Background To discriminate between sporadic and hereditary parathyroid tumours and characterize multiple endocrine neoplasia type 1 (MEN1) somatic mutations, MEN1 gene mutations were examined in patients with apparently sporadic parathyroid tumours. Methods DNA was extracted from fresh frozen parathyroid tumour specimens from 112 patients, as well as from peripheral blood leucocytes (PBL) from 60 of the 112 patients. Sequencing was performed to examine exons 2–10 of the MEN1 gene for mutations. In addition, exons 10 and 11 of the RET gene were sequenced. Results MEN1 mutations were found in 25 (22 per cent) of the 112 patients. Two patients had two simultaneous point-mutations. A total of 27 mutations were characterized, 24 of which have not been reported previously. There were seven nonsense mutations, ten frameshift mutations, two splice-site deletions, five missense mutations and three in-frame mutations. Nineteen mutations resulted in truncation of menin protein. Germline MEN1 mutations were found in three of 60 patients who had no family history of endocrine tumours associated with MEN1, and these patients were identified as MEN1 gene family probands. No somatic or germline RET exon 10 and 11 mutations were found in this series. Conclusion These findings suggest that MEN1 gene mutation may be associated not only with endocrine tumours of affected patients with MEN1 but also with sporadic parathyroid tumours. MEN1 gene analysis can distinguish inheritable from non-inheritable parathyroid tumours and MEN1 gene evaluation of patients with apparently sporadic parathyroid tumours is necessary before parathyroid surgery.
Germline mutations in the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2 (MEN 2A and 2B) and familial medullary thyroid carcinoma (FMTC). Point mutations or in-frame deletions of exons 10, 11, 13, 14 and 16 are associated with sporadic medullary thyroid carcinoma (MTC). To understand further the role of the RET gene in sporadic MTC, we examined mutations in exons 12 and 15 of RET in patients with sporadic MTC. DNAs were extracted from 39 formalin-fixed tumor tissues and corresponding normal thyroid tissues or peripheral blood leukocytes. DNA sequencing was used to identify mutations in exons 12 and 15 of RET. In this study, one novel somatic mutation was found in exon 12 and five novel mutations or deletions were found in exon 15. Of the patients with mutations, one had an in-frame 12-bp deletion (nt. 2625-2636), one had point mutations in both codons 884 and 908, and the remaining three had point mutations in codons 748, 876 and 901, respectively. Together with our previous identification of somatic mutations in exons 10, 11, 13, 14 and 16, somatic alterations were found in 10 out of 39 (25.6%) sporadic MTCs. There was no association of RET gene mutations with tumor recurrence or prognosis. These results suggest that mutations occur frequently in the RET coding region in addition to the previously reported mutation hot spots, and there is a different spectrum of mutations between sporadic and hereditary MTC.Key words: Sporadic medullary thyroid carcinoma -RET gene -Point mutation -Multiple endocrine neoplasia -Tyrosine kinase domainThe RET proto-oncogene on human chromosome 10q11.2 encodes a protein receptor tyrosine kinase that includes an extracellular region with a cysteine-rich domain, a transmembrane region and an intracellular region with a tyrosine kinase domain. Germline point mutations in RET have been found to cause MEN 2A, 2B and FMTC.1, 2) RET gene was first isolated by transfection of NIH 3T3 cells with a human T-cell lymphoma DNA, and was activated by fusion of the tyrosine kinase domain of this gene to the 5′-terminal portion of another gene, 3) i.e., H4 gene (RET/PTC1) 4) the regulatory subunit RIα of cAMP-dependent protein kinase A (RET/PTC2), 5) ELE1 gene (RET/PTC3 and RET/PTC4) [6][7][8] and RFG5 gene (RET/PTC5). 9) In MEN 2A families, germline mutations are concentrated in five cysteine codons: codons 609, 611, 618 and 620 in exon 10, and codon 634 in exon 11. 10) A small number of MEN2A families has germline mutations at codons 790. 11) In MEN 2B, approximately 95% of families have an M918T germline mutation in exon 16, [12][13][14] and recent research revealed A883F and V804M with Y806C germline mutation as another cause of MEN 2B. [15][16][17] Germline mutations in RET have been found in 88% of FMTC families, and the majority of mutations in FMTC occur in the same five cysteine codons altered in MEN 2A.10) C630F, C630Y, E768D, L790F, Y791F, V804L, V804M and S891A germline mutations have been found in some FMTC families. 11,[18][19][20][21][22][23] Various somat...
Germline mutations in the RET proto-oncogene have been shown to be the underlying cause of multiple endocrine neoplasia type 2 (MEN 2A and 2B) and familial medullary thyroid carcinoma (FMTC). Some cases of sporadic medullary thyroid carcinoma (sporadic MTC) are reported to have specific codon 918, 883 and 768 mutations of the RET gene in tumor tissues. We examined RET gene mutations in 40 Japanese cases who had previously undergone surgery for sporadic MTC. DNA extracted from formalin-fixed tumor tissues and corresponding normal thyroid tissues or peripheral blood leukocytes was analyzed for mutations of exon 10, 11, 13, 14 and 16 of the RET gene by DNA sequencing and by mutation-specific restriction enzyme analysis. Germline RET point mutations were found in six of 40 cases (15%), cysteine residues at codon 618 in two, codon 634 in three and valine residue at codon 804 in one, and were newly identified as heritable MTC. Of the remaining 34 sporadic MTC cases, four (12%) had tumor-specific RET point mutations. Two were found in exon 16; one case showed an ATG to ACG (Met to Thr) mutation at codon 918, and the other showed two point mutations, ATG to ACG (Met to Thr) at codon 918 and GCA to GTA (Ala to Val) at codon 919 with loss of the wild-type allele, suggesting that both alleles at the RET locus were altered. The other two were found in exon 13; one case showed a CCG to TCG (Pro to Ser) mutation at codon 766 and the other showed a silent mutation, GTC to GTT (Val) at codon 778 with loss of the wild-type allele. There was no association of sporadic mutations with recurrence or prognosis in patients with sporadic MTCs. The low rate of somatic RET mutation at codon 918 in our sporadic MTC suggests that as yet unknown factors may be involved. Genetic alterations in both alleles may have an important role in a small fraction of sporadic MTCs.Key words: Sporadic medullary thyroid carcinoma -RET gene -Point mutation -Allele lossMultiple endocrine neoplasia Specific germline mutations in the RET proto-oncogene on chromosome 10q11.2 have been shown to be the underlying cause of multiple endocrine neoplasia (MEN) 2A, 2B and familial medullary thyroid carcinoma (FMTC).1, 2) Mutations in MEN 2A and FMTC occur in a cysteine-rich extracellular region and are concentrated on cysteine residues at codons 609, 611, 618, 620 or 634 of exon 10 or 11. 3,4) In MEN 2B, mutations are found in the intracellular tyrosine kinase domain at codon 918 of exon 16.5-7) In addition, mutations at codon 768 of exon 13 and codon 804 of exon 14 were reported in some FMTC families. 8,9) More than half of all MTC cases are sporadic MTC. Clinically, sporadic MTC is characterized by negative family history in patients who are usually in their fifties or sixties when MTC is diagnosed. Occasionally, patients who undergo thyroidectomy for benign thyroid disease are diagnosed as MTC postoperatively. Before the susceptibility gene for MEN 2 was discovered, patients without a family history of MTC or pheochromocytoma were likely to be regarded as having t...
Effects of dietary iodine on the induction of thyroid carcinoma using N‐nitrosobis(2 hydroxypropyl)amine (BHP) were studied. Male Wistar rats were fed with an iodine‐adequate diet (IAD group), an iodine‐rich diet (IRD group) and an iodine‐deficient diet (IDD group), respectively, until the time of sacrifice. From the 2nd experimental month, animals were injected with BHP once a week for 10 weeks. In the IAD and IRD groups, benign nodules and papillary carcinoma were found. The incidence of rats with benign nodules was 100% in both groups and animals with papillary carcinoma in the IAD and IRD groups comprised 33% and 29%, respectively. The area of the thyroid gland occupied by nodular lesions was much narrower in the IRD group than in the IAD group. In the IDD group, the thyroid showed marked enlargement due to multiple nodular proliferation of follicle cells. The incidence of rats with carcinoma was 100%, and not only papillary but also follicular carcinoma and one pulmonary metastasis were found. As the iodine content of the diet decreased, the nodular lesions increased in width and number, and the incidence of carcinoma in rats became higher. These effects of dietary iodine are probably related to the goitrogenic and/ or promoting effects of TSH. Acta Pathol Jpn 40: 705‐712, 1990.
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