Intragenic allelic loss and promoter hypermethylation of the RIZ1 tumor suppressor gene in parathyroid tumors and pheochromocytomas

doi:10.1016/S0039-6060(03)00422-7

Surgery

Volume 134, Issue 6, December 2003, Pages 932-939

https://doi.org/10.1016/S0039-6060(03)00422-7 Get rights and content

Abstract

Background

Loss of heterozygosity (LOH) at chromosome 1p is a common abnormality in both parathyroid tumors and pheochromocytomas. The recently characterized tumor suppressor gene RIZ1, located at 1p36, has emerged as a putative candidate to be involved in endocrine tumorigenesis.

Material

Presence of allelic loss, promoter hypermethylation, and mutational aberrations of the RIZ1 gene were investigated using PCR- based techniques in 47 parathyroid tumors and 23 pheochromocytomas. Gene expression studies used the RNAse protection assay.

Results

RIZ1 mRNA is expressed in pathologic tissues of the parathyroid and adrenal medulla. Thirteen of 47 (28%) parathyroid tumors, and 9/23 (39%) pheochromocytomas displayed LOH within the RIZ1 gene locus. Promoter hypermethylation of RIZ1 was detected in 36% of the parathyroid tumors and was related to LOH at the RIZ1 locus (P = .01), and absence of somatic mutation of the MEN1 gene (P = .044). In the pheochromocytomas, none of the benign tumors, but 2/4 malignant specimens exhibited RIZ1 promoter hypermethylation.

Conclusion

Alteration of the RIZ1 gene locus via intragenic allelic loss and promoter hypermethylation seem common in parathyroid tumors. Inactivation of the RIZ1 gene may cause parathyroid tumorigenesis via a mechanism in which genetic alteration of the MEN1 gene is redundant.

Section snippets

Subjects and tumor samples

Forty-seven patients (39 women and 8 men; age [mean±SEM] 67±2 years; range 15 to 85 years) with operatively verified, nonfamilial pHPT were included into the study. HPT was due to a single adenoma (n = 38), parathyroid cancer (n = 1), or hyperplasia (n = 8) on conventional histopathologic analysis of the operative specimens. Parathyroid hyperplasia of the chief cell (n = 7) or water-clear cell type (n = 1) was defined as a multiglandular parathyroid enlargement. Tumor DNA was extracted from cryosections

Results

RIZ1 gene expression was identified in tumor tissue of parathyroid and adrenal medulla using the RNAse protection assay. The expected 284 nucleotide fragment, as well as the 125 nucleotide control (Actin) fragment were seen in the analyzed specimens. Also, the expected RIZ2A and RIZ2B fragments, which represents transcripts with a promoter other then RIZ1, were identified (Fig 1).

A total of 9 polymorphic microsatellite markers located at chromosome 1p36.13-p36.23, within and flanking the RIZ1

Discussion

The RIZ1 tumor suppressor gene is a strong candidate to be involved in endocrine tumors on the basis of (1) its localization to chromosome 1p36, which is the most commonly deleted region in such neoplasias²²; (2) its high expression in neuroendocrine cells,¹⁷ including parathyroid and adrenal medulla as shown in this study; (3) its putative role in the Rb pathway,¹³ often targeted by inactivation in endocrine tumors¹²; and (4) its interaction with nuclear hormone receptors and involvement in

Acknowledgements

The colleagues at the Endocrine Surgery Unit, Department of Surgery, Uppsala University Hospital, are acknowledged for excellent patient care and help in preserving tumor specimens.

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Molecular pathogenesis of parathyroid tumours
2018, Best Practice and Research: Clinical Endocrinology and Metabolism
Citation Excerpt :
Finally, the tumor suppressor gene, PR/SET domain 2 (PRDM2/RIZ1), encoding a zinc finger protein that acts as a H3K9 lysine-methyltransferase. It has a molecular partners both the PRC2 and the EZH2 proteins and was found hypermethylated in the 36% of parathyroid tumours with a corresponding loss PRDM2/RIZ1 protein expression of [118]. Several miRNAs were reported as associated or involved at major/lesser extent in parathyroid tumorigenesis (for a detailed review see [119]).
Parathyroid tumors represent an elusive endocrine neoplasia, which lead to primary hyperparathyroidism, pHPT, a common endocrine calcium disorder characterized by hypercalcemia and normal-high parathormone secretion. Parathyroid tumours are benign adenomas or multiple glands hyperplasia in the vast majority (>99% of cases), while malignant neoplasms are rare (less than 1%). Despite pHPT is a common disorder, our knowledge about the genetic predisposition and molecular pathophysiology is limited to the familial syndromic forms of parathyroid tumour, that, however, represent not more than the 10% of all the cases; instead, the pathophysiology of sporadic forms remains an open field, although data about epigenetic mechanisms or private genes have been supposed.
Here we present an overview of more recent acquisitions about the genetic causes along with their molecular mechanisms of benign, but also, malignant parathyroid tumours either in sporadic and familial presentation.
Alterations of DNA methylation in parathyroid tumors
2018, Molecular and Cellular Endocrinology
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While it is upregulated in stem cells, PRDM2 is downregulated in prolactin-secreting adenomas (Gao et al., 2015). Similarly, 36% parathyroid tumors were characterized by promoter hypermethylation of PRDM2/RIZ1 and RIZ1 locus loss of heterozygosity (Carling et al., 2003); indeed, reduced PRDM2/RIZ1 protein expression could not be detected in parathyroid tumors (Steele-Perkins et al., 2001). DNA methylation and chromatin changes, though just partially investigated, are heterogeneous among parathyroid tumors and show some main features:
Parathyroid tumors are common endocrine neoplasias associated with primary hyperparathyroidism, a metabolic disorder characterized by parathormone hypersecretion. Parathyroid neoplasia are frequently benign adenomas or multiple glands hyperplasia, while malignancies are rare. The epigenetic scenario in parathyroid tumors has just begun to be decoded: DNA methylation, histones and chromatin modifiers expression have been investigated so far. The main findings suggest that DNA methylation and chromatin remodeling are active and deregulated in parathyroid tumors, cooperating with genetic alterations to drive the tumor phenotype: the tumor suppressors menin and parafibromin, involved in parathyroid tumorigenesis, interact with chromatin modifiers, defining distinct epigenetic derangements. Many epigenetic alterations identified in parathyroid tumors are common to those in human cancers; moreover, some aspects of the epigenetic profile resemble epigenetic features of embryonic stem cells. Epigenetic profile may contribute to define the heterogeneity of parathyroid tumors and to provide targets for new therapeutic approaches.
Epigenetic processes in sporadic parathyroid neoplasms
2018, Molecular and Cellular Endocrinology
Citation Excerpt :
Another previously described hypermethylated promoter gene is the tumor suppressor Rb-Interacting Zinc finger 1 (RIZ1) gene, reported in 40% of PTs, and significantly associated with loss of heterozygosity of the RIZ1 gene. The association between hypermethylation and loss of heterozygosity of RIZ1 gene is consistent with the Knudson 2-hit hypothesis related to the inactivation of tumor suppressor gene during carcinogenesis (Carling et al., 2003). This gene is described as a posttranscriptional regulator during neuronal differentiation and pathogenesis of retinoblastoma and is usually silenced in human cancers.
Parathyroid tumors (PTs) are highly variable in their genetic background. Increasing evidence demonstrates that endocrine diseases can be caused by epigenetic alterations. The present review is focused on epigenetic aberrations related to PTs. DNA methylation, posttranslational histone modification, and noncoding RNAs are epigenetic mechanisms involved in parathyroid tumorigenesis. The information in this review has the potential to define epigenetic signatures associated with PTs for future use as diagnostic markers and lead to the development of new epigenetic drugs with therapeutic applications for these tumors. However, several epigenetic aspects regarding the biomarkers involved and their interactions in tumorigenesis on PTs are still unknown. Key to future epigenetic research would be a focus on global epigenetic identification of biomarkers in the different types of PTs, especially in parathyroid carcinoma. Better understanding may be useful for diagnostic and therapeutic uncertainty.
Hyperparathyroidism
2018, Genetics of Bone Biology and Skeletal Disease: Second Edition
Hyperparathyroidism is a common disorder characterized by excessive secretion of parathyroid hormone (PTH) and resultant hypercalcemia. Primary hyperparathyroidism typically occurs in the setting of hypercellular growth of one or more parathyroid glands, associated with dysregulation of PTH release. Rarely, ectopic secretion of PTH by a nonparathyroid tumor has been described. Primary hyperparathyroidism may occur in the context of the inherited familial syndromes multiple endocrine neoplasia types 1, 2, and 4 (MEN 1, 2, and 4); the hereditary hyperparathyroidism–jaw tumor syndrome (HPT-JT); familial hypocalciuric hypercalcemia (FHH); and neonatal severe hyperparathyroidism (NSHPT), and, when it is the only recurrent clinical manifestation of disease within a family, familial isolated hyperparathyroidism (FIHPT). Most commonly, parathyroid neoplasia is sporadic and caused by a single benign adenoma. Insights into the molecular pathogenesis of both familial and sporadic primary hyperparathyroidism will be covered in this chapter.
RIZ1 is regulated by estrogen and suppresses tumor progression in endometrial cancer
2017, Biochemical and Biophysical Research Communications
Citation Excerpt :
Their studies in prostate cancer demonstrated that RIZ1 expression was lost in poorly differentiated ones. The disappearance of the PR-domain-containing RIZ1 gene product, has already been described in many tumors because genetic alterations such as gene mutations [12,24,25], allelic loss [24,26] and promoter hypermethylation [8]. [27] As discussed in a recent study, that frameshift mutations in the two coding polyadenosine tracks of RIZ gene were found in sporadic cancers with microsatellite instability positive (MSI+) such as 48% (19/40) of gastric carcinomas, 33% (6/18) of endometrial carcinomas and 26% (14/51) of colorectal carcinomas [19].
Endometrial cancer (EC) is the estrogen-dependent gynecologic malignancy, however the molecular mechanism involved in the development and progression of EC remain unclear. The aim of this study was to investigate the role of RIZ1 in EC. Immunohistochemical analysis revealed that RIZ1was decreased in EC than in normal endometrium. Lower RIZ1 level was correlated with high-grade carcinoma (p = 0.048) and positive expression of ERα (p = 0.004). In EC cells, estrogen could down regulated the expression of RIZ1, however, ICI182,780 could up regulated the expression of RIZ1. Besides, in vitro and in vivo, RIZ1 could remarkably suppress tumor proliferation, metastasis and invasion. Our data support that RIZ1 was a novel tumor suppressor and could provide a potential therapeutic target in human EC.
Regulation of Calcium Homeostasis and Genetic Disorders that Affect Calcium Metabolism
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^☆

Presented at the 24th Annual Meeting of the American Association of Endocrine Surgeons, San Diego, California, May 11-14, 2003.

Supported by the Swedish Society of Medical Research, the Fredrik and Ingrid Thuring Foundation, the Swedish Medical Research Council, the Wennergren Foundation, NIH grant R01-CA76146, grants from the Tobacco Related Disease Research Program (TRDRP-7RT0026), and the Cancer Research Program of California (CCRP-1I0023).

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Intragenic allelic loss and promoter hypermethylation of the RIZ1 tumor suppressor gene in parathyroid tumors and pheochromocytomas☆

Abstract

Background

Material

Results

Conclusion

Section snippets

Subjects and tumor samples

Results

Discussion

Acknowledgements

Trends Endocrinol & Metab

Surgery

Am J Kidney Dis

Genomics

Genomics

HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome

Nat Genet

Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma

N Engl J Med

Genomic localization of novel candidate tumor suppressor gene loci in human parathyroid adenomas

Cancer Res

Localisation of a gene causing endocrine neoplasia to a 4 cM region on chromosome 1p35-p36

J Med Genet

Analysis of the RAD54 gene on chromosome 1p as a potential tumor-suppressor gene in parathyroid adenomas

Int J Cancer

Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas

J Med Genet

Comparative genomic hybridization reveals frequent losses of chromosomes 1p and3q in pheochromocytomas and abdominal paragangliomas, suggesting a common genetic etiology

Am J Pathol