Identification of a Novel Point Mutation in the RET Gene (Ala883Thr), Which Is Associated with Medullary Thyroid Carcinoma Phenotype Only in Homozygous Condition (original) (raw)
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Surgery, 2002
Background. Only 9 families with familial medullary thyroid carcinoma due to V804M mutation have been reported until now. We describe a large kindred with not only heterozygous but also homozygous members with the V804M mutation. This is, to our knowledge, the first report of a homozygous RET mutation. Methods. Fifty-three members from 4 successive generations of a family with a high level of consanguinity underwent genetic analysis. The pentagastrin provocative test and biochemical screening to rule out either hyperparathyroidism or pheochromocytoma were performed only on gene carriers of the mutation. Results. Twenty-six gene carriers for V804M mutation were identified (4 homozygous and 22 heterozygous). Three of 4 homozygous patients underwent total thyroidectomy. In 1 patient neither medullary thyroid carcinoma nor C-cell hyperplasia was detected, and in another patient only 3 small foci of C-cell hyperplasia were found on the histologic examination. The pentagastrin stimulation test result was within the normal range in all the heterozygous gene carriers and, consequently, thyroidectomy was not indicated. The screening for both hyperparathyroidism and pheochromocytoma was negative in all patients. Conclusions. In the family reported, the V804M mutation in heterozygous patients seems not to be enough to express the full disease. This finding strongly supports the concept of the indolent behavior of V804M RET proto-oncogene mutation. In addition, our results suggest that when counseling for preventive total thyroidectomy, the specific mutation of RET proto-oncogene and also the natural history of the disease within a particular family should be considered.
Familial medullary thyroid carcinoma is related to germ-line mutations in the RET oncogene, mainly in cysteine codon 10 or 11, whereas noncysteine mutations in codons 13-15 are rare. We now report a new missense point mutation in exon 8 of the RET gene (1597G3 T) corresponding to a Gly 533 Cys substitution in the cystein-rich domain of RET protein in 76 patients from a 6-generation Brazilian family with 229 subjects, with ascendants from Spain. It is likely that the mutation causes familial medullary thyroid carcinoma (FMTC), because no other mutation was found in RET, the mutation cosegregates with medullary thyroid carcinoma (MTC) or C cell hyperplasia (CCH) in patients subjected to surgery, and family members without the mutation are clinically unaffected. The histological analysis of 35 cases submitted to thyroidectomy revealed that 21 patients had MTC after the age of 40 yr and 8 before the age of 40 yr, 4 presented MTC or CCH before the age of 18 yr, 2 died due to MTC at the age of 53 and 60 yr, and CCH was found in a 5-yr-old child, suggesting a clinical heterogeneity. To improve the diagnosis of FMTC, analysis of exon 8 of RET should be considered in families with no identified classical RET mutations. (J Clin Endocrinol Metab 88: 5438 -5443, 2003)
Journal of Molecular Medicine, 2003
Medullary thyroid carcinoma (MTC) occurs as a sporadic form or, less frequently, as an autosomal dominant inherited familial disorder. Germline mutations in the RET proto-oncogene in exons 10, 11, 13, 14, 15, and 16 are found in most of the familial cases (nearly 95%). Somatic mutations in sporadic MTC are detected in 23-69% of patients. The most frequent somatic mutation is located in exon 16 at codon 918, and only a small percentage of mutations are found in exons 10, 11, 13, and 15. We have searched for somatic mutations in Czech MTC patients using direct sequencing. We report here two new somatic missense mutations in exon 16 of the RET proto-oncogene associated with the sporadic MTC detected in two Czech men. A homozygous mutation at codon 922 TCC(Ser)!CCC(Pro) as a result of loss of heterozygosity was revealed in the first patient. In the second one a heterozygous mutation at codon 930 ACG(Thr)!ATG(Met) was found.
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 …, 2002
Sixty-one heterozygotes harboring the germline V804L mutation of the RET protooncogene were identified in five independent families. A total of 31 subjects underwent surgery. Histology identified C cell hyperplasia in 30 cases, isolated in 12 and associated with medullary thyroid carcinoma (MTC) in 18. Six patients with MTC had lymph node metastases. Among the 14 patients with basal detectable calcitonin (CT) level, 12 had MTC and 2 had isolated C cell hyperplasia. In most individuals carrying 804 RET mutation, C cell disease displayed late onset and an indolent course; a pentagastrin test was negative in the majority of heterozygotes during the first 2 decades and was positive in only half of them during the third and fourth decades of life. Interestingly, concomitant somatic M918T was detected in a 12-yr-old girl with MTC and was likely to be responsible for both the early clinical appearance and the aggressiveness of the disease. Our data show that in these gene carriers, surgery may be postponed to the fourth decade of life or until the pentagastrin stimulation test becomes positive. Indeed, our data should be confirmed on a larger series of V804L carriers, but may offer a balanced strategy to keep under control and prevent development of the full disease phenotype.
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
The Journal of Clinical Endocrinology & Metabolism, 2005
The effect of mutations at codon 804 in the RET protooncogene is disputed. Some studies have suggested that the V804L mutation causes the low penetrance multiple endocrine neoplasia type 2 syndrome, with late onset and relatively indolent course, whereas others have reported that V804L and V804M have an aggressive potential. In this paper, we report three apparently unrelated medullary thyroid carcinoma cases homozygous for these mutations. To clarify the phenotypic heterogeneity associated with these mutations, we compare the clinical data and age of diagnosis among these three homozygous patients, six other heterozygous cases from the same populations, and other homozygous and heterozygous subjects reported previously. The data are consistent with a model in which codon 804 mutations have low penetrance, the developing of medullary thyroid carcinoma being associated with a second germline or somatic mutation. The activity and (in the case of somatic mutations) timing of these other genetic alterations in the RET gene may explain the wide clinical variability associated with germline mutations at codon 804. (J Clin Endocrinol Metab 90: 3454 -3457, 2005)
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...