Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2

Gardner, Emily; Papi, Laura; Easton, Douglas F.; Cummings, Timothy S.; Jackson, Charles E.; Kaplan, Michael M.; Love, Donald R.; Mole, Sara; Moore, Julia K.; Mulligan, Lois M.; Norum, Robert A.; Ponder, M. A.; Reichlin, Seymour; Stall, Glenn M.; Telenius, H; Telenius‐Berg, Margareta; Tunnacliffe, Alan; Ponder, Bruce A.J.

doi:10.1093/hmg/2.3.241

Cited by 90 publications

(23 citation statements)

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“…Medullary thyroid carcinoma (MTC) arises from calcitonin-producing parafollicular (C) cells of the thyroid and accounts for 5%-8% of all thyroid cancers (1). MTC is sporadic in about 75% of the cases; in the remaining cases, it is familial MTC (FMTC) or occurs as a component of the autosomal dominant familial multiple endocrine neoplasia type 2 (MEN2A and MEN2B).…”

Section: Introductionmentioning

confidence: 99%

Calcium/Calmodulin-Dependent Protein Kinase II and Its Endogenous Inhibitor α in Medullary Thyroid Cancer

Russo

Salzano²,

Falco

et al. 2014

Clinical Cancer Research

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Purpose: Calcium/calmodulin-dependent kinase II (CaMKII) is involved in the regulation of cell proliferation. Its endogenous inhibitor (hCaKIINa) is expressed in some cell types. We determined the role of CaMKII in RET-stimulated proliferation and hCaMKIINa in medullary thyroid carcinoma (MTC).Experimental Design: We analyzed the role of RET mutants on CaMKII activation in NIH3T3 and in MTC cell lines, and determined the effect of CaMKII inhibition on RET/ERK pathway and cell proliferation. Then the expression of hCaKIINa mRNA was determined by real-time PCR in primary MTC and it was correlated with some clinicopathologic parameters.Results: RET C634Y and RET M918T mutants expressed in NIH3T3 cells induced CaMKII activation. CaMKII was activated in unstimulated MTC cells carrying the same RET mutants and it was inhibited by RET inhibition. Inhibition of CaMKII in these cells induced a reduction of Raf-1, MEK, and ERK phosphorylation, cyclin D expression, and cell proliferation. hCaKIINa mRNA expression in primary MTC was very variable and did not correlate with gender and age at diagnosis. Serum calcitonin, (R 2 ¼ 0.032; P ¼ 0.017), tumor volume (P ¼ 0.0079), lymph node metastasis (P ¼ 0.033), and staging (P ¼ 0.0652) were negatively correlated with the hCaKIINa mRNA expression. Conclusions: CaMKII is activated by RET mutants and is activated at baseline in MTC cells where it mediates the oncogenic pathway leading to cell proliferation. The mRNA expression of its endogenous inhibitor hCaKIINa inversely correlates with the severity of MTC. CaMKII might represent a new target for MTC therapy and hCaKIINa is a marker of disease extension.

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Section: Introductionmentioning

confidence: 99%

Calcium/Calmodulin-Dependent Protein Kinase II and Its Endogenous Inhibitor α in Medullary Thyroid Cancer

Russo

Salzano²,

Falco

et al. 2014

Clinical Cancer Research

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“…gion, where the RET proto-oncogene has also been mapped [2,3]. Germline mutations of the RET proto-oncogene have been described in patients affected with MEN 2A, FMTC or MEN 2B [4][5][6][7][8][9][10].…”

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confidence: 99%

Mutations in the Cysteine-Rich Region of the RET Proto-Oncogene in Patients Diagnosed as Having Sporadic Medullary Thyroid Carcinoma.

et al. 1995

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In this region, no mutations were detected in any tumors from patients with MEN 2B and NF1, and sporadic pheochromocytomas.But mutations were detected and identified in 3 clinically apparent sporadic MTCs and TT cells. A 6 base pair (bp) deletion causing the loss of a cysteine residue at codon 634 and a mutation causing substitution from cysteine to tyrosine at codon 634 were detected in 2 sporadic MTCs as somatic events. In a female patient diagnosed as having sporadic MTC, a mutation at codon 618 was detected not only in tumor tissues, but also in her leukocytes, suggesting a germline mutation of the RET proto-oncogene. In TT cells a heterozygous mutation at codon 634 was detected.These results suggest that RET mutations within a cysteine-rich region may also play an important role in the tumorigenesis of sporadic MTCs, and mutations of RET proto-oncogene should be screened in clinically sporadic cases to exclude hereditary MTCs.

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“…The loci of three syndromes, including MEN 2A, familial thyroid medullary carcinoma (FMTC), and MEN 2B, have been assigned by linkage to the chromosome 10g11.2 region, where the RET proto-oncogene had also been mapped [5,6]. Recently, germline mutations of the RET proto-oncogene have been described in patients affected with MEN 2A, FMTC, and MEN 2B [7][8][9][10][11][12][13].…”

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confidence: 99%

Tumor-Specific Mutations in the Tyrosine Kinase Domain of the RET Proto-Oncogene in Pheochromocytomas of Sporadic Type.

et al. 1995

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Abstract.Sporadic pheochromocytomas, sporadic medullary thyroid carcinomas (MTCs), pheochromocytomas and/or MTCs in multiple endocrine neoplasia (MEN) 2A or 2B were screened for mutations in the tyrosine kinase domain of the RET proto-oncogene by direct sequencing of PCR-amplified products or sequencing subcloned DNAs from PCR-products. All tumors of 4 MEN 2B patients were confirmed to contain a heterozygous missense mutation at codon 918 (ATG-~ACG; Met-Thr) of the RET proto-oncogene as well as their leukocytes. The same tumor-specific mutations at codon 918 were also found in 5/16 (31%) sporadic pheochromocytomas.These results suggest that mutations of the RET proto-oncogene in its tyrosine kinase domain play a role not only as the predisposing gene for MEN 2B, but also as a tumorigenic factor for pheochromocytomas of sporadic type.

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Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2

Cited by 90 publications

References 0 publications

Calcium/Calmodulin-Dependent Protein Kinase II and Its Endogenous Inhibitor α in Medullary Thyroid Cancer

Calcium/Calmodulin-Dependent Protein Kinase II and Its Endogenous Inhibitor α in Medullary Thyroid Cancer

Mutations in the Cysteine-Rich Region of the RET Proto-Oncogene in Patients Diagnosed as Having Sporadic Medullary Thyroid Carcinoma.

Tumor-Specific Mutations in the Tyrosine Kinase Domain of the RET Proto-Oncogene in Pheochromocytomas of Sporadic Type.

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