnecessary thyroidectomy in RET mutation-negative family members. Therefore, DNA analysis should always be performed prior to thyroidectomy in family members with elevated C-cell test results. The DNA test is the gold standard for assessment of disease gene carriership in families with a known disease gene mutation.
72. Wells SA Jr, Chi D, Toshima K, Dehner LP, Coffin CM, Dowton SB, Ivanovich JL, DeBenedetti MK, Dilley WG, Moley JF, Norton JA, Donis-Keller H: Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 1994, 220:237-250.
73. Pacini F, Romei C, Miccoli P, Elisei R, Molinaro E, Mancusi F, Iacconi P, Basolo F, Martino E, Pinchera A: Early treatment of hereditary medullary thyroid carcinoma after attribution of multiple endocrine neoplasia type 2 gene carrier status by screening for ret gene mutations. Surgery 1995, 118:1031-1035.
74. Lips CJM, Landsvater RM, Höppener JWM, Geerdink RA, Blijham GH, Jansen-Schillhorn van Veen JM, Feldberg MAM, van Gils APG, Hoogenboom H, Berends MJH, Beemer FA, Ploos van Amstel HK, van Vroonhoven TJMV, Vroom TM: From medical history and biochemical tests to presymptomatic treatment in a large MEN 2A family. J Intern Med 1995, 238:347-356. This paper (as well as Wells et al., Ann Surg 1994, 220:237-250 and Pacini et al., Surgery 1995, 118:1031-1035) describes false-negative results of the clinical C-cell test: MEN 2A family members with a negative C-cell test who do have MTC as assessed by pathologic investigation after presymptomatic thyroidectomy in proven disease gene carriers (RET mutation positive). Keeping in mind that MEN 2A and 2B RET genes act as dominantly transforming oncogenes, and that the RET gene is expressed already during prenatal development (at least in rodents), tumor development in MEN 2 gene carriers can be expected to begin at a very young age and perhaps even before birth. This should be kept in mind when discussing the appropriate age for presymptomatic thyroidectomy in MEN 2 gene carriers.
75. Lips CJM, Landsvater RM, Höppener JWM, Geerdink RA, Blijham GH, Jansen-Schillhorn van Veen JM, Feldberg MAM, van Gils APG, Hoogenboom H, Berends MJH, Beemer FA, Ploos van Amstel HK, van Vroonhoven TJMV, Vroom TM: From medical history and biochemical tests to presymptomatic treatment in a large MEN 2A family. J Intern Med 1995, 238:347-356. This paper (as well as Wells et al., Ann Surg 1994, 220:237-250 and Pacini et al., Surgery 1995, 118:1031-1035) describes false-negative results of the clinical C-cell test: MEN 2A family members with a negative C-cell test who do have MTC as assessed by pathologic investigation after presymptomatic thyroidectomy in proven disease gene carriers (RET mutation positive). Keeping in mind that MEN 2A and 2B RET genes act as dominantly transforming oncogenes, and that the RET gene is expressed already during prenatal development (at least in rodents), tumor development in MEN 2 gene carriers can be expected to begin at a very young age and perhaps even before birth. This should be kept in mind when discussing the appropriate age for presymptomatic thyroidectomy in MEN 2 gene carriers.
76. Lips CJM, Landsvater RM, Höppener JWM, Geerdink RA, Blijham GH, Jansen-Schillhorn van Veen JM, Feldberg MAM, van Gils APG, Hoogenboom H, Berends MJH, Beemer FA, Ploos van Amstel HK, van Vroonhoven TJMV, Vroom TM: From medical history and biochemical tests to presymptomatic treatment in a large MEN 2A family. J Intern Med 1995, 238:347-356. This paper (as well as Wells et al., Ann Surg 1994, 220:237-250 and Pacini et al., Surgery 1995, 118:1031-1035) describes false-negative results of the clinical C-cell test: MEN 2A family members with a negative C-cell test who do have MTC as assessed by pathologic investigation after presymptomatic thyroidectomy in proven disease gene carriers (RET mutation positive). Keeping in mind that MEN 2A and 2B RET genes act as dominantly transforming oncogenes, and that the RET gene is expressed already during prenatal development (at least in rodents), tumor development in MEN 2 gene carriers can be expected to begin at a very young age and perhaps even before birth. This should be kept in mind when discussing the appropriate age for presymptomatic thyroidectomy in MEN 2 gene carriers.
77. Toogood AA, Eng C, Smith DP, Ponder BAJ, Shalet SM: No mutation at codon 918 of the RET gene in a family with multiple endocrine neoplasia type 2B. Clin Endocrinol 1995, 43:759-762.
78. Eng C, Mulligan LM, Smith DP, Healy CS, Frilling A, Raue F, Neumann HP, Ponder MA, Ponder BAJ: Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma. Clin Endocrinol 1995, 43:123-127. This paper reports that sometimes apparently sporadic MTCs turn out to harbor a germline RET gene mutation. As with patients with apparently sporadic pheochromocytoma who turn out to have a germline RET mutation, this indicates heritable disease and necessitates proper clinical treatment of the proband and his or her f+amily. We advise that in all cases of apparently sporadic MTC or pheochromocytoma, the presence of a germline RET gene mutation should be investigated.
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