Molecularly genetic analysis of von Hippel-Lindau associated central nervous system hemangioblastoma

Abstract

Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited cancer predisposition syndrome, characterized by development of a variety of neoplasms in multiple organs. Central nervous system hemangioblastoma (CHB) is the most common manifestation of VHL disease. The germline mutations in the VHL tumor suppressor gene are responsible for the inherited cancer predisposition syndrome. To expand the VHL mutation data and to investigate the tumorigenesis of VHL-associated CNS hemangioblastoma, 24 CHB tissue samples and blood samples of 14 patients from 10 Chinese VHL families were collected and subjected to molecular genetic analysis. Six distinctive germline mutations were identified, and the 601 G to C (Val130Phe) mutation is reported for the first time. Somatic mutations analysis of the VHL gene in VHL-associated CHB showed that loss of heterozygosity (LOH) occurred in more than half of the cases. In addition, expression of the ZAC1 tumor suppressor gene protein was studied using immunohistochemistry staining in CHB tissues with a specific polyclonal antibody. The ZAC1 protein was lost in all CHB. Our data exhibited high frequency of LOH of ZAC1 gene in VHL-associated CHB, indicating that ZAC1 may have a role in tumorigenesis of VHL-associated CHB.

Germline mutations of the VHL gene in seven Chinese families with von Hippel-Lindau disease

“…These mutations occurred in four or more VHL families, and the occurrence rate of common mutations is estimated to be nearly 10% in the Western population (20,21). Although we did not identify any common mutations in our study, these mutations have been reported by others studying Chinese patients (6,8,9). China is geographically vast, and as such it is expected to present different mutation spectrums in different areas.…”

“…Another manuscript by Zhang et al (6) described 26 germline mutations identified in 27 probands. Mao et al (7) reported VHL genetic findings in three other Chinese families, while Zhou et al (8) reported their findings of six distinctive germline mutations from ten Chinese families with VHL-associated CNS hemangioblastoma. Finally, Siu et al (9) found nine different mutations in nine other Chinese VHL families.…”

“…Finally, Siu et al (9) found nine different mutations in nine other Chinese VHL families. The detection rate reported in China varies from 66-97% (6)(7)(8)(9), and the so-called 'mutation hotspot' that has been identified in other ethnicities has yet to be defined in the Chinese. It is important to remember that China is geographically vast and is composed of many different districts that are characterized by distinct and long histories of genetic evolution.…”

Family history of von Hippel–Lindau disease was uncommon in Chinese patients: suggesting the higher frequency of de novo mutations in VHL gene in these patients

“…17,20,[22][23][24][25] There were totally 70 families that were clinically diagnosed as VHL disease and had the data of VHL mutations ( Table 3). The spectrum of VHL mutations in Chinese patients is comparable to the findings of large scale investigations from other countries, 11,21 but with some unique characteristics ( Table 3).…”

Expression of Endoplasmic Reticulum Stress Related Genes in Blood Cells of Obese Boys with and without Insulin Resistance

“…It is interesting to note that degradome products of this matricellular protein may modulate the pathological angiogenesis in the retina [20]. The PLAGL1 (pleiomorphic adenoma gene-like 1) gene encodes a C2H2 zinc finger protein, which is a transcriptional regulator with anti-proliferative properties [21,22].…”