RET oncogene mutations in 75 cases of familial medullary thyroid carcinoma in Japan (original) (raw)
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Journal of Human Genetics, 1998
Multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) and familial medullary thyroid carcinomas (FMTC) are caused by germline mutations in the RET proto-oncogene. To investigate the spectrum of RET mutations among Japanese patients, we screened the RET gene in 71 patients with thyroid carcinomas. The panel included representatives of 44 families carrying FMTC or MEN2, 22 sporadic medullary thyroid carcinomas (MTCs), and five MTCs without familial information. Mutations in nucleotide sequences encoding one of three specific cysteine residues in the extracellular domain of the RET protein were found in 33 of the 34 MEN2A patients and in five of the six FMTC patients examined. A mutation at codon 918, causing the substitution of threonine for methionine in the tyrosine kinase domain of the protein, was found in germline DNAs of all four patients with MEN2B and in two of the 22 patients with sporadic MTCs; codon 918 was mutated somatically in tumor DNAs from three other sporadic cases. Germline mutations of codon 768, GAG to GAC (Glu to Asp), were detected in one FMTC, in one patient with sporadic MTC, and in one of the patients without familial information. Two somatic mutations, an Asp to Gly substitution at codon 631 and a Cys to Arg substitution at codon 634, had not been reported previously. Of five germline mutations found among the 22 sporadic cases, four were confirmed as de novo mutations since in each case neither parent carried the mutation. As nearly one-fourth of the patients with sporadic MTCs carried germline mutations and 50% of their children are expected to develop MTC and other endocrine tumors, these results indicated the importance of careful clinical surveillance of family members of any patient with MTC.
Journal of Clinical …, 1998
One hundred and eighty-one families with multiple endocrine neoplasia type 2A (MEN-2A) or familial medullary thyroid carcinoma (FMTC) have been investigated for mutations in the ret protooncogene in Germany. In 8 families with FMTC or MEN-2A, no mutation could be detected in the cysteine-rich domain encoded in exons 10 and 11 of the ret protooncogene. DNA sequencing of additional exons (no. 13-15) revealed rare noncysteine mutations in 3 families (codons 631, 768, and 844). In contrast to these rare events, heterozygous missense mutations in exon 13, codons 790 and 791, were found in 5 families (4 with MTC only; 1 family with MTC and pheochromocytoma) and
2016
BACKGROUND Medullary thyroid carcinoma (MTC) is a type of thyroid neoplasm which originates from parafollicular cells, and it is commonly diagnosed by calcitonin screening. Besides the sporadic form, the heritable form of MTC is characterized by constitutive activation of the RET (REarranged during Transfection) proto-oncogene caused by different mutations. METHOD We collected data regarding RET genetic screening performed in the Center for Endocrine Surgery in Belgrade during a 20-year-period. The study group included 249 MTC patients who were genetically tested for RET mutations by Sanger's sequencing method. RESULTS Genetic screening of the study population revealed nine different mutations of the RET gene in 42 carriers. The most common mutation was C634F, and it has been detected in 31 % (13/42) of individuals, while C618R, L790F, and S904S were present in only 2 % (1/42) each in the study group. Detected mutations were unequally distributed in different RET gene exons. Amo...
Thyroid, 2005
Hereditary medullary thyroid carcinoma (MTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. Associations between specific RET mutations (genotype) and the aggressiveness of MTC and presence or absence of other endocrine neoplasms (phenotype) are well documented. Mutations in six exons (10, 11, 13, 14, 15, and 16) located in either cysteine-rich or tyrosine kinase domains cause one of three distinctive clinical subtypes: familial MTC, multiple endocrine neoplasia (MEN) type 2A (including variants with Hirschsprung's disease and cutaneous lichen amyloidosis), and MEN 2B. Hallmarks of MEN 2A include MTC, pheochromocytoma, and hyperparathyroidism. MEN 2B is associated with an earlier onset of MTC and pheochromocytoma, the absence of hyperparathyroidism, and the presence of striking physical stigmata (e.g., coarse facies, ganglioneuromatosis, and marfanoid habitus). Familial MTC is not associated with other endocrine neoplasms; however, the accurate distinction between familial MTC and MEN 2A may be difficult in kindreds with small size, incomplete histories, or a predominance of young individuals who may not have yet fully manifested the syndrome. Genetic testing detects greater than 95% of mutation carriers and is considered the standard of care for all first-degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and the extent of surgery are based upon a model that utilizes genotype-phenotype correlations to stratify mutations into three risk levels.
The Journal of Clinical Endocrinology & Metabolism, 2004
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 in-volve 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. (J Clin Endocrinol Metab 89: 3521-3526, 2004) Abbreviations: MTC, Medullary thyroid carcinoma; FMTC, familial MTC; MEN, multiple endocrine neoplasia; TK, tyrosine kinase. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.
Cancer research, 1996
Inherited cancer syndromes predispose an individual to development of specific tumors. Somatic and germline mutations in the same tumor suppressor gene, as described in Knudson's two-mutation model, are well recognized. Inherited mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, predispose individuals to the multiple endocrine neoplasia type 2 (MEN 2) cancer syndromes. The major component tumor of these syndromes is medullary thyroid carcinoma (MTC). To date, somatic mutations in RET have not been identified in tumors from individuals with MEN 2, although they have been well documented in sporadic MEN 2-related tumors. We have identified, among 16 MEN 2 cases with well-defined RET germline mutations, a somatic missense mutation at codon 918 of RET in 3 of 15 MTCs and in a sample with hyperplastic C-cells (presumed precursor to hereditary MTC). We suggest that the presence of a somatic mutation, in addition to the preexisting germline mutation in here...
The rearranged during transfection (RET) gene is a proto-oncogene; active mutations frequently occur in medullary thyroid carcinoma (MTC). This study investigated the spectrum of germline RET mutations and clinical features in Chinese hereditary MTC patients. A total of 53 family members from 11 different hereditary MTC families were recruited for detection of RET exon 8, 10, 11, 13, 14, 15, and 16 mutations, in genomic DNA from peripheral blood leucocytes using polymerase chain reaction (PCR) and direct DNA sequencing. Of the 53 participants, eight different germline RET mutations were detected in 37 individuals. These RET mutations were distributed in exons 10, 11, 13, and 16. The most frequent RET mutation was localized at exon 11 codon 634 (67.6 %; 25/37) and the most prevalent mutation was C634R (37.8 %; 14/37). The most frequent phenotype was multiple endocrine neoplasia type 2A (MEN2A). The incidences of MTC, pheochromocytoma, and hyperparathyroidism in the MEN2A patients were 100, 36.4 and 18.2 %, respectively. The phenotype of families with Y606C or L790F mutation was categorized as familial medullary thyroid carcinoma. Moreover, one proband was identified with multiple endocrine neoplasia type 2B and carried a de novo mutation of M918T. Two families with C618S/Y mutation were categorized as unclassified multiple endocrine neoplasia type 2. Our results further substantiate that most germline mutations of the RET proto-oncogene were localized at codon 634 in Chinese hereditary MTC patients and carriers. RET mutation at codon 634 was always associated to the phenotype of MEN2A. Screening of RET mutations should be probably limited to exons 10, 11, 13 and 16 initially to be cost-effective in China.
The Journal of Clinical Endocrinology & Metabolism, 1997
Specific mutations in the ret protooncogene have been found associated with multiple endocrine neoplasia type 2A (MEN 2A) and type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). Mutations in one of five cysteine residues in the extracellular domain have been found in over 95% of families with MEN 2A and 88% of families with FMTC. In MEN 2B patients, a specific mutation at codon 918, substituting a threonine for a methionine, has been found in 95% of cases. In FMTC, in addition to the mutations of the extracellular cysteines, three intracellular base pair changes have been reported at codons 768 and 804. Here we describe a novel intracellular mutation in exon 15 of the ret gene that leads to the substitution of an alanine for a serine at codon 891 in a family with medullary thyroid carcinoma. This amino acid change may be important in determining substrate specificity or, alternatively, may play a role in ATP binding.