Differential promoter methylation may be a key molecular mechanism in regulating BubR1 expression in cancer cells

The BubR1 mitotic-checkpoint protein monitors proper attachment of microtubules to kinetochores, and links regulation of chromosome-spindle attachment to mitotic-checkpoint signaling. Thus, disruption of BubR1 activity results in a loss of checkpoint control, chromosomal instability caused by a premature anaphase, and/or the early onset of tumorigenesis. The mechanisms by which deregulation and/or abnormalities of BubR1 expression operate, however, remain to be elucidated. In this study, we demonstrate that levels of BubR1 expression are significantly increased by demethylation. Bisulfite sequencing analysis revealed that the methylation status of two CpG sites in the essential BubR1 promoter appear to be associated with BubR1 expression levels. Associations of MBD2 and HDAC1 with the BubR1 promoter were significantly relieved by addition of 5-aza-2'-deoxycytidine, an irreversible DNA methyltransferase inhibitor. However, genomic DNA isolated from 31 patients with colorectal carcinomas exhibited a +84A/G polymorphic change in approximately 60% of patients, but this polymorphism had no effect on promoter activity. Our findings indicate that differential regulation of BubR1 expression is associated with changes in BubR1 promoter hypermethylation patterns, but not with promoter polymorphisms, thus providing a novel insight into the molecular regulation of BubR1 expression in human cancer cells.

A Case of Type 1 von Hippel-Lindau (VHL) Disease associated with VHL Germline Mutation / 대한내분비학회지

Von Hippel-Lindau (VHL) disease is an autosomal dominant neoplasia syndrome that result from a germline mutation in the VHL gene. Germline mutation in the VHL gene lead to the development of hemangioblastomas of the central nervous system and retina, cysts and clear cell carcinoma of the kidney, cyst adenomas of other organs, and pheochromocytoma. VHL is a tumor suppressor gene on the short arm of chromosome 3. VHL disease has been classified into two main clinical subtypes depending on the presence (type 2) or absence (type 1) of pheochromocytoma. Type 2 has been subdivided into three categories depending on the presence (type 2B) or absence (type 2A) of renal cell carcinoma, with type 2C being a rare subtype in which pheochromocytoma is the sole manifestation of VHL disease. Recently we experienced a family with VHL type 1 who carry C to T (Q73X) transition in codon 217 nonsense germline mutation in exon 1 of VHL gene. The authors report this case with literature review.

A Case Report of von Hippel-Lindau Disease Manifested in a Monozygous Twin / 대한내분비학회지

Von Hippel-Lindau (VHL) disease is an autosomal dominant disease, which forms hypervascular tumors in multiple organs, such as hemangioblastomas in the retina and central nervous system, renal cell carcinomas, pheochromocytomas and cysts in various organs. Recent advances in gene testing have made it possible to screen family members for VHL disease. We experienced a 28 year-old male, who was diagnosed with bilateral pheochromocytomas through a family screening test when his elder monozygous twin brother was diagnosed with a pheochromocytoma. He received no treatment until December, 2004, when he visited the Emergency room due to a headache. A hemangioma of the cerebellum was seen in the brain MR study, leading to the diagnosis of type 2A VHL disease. An abdominal CT scan revealed no lesions of the pancreas or kidney. There was no evidence of a hemangioma in the retinal scan. The subsequent gene testing showed a germline mutation in exon 3 codon 167 of the VHL gene. The mother of the patient was revealed to have the same mutation of the VHL gene, but the elder brother of the patient did not.

Microarray Applications in Cancer Research / Journal of the Korean Cancer Association, 대한암학회지

DNA microarray technology permits simultaneous analysis of thousands of DNA sequences for genomic research and diagnostics applications. Microarray technology represents the most recent and exciting advance in the application of hybridization-based technology for biological sciences analysis. This review focuses on the classification (oligonucleotide vs. cDNA) and application (mutation-genotyping vs. gene expression) of microarrays. Oligonucleotide microarrays can be used both in mutation-genotyping and gene expression analysis, while cDNA microarrays can only be used in gene expression analysis. We review microarray mutation analysis, including examining the use of three oligonucleotide microarrays developed in our laboratory to determine mutations in RET, beta-catenin and K-ras genes. We also discuss the use of the Affymetrix GeneChip in mutation analysis. We review microarray gene expression analysis, including the classifying of such studies into four categories: class comparison, class prediction, class discovery and identification of biomarkers.

A Case of Papillary Thyroid Carcinoma Combined with Multiple Endocrine Neoplasia Type 2A / 대한내분비학회지

Multiple endocrine neoplasia (MEN) type 2A is a syndrome of medullary thyroid carcinomas, pheochromocytomas and parathyroid hyperplasia. The simultaneous occurrence of medullary, and papillary, thyroid carcinomas is rare because they are derived from, apparently, different germ layers, the former from the neuroectoderm and the latter from the endoderm. We report a case of a papillary thyroid carcinoma, combined with a medullary thyroid carcinoma, in a patient with MEN type 2A. Molecular genetic studies for screening a RET proto-oncogene mutation revealed a point mutation in codon 631 on chromosome 10, which is reported as highly uncommon in MEN type 2A.