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Succinate Dehydrogenase B Mutations and EPAS1 Overexpression Predict Invasion and Metastasis of Pheochromocytomas or Paragangliomas

Author: DengJianHua
Tutor: LiHanZhong;JiZhiGang;MaoQuanZong
School: Beijing Union Medical College
Course: Department of Urology
Keywords: Pheochromocytoma / paraganglioma Succinate dehydrogenase B Hypoxia-inducible factor Insulin-like growth factor Tissue microarray
CLC: R736.6
Type: PhD thesis
Year: 2011
Downloads: 51
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Purpose: pheochromocytoma (PHEO) and paraganglioma (PGL) is a tumor of the adrenal medulla and ganglia of the abdomen, chest, head and neck sources. Function (secretion of catecholamines) and cases of non-functional gene mutations account for about 30%. In addition to the RET, VHL and outside NF-1 encoding succinate dehydrogenase complex subunit nuclear genes SDHB, SDHC, SDHD and SDHAF2 PHEO / PGL susceptibility genes. About 15% of PHEO / PGL patients by SDHB, SDHC and SDHD gene mutations cause hereditary pheochromocytoma / paraganglioma syndrome (HPPS) gene mutation causes related protein expression with pheochromocytoma nerve section of tumor invasion and metastasis mechanism is not clear. The purpose of this study was to explore the relationship of SDHB mutations and EPAS1 overexpression PHEO / PGL invasion and metastasis, and to identify the gene mutation EPAS1, IGF-1 and MIB-1 index as malignant lesions predict clinical significance. Materials and methods: 1. SDH, VHL and RET germline mutations in the gene analysis of 43 cases of patients with PHEO / PGL. And clinical characteristics, including gender, age, tumor site and frequently-occurring disease change line correlation analysis results. The SDHB Gene (1q36.1-1q35, outer exons 1-8), SDHC gene (1q21, outer exons 1-5), SDHD gene (11q23, exon sub 1 to 4), SDHAF2 gene (11q12.2 , exons 1-4), RET proto-oncogene (10q11.2, exons 10, 11, 13, 14 and 15 and 16), and the VHL gene (3p25.3, outside exons 1-3) directly for DNA sequence analysis, the simultaneous detection PHEO / PGL peripheral blood samples of succinate dehydrogenase in the degree of methylation of the B promoter region. 2 of 64 cases of PHEO / PGL paraffin sections of tissue specimens SDHB EPAS1, VEGF-1R, CgA and MIB-1 immunohistochemical staining. Identified as positive granular cytoplasmic staining, counting five high-power field, 200 cells / field, a total of 1,000 gt; 50% strongly positive (), 11% -50% as moderately positive (), weakly positive diffuse cytoplasmic light dye and the lack of a clear positive particles, negative comparison with known positive internal reference, no staining. 3 Previous studies have shown activation of the insulin-like growth factor I receptor (IGF-IR) can produce strong neuroprotective effects, we study IGF-Ⅰ rat pheochromocytoma PC-12 cell differentiation and proliferation ability of PC12 cells is placed in the recombinant human IGF-1 environment, to observe the regulation of IGF-1 stimulation of the proliferation and differentiation of PC12 cells and the release of catecholamines. Results: 1. Gene mutation in 17 cases (17.5%, 17/97). The most common is the RET proto-oncogene mutations (8.24%, 8/97), seven patients with SDHB gene mutation (7.2%, 7/97), two cases of VHL gene mutation (2.06%, 2/97). Or the clinical features of the mutation in two groups statistically significant difference. 2. EPAS1 negative staining in normal adrenal medulla, pheochromocytoma tumor and paraganglioma moderate positive expression in benign, highly expressed in malignant paraganglioma. 17 patients with known VHL, RET and SDHB mutations of the tumor 15 cases showed positive staining. The case of VHL disease pheochromocytoma stained weakly positive. Germline gene mutations in 46 tumor specimens, 13 cases were positive. A clinical features consistent with familial paraganglioma specimens, but no SDH gene mutations into the negative, immunohistochemistry was weak diffuse staining. In addition, correlation analysis, EPAS1 positive expression of CgA, MIB-1, VEGF-1R, and CD34 are closely related. Experimental results show that 3.IGF-1 affect the proliferation and differentiation of PC-12 cells: compared with the addition of norepinephrine (NE), recombinant human IGF-1 by activating different signaling pathways, synergistic increase in rat pheochromocytoma PC12 The efficiency of cell proliferation and growth, and associated with a given dose and duration. Conclusion: Our study shows that: (1) genetic susceptibility chromaffin tissue tumors in the higher frequency, about 7.2% of paraganglioma SDHB germline gene mutations and SDHB mutations prevalent in the retroperitoneal paraganglioma and malignant paraganglioma; (2) SDHB gene mutation causes overexpression of paraganglioma EPAS1, thus making the downstream elements of CD34, VEGF-1R, IGF and TGF activation may be malignant invasion and metastasis One of the mechanisms; (3) IGF PHEO / PGL tumor cell differentiation and proliferation of regulatory networks. However, the complex regulation involving many factors, as well as multi-step synthesis and / or degradation, still need further study.

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CLC: > Medicine, health > Oncology > Internal endocrine tumors > Adrenal tumors
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