Genetic events in tumour initiation and progression in multiple endocrine neoplasia type 2

Mulligan, Lois M.; Gardner, Emily; Smith, Barbara A.; Mathew, C G; Ponder, Bruce A.J.

doi:10.1002/gcc.2870060307

Cited by 117 publications

(69 citation statements)

References 32 publications

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“…We next used a panel of four microsatellite markers spanning the 20p13 region close to, and flanking, the GFRA4 locus. We identified partial loss of one allele at all informative loci in tumour DNA from one individual with a known RET mutation (not shown), consistent with previous studies showing that allele loss on chromosome 20 is rare in MTC (Mulligan et al, 1993). Interestingly, GFRA4 lies on chromosome 20p in a region at one time implicated in MEN 2, based on cytogenetically detectable interstitial deletions found in some families Van Dyke et al, 1984).…”

supporting

confidence: 90%

A model for GFRα4 function and a potential modifying role in multiple endocrine neoplasia 2

et al. 2004

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Mutations of the RET proto-oncogene are found in the majority of patients with the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). A minority of cases, however, have no detectable RET mutation and there is considerable phenotypic variation within and among MEN 2 families with the same RET mutation, suggesting a role for other loci in this disease. A candidate for such a gene is glial cell line-derived neurotrophic factor receptor alpha 4 (GFRA4), which encodes a cell surfacebound co-receptor (GFRa4) required for interaction of RET with its ligand persephin. The GFRA4 gene has multiple alternative splices leading to three distinct protein isoforms that are prominently expressed in thyroid. We postulated that mutations of GFRA4 contribute to MEN 2 in the absence of RET mutations or modify the RET mutation phenotype. We screened patients with MEN 2 or MEN 2-like phenotypes, with and without RET mutations, for variants of GFRA4. We identified 10 variants, one of which was over represented in, and two of which were found exclusively in, our patient populations. One of these was a single-base substitution upstream of the GFRa4 coding region, where it may alter gene expression. The second was a 7 bp insertion, which results in a change in reading frame for all three GFRa4 isoforms. This would cause a relative shift in membrane bound and soluble forms of GFRa4, which would significantly alter the formation of RET signalling complexes. Our data suggest a model of wild-type GFRa4 isoform expression that includes both activating and inhibiting co-receptors for RET.

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confidence: 90%

A model for GFRα4 function and a potential modifying role in multiple endocrine neoplasia 2

et al. 2004

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“…In MTC as in other tumors, accu-mulation of genetic alterations, functional loss of tumor suppressor genes, and activation of oncogenes contribute to tumor development. Mulligan et al 35) found that frequent LOH on chromosomes 1p, 3p, 3q and 22q occurred somatically in MTCs and pheochromocytomas of MEN type 2 cases. LOH on chromosomes 1, 3, 11, 17 and 22 in MTCs or pheochromocytomas has also been reported.…”

Section: Resultsmentioning

confidence: 99%

Novel Point Mutations and Allele Loss at the RET Locus in Sporadic Medullary Thyroid Carcinomas

Uchino

Noguchi

Adachi

et al. 1998

Japanese Journal of Cancer Research

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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...

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“…Before the year 2000, there were three forms of syndromic familial pheochromocytoma: von Hippel-Lindau (VHL) (Latif et al 1993); multiple endocrine neoplasia type 2 (MEN2) (Mulligan et al 1993); and neurofibromatosis type 1 (NF1) (Viskochil et al 1990). The mutated genes, responsible for these syndromes are VHL, RET and NF1 respectively.…”

Section: Introductionmentioning

confidence: 99%

15 YEARS OF PARAGANGLIOMA: Metabolism and pheochromocytoma/paraganglioma

Mannelli

Rapizzi

Fucci

et al. 2015

Endocrine-Related Cancer

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The discovery of SDHD as a pheochromocytoma/paraganglioma susceptibility gene was the prismatic event that led to all of the subsequent work highlighting the key roles played by mitochondria in the pathogenesis of these tumors and other solid cancers. Alterations in the function of tricarboxylic acid cycle enzymes can cause accumulation of intermediate substrates and subsequent changes in cell metabolism, activation of the angiogenic pathway, increased reactive oxygen species production, DNA hypermethylation, and modification of the tumor microenvironment favoring tumor growth and aggressiveness. The elucidation of these tumorigenic mechanisms should lead to novel therapeutic targets for the treatment of the most aggressive forms of pheochromocytoma/paraganglioma.

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Genetic events in tumour initiation and progression in multiple endocrine neoplasia type 2

Cited by 117 publications

References 32 publications

A model for GFRα4 function and a potential modifying role in multiple endocrine neoplasia 2

A model for GFRα4 function and a potential modifying role in multiple endocrine neoplasia 2

Novel Point Mutations and Allele Loss at the RET Locus in Sporadic Medullary Thyroid Carcinomas

15 YEARS OF PARAGANGLIOMA: Metabolism and pheochromocytoma/paraganglioma

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