Gene Expression of Parathyroid Tumors

Haven, Carola J.; Howell, Viive M.; Eilers, Paul H.C.; Dunne, Robert; Takahashi, Masayuki; Puijenbroek, Marjo van; Furge, Kyle A.; Kievit, J.; Tan, Min‐Han; Fleuren, Gert Jan; Robinson, Bruce G.; Delbridge, Leigh; Philips, Jeanette; Nelson, Anne E.; Krause, U.; Dralle, Henning; Hoang‐Vu, Cuong; Gimm, Oliver; Morreau, Hans; Marsh, Deborah J.; Teh, Bin Tean

doi:10.1158/0008-5472.can-04-2063

Cited by 98 publications

(28 citation statements)

References 20 publications

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“…DNA was extracted from tissue stored at K80 8C according to standard procedures. The HRPT2 mutation status and allelic loss in the HRPT2 region have been previously reported for the majority of these specimens (Howell et al 2003, Haven et al 2004. For all samples, the entire coding and flanking intronic regions were sequenced.…”

Section: Tumor Samplesmentioning

confidence: 97%

CDC73/HRPT2 CpG island hypermethylation and mutation of 5′-untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors

Hahn¹,

Howell²,

Gill³

et al. 2010

Endocrine-Related Cancer

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The tumor suppressor HRPT2/CDC73 is mutated in constitutive DNA from patients with the familial disorder hyperparathyroidism-jaw tumor syndrome and in w70% of all parathyroid carcinomas. In a number of HRPT2 mutant tumors however, expression of the encoded protein parafibromin is lost in the absence of a clear second event such as HRPT2 allelic loss or the presence of a second mutation in this tumor suppressor gene. We sought to determine whether hypermethylation of a 713 bp CpG island extending 648 nucleotides upstream of the HRPT2 translational start site and 65 nucleotides into exon 1 might be a mechanism contributing to the loss of expression of parafibromin in parathyroid tumors. Furthermore, we asked whether mutations might be present in the 5 0 -untranslated region (5 0 -UTR) of HRPT2. We investigated a pool of tissue from 3 normal parathyroid glands, as well as 15 individual parathyroid tumor samples including 6 tumors with known HRPT2 mutations, for hypermethylation of the HRPT2 CpG island. Methylation was not identified in any specimens despite complete loss of parafibromin expression in two parathyroid carcinomas with a single detectable HRPT2 mutation and retention of the wild-type HRPT2 allele. Furthermore, no mutations of a likely pathogenic nature were identified in the 5 0 -UTR of HRPT2. These data strongly suggest that alternative mechanisms such as mutation in HRPT2 intronic regions, additional epigenetic regulation such as histone modifications, or other regulatory inactivation mechanisms such as targeting by microRNAs may play a role in the loss of parafibromin expression.

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Section: Tumor Samplesmentioning

confidence: 97%

CDC73/HRPT2 CpG island hypermethylation and mutation of 5′-untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors

Hahn¹,

Howell²,

Gill³

et al. 2010

Endocrine-Related Cancer

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“…Genome-wide gene expression profiling is becoming useful for the classification of many types of cancer (6,7), including AML and acute lymphoblastic leukemia (8)(9)(10)(11)(12)(13)(14)(15). Although AML subtypes can be distinguished by oligonucleotide microarrays, the results of analysis of different translocations between laboratories are not always similar.…”

mentioning

confidence: 99%

Gene expression profiles in acute myeloid leukemia with common translocations using SAGE

Lee

Chen

Zhou

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Identification of the specific cytogenetic abnormality is one of the critical steps for classification of acute myeloblastic leukemia (AML) which influences the selection of appropriate therapy and provides information about disease prognosis. However at present, the genetic complexity of AML is only partially understood. To obtain a comprehensive, unbiased, quantitative measure, we performed serial analysis of gene expression (SAGE) on CD15 ؉ myeloid progenitor cells from 22 AML patients who had four of the most common translocations, namely t(8;21), t(15;17), t(9;11), and inv(16). The quantitative data provide clear evidence that the major change in all these translocation-carrying leukemias is a decrease in expression of the majority of transcripts compared with normal CD15 ؉ cells. From a total of 1,247,535 SAGE tags, we identified 2,604 transcripts whose expression was significantly altered in these leukemias compared with normal myeloid progenitor cells. The gene ontology of the 1,110 transcripts that matched known genes revealed that each translocation had a uniquely altered profile in various functional categories including regulation of transcription, cell cycle, protein synthesis, and apoptosis. Our global analysis of gene expression of common translocations in AML can focus attention on the function of the genes with altered expression for future biological studies as well as highlight genes͞pathways for more specifically targeted therapy.hematopoietic cell differention ͉ diagnostic microarray T he pathogenesis of acute myeloid leukemia (AML) in many patients is linked to oncogenic fusion proteins, generated as a consequence of chromosome translocations or inversions (1). Many different translocations have been described in AML, the most frequent being the t(9;11), t(15;17), t(8;21), and inv(16), which, taken together with their variants, account for Ϸ20-30% of AML cases (2, 3), although a recent analysis by Mitelman et al. (4) suggests that the proportion may be closer to 10%. These recurring translocations are now the basis for classification of some patients with AML. Despite genetic heterogeneity, there is increasing evidence for some common molecular and biological mechanisms in the genesis of AML. In particular, one of the components of each fusion protein is almost invariably a transcription factor, frequently involved in the regulation of myeloid cell differentiation (5). As a consequence, AML-associated fusion proteins function as aberrant transcriptional regulators with the potential to interfere with the normal processes of myeloid cell differentiation.Genome-wide gene expression profiling is becoming useful for the classification of many types of cancer (6, 7), including AML and acute lymphoblastic leukemia (8-15). Although AML subtypes can be distinguished by oligonucleotide microarrays, the results of analysis of different translocations between laboratories are not always similar. This lack of consistency has probably resulted from the heterogeneous nature of clinical samples (age, se...

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“…Therefore, parafibromin emerges as a regulator of a posttranscriptional pathway critical to cell-cycle progression [39]. In line with these observations, histone H1.2 (histone cluster 1 H1 family member c; HIST1H1C ( 6p22.2 )) has been reported up-regulated and highly overexpressed in seven sporadic PCas, together with the upregulation of histone H2A ( HIST1H2AC ( 6p22.2 )) and histone H2B ( HIST1H2BC ( 6p22.2 ) ; HIST1H2BD; HIST1H2BK; HIST1H2BO ) [40] (Figure 2). These genes belong to the histone microcluster on chromosome 6p22.2-p21.3.…”

Section: Dna Methylation In Parathyroid Cancersmentioning

confidence: 73%

Epigenetic Alterations in Parathyroid Cancers

Verdelli

Corbetta

2017

IJMS

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Parathyroid cancers (PCas) are rare malignancies representing approximately 0.005% of all cancers. PCas are a rare cause of primary hyperparathyroidism, which is the third most common endocrine disease, mainly related to parathyroid benign tumors. About 90% of PCas are hormonally active hypersecreting parathormone (PTH); consequently patients present with complications of severe hypercalcemia. Pre-operative diagnosis is often difficult due to clinical features shared with benign parathyroid lesions. Surgery provides the current best chance of cure, though persistent or recurrent disease occurs in about 50% of patients with PCas. Somatic inactivating mutations of CDC73/HRPT2 gene, encoding parafibromin, are the most frequent genetic anomalies occurring in PCas. Recently, the aberrant DNA methylation signature and microRNA expression profile have been identified in PCas, providing evidence that parathyroid malignancies are distinct entities from parathyroid benign lesions, showing an epigenetic signature resembling some embryonic aspects. The present paper reviews data about epigenetic alterations in PCas, up to now limited to DNA methylation, chromatin regulators and microRNA profile.

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Gene Expression of Parathyroid Tumors

Cited by 98 publications

References 20 publications

CDC73/HRPT2 CpG island hypermethylation and mutation of 5′-untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors

CDC73/HRPT2 CpG island hypermethylation and mutation of 5′-untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors

Gene expression profiles in acute myeloid leukemia with common translocations using SAGE

Epigenetic Alterations in Parathyroid Cancers

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