Intragenic allelic loss and promoter hypermethylation of the RIZ1 tumor suppressor gene in parathyroid tumors and pheochromocytomas☆
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 MetabolismCitation 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]).
Alterations of DNA methylation in parathyroid tumors
2018, Molecular and Cellular EndocrinologyCitation Excerpt :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:
Epigenetic processes in sporadic parathyroid neoplasms
2018, Molecular and Cellular EndocrinologyCitation 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.
Hyperparathyroidism
2018, Genetics of Bone Biology and Skeletal Disease: Second EditionRIZ1 is regulated by estrogen and suppresses tumor progression in endometrial cancer
2017, Biochemical and Biophysical Research CommunicationsCitation 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].
Regulation of Calcium Homeostasis and Genetic Disorders that Affect Calcium Metabolism
2015, Endocrinology: Adult and Pediatric
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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).