Deletion of genes on chromosome 1 in endocrine neoplasia

Mathew, Christopher G.; Smith, Barbara A.; Thorpe, Karen L.; Wong, Zilla; Royle, Nicola J.; Jeffreys, A. J.; Ponder, Bruce A.J.

doi:10.1038/328524a0

Cited by 239 publications

(92 citation statements)

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“…LOH on chromosomes 1, 3, 11, 17 and 22 in MTCs or pheochromocytomas has also been reported. [36][37][38][39][40][41] Alterations in other gene(s) may also contribute to the progression of MTC and phenotypic variation among families with MEN 2A with the same RET germline mutation. It is necessary to investigate alterations in other coding and intronic regions throughout the entire RET gene, LOH at the site of candidate tumor suppressor genes and activation of other oncogenes in sporadic MTCs.…”

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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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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“…After examination of a hematoxylin-phloxine-a ron-stained section, tumour tissues were microdissected from contaminating normal cells and the DNA extracted according to published protocols (Wright and Manos, 1990;Feilotter et al, submitted). Control blood DNAs from a panel of 60 unrelated individuals were extracted using established protocols (Mathew et al, 1987).…”

Section: Samplesmentioning

confidence: 99%

Analysis of PTEN and the 10q23 region in primary prostate carcinomas

Nagai²,

et al. 1998

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Deletions involving chromosome 10q23 occur frequently in prostatic carcinomas. Recently, a novel tumour suppressor gene, PTEN, mapping to this interval, has been identi®ed. Mutation or deletion of PTEN has been observed in a proportion of prostate cancer cell lines; however, primary prostate carcinomas have not been studied. We have investigated the involvement of PTEN in primary prostatic adenocarcinomas using a panel of 51 matched normal and prostate tumour DNAs. We ®rst determined the proportion of tumours with allele loss at loci in 10q23 which span the region containing the PTEN gene. Our results show that LOH involving 10q23 is common in primary prostate carcinomas. Twenty-®ve of 51 (49%) tumours showed loss of heterozygosity (LOH) over the region spanning the PTEN locus. We next directly analysed the PTEN gene for mutations of the coding region using single strand conformation polymorphism (SSCP) and sequence analyses. Of those tumours with LOH, only a single tumour was found to carry a missense mutation in PTEN. No mutations in PTEN were identi®ed in tumours without LOH. Our results suggest either that mutation of PTEN is a late event in prostate tumorigenesis, or that another tumour suppressor gene important in prostate cancer may lie close to PTEN in 10q23.

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“…Williamson et al have reported a 27% of LOH at 1p32-pter and mapped a candidate gene in the region flanked by D1S228 and D1S507 (6). 1p36 is also interesting because other endocrine tumors, such as pheochromocytoma, medullary thyroid carcinoma, and anterior pituitary adenoma have also been demonstrated harboring LOH in this region (7). A potent tumor suppressor gene is considered to be located in the distal region of 1p.…”

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confidence: 99%

Frequent Loss of Heterozygosity at 1p36.3 and p73 Abnormality in Parathyroid Adenomas

et al. 2001

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Although 1p is one of the most common loci showing loss of heterozygosity (LOH) in primary parathyroid adenoma, fine mapping has not been previously examined. In this study, we analyzed LOH in 32 primary parathyroid adenomas using five microsatellite markers at 1p36 (proximal-D1S507-D1S450-D1S2893-D1S468-D1S243-distal). All cases were heterozygous for at least one marker. The frequency of LOH varied from 41.2% (D1S468) to 7.1% (D1S507) among the different markers. LOH was detected consistently in a group of nine adenomas (28.1%, 9/32). A single region (7 cM) showing a consistent LOH at 1p36.3 was obtained that was flanked distally by D1S468 and proximally by D1S2893. Because the p73 gene is localized within this region and acts as a tumor suppressor gene, we examined the possible involvement of p73 in the development of parathyroid tumor. Allelic loss of p73 was identified in four adenomas (25%, 4/16 informative cases) that were all from the group of the nine adenomas with LOH, but somatic mutation was not detected in the remaining allele. At the StyI polymorphism of Exon 2, four of the six adenomas with LOH at 1p36 were heterozygous and expressed the GC allele. Of the six heterozygous adenomas without LOH, 4 showed biallelic and 2 monoallelic expressions (GC allele). All adenomas mainly expressed the p73␣ isoform. p73 protein was observed in five of the six adenomas with LOH and in two of the six adenomas without LOH. There were no differences in p73 protein levels between the samples with and without LOH. In conclusion, a candidate gene for parathyroid tumorigenesis is present within a 7-cM region at 1p36.3, however p73 is unlikely to be the target of the LOH at 1p36.3. KEY WORDS: 1p36, Hyperparathyroidism, Loss of heterozygosity, Parathyroid neoplasia, p73. Mod Pathol 2001;14(4):273-278Parathyroid adenoma is one of the most common endocrine tumors, characterized by excessive secretion of parathyroid hormone (PTH) and enlargement of mostly one parathyroid gland. The molecular mechanism of parathyroid tumorigenesis is still poorly understood (1). MEN 1 gene abnormality has been found in only about 20% of the sporadic parathyroid adenomas. Cyclin D1/PTH gene rearrangement seems to be involved only in a small subset of these tumors, and p53 gene mutations also appear to be rare. To localize the gene responsible for parathyroid tumorigenesis, loss of heterozygosity (LOH) has been analyzed in various loci, and different frequencies of LOH have been identified (2, 3

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Deletion of genes on chromosome 1 in endocrine neoplasia

Cited by 239 publications

References 0 publications

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

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

Analysis of PTEN and the 10q23 region in primary prostate carcinomas

Frequent Loss of Heterozygosity at 1p36.3 and p73 Abnormality in Parathyroid Adenomas

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