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.

Hereditary Colorectal Cancer / 대한소화기학회지

Hereditary syndromes cause approximately 5 to 15% of overall colorectal cancer (CRC) cases. Hereditary CRC is conventionally divided into two major categories: hereditary non-polyposis colorectal cancer (HNPCC) and those related to polyposis syndromes including familial adenomatous polyposis (FAP), Peutz-Jegher syndrome (PJS), and juvenile polyposis (JP). The screening for the cancer and methods of treatment applied to patients with hereditary CRC are quite different from those applied to the general population. The genes responsible for these syndromes has recently identified, as a result, genetic testing has become the most important determining factor in clinical decisions. Germ-line mutation of the APC gene induces FAP, an autosomal dominant disorder, characterized by the development of hundreds to thousands of colonic adenomas. CRC appears in almost all affected individuals by the time they are 50 years of age. An affected individual should undergo colectomy by his/her late teens. Furthermore, according to the findings of genetic testing, at-risk family members also need endoscopic surveillance and surgery. Recently, a mutation on the MYH gene is increasingly being investigated in patients with multiple polyps, and autosomal recessive MYH polyposis is considered to be a new category of polyposis. More common than FAP, HNPCC is caused by germ-line mutations in DNA mismatch repair genes, mainly MLH1 and MSH2. Although there is no polyposis, polyps seem to be more villous and dysplastic and appear to grow rapidly into CRCs. The aggregate lifetime risk of CRC is about 80% for mutation carriers. The risk for other types of cancer, such as endometrial, ovarian, small bowel, and transitional cell cancer, is also increased. The Amsterdam criteria and Bethesda guidelines are the best-known tools for diagnosis and genetic testing, and colectomy followed by endoscopic follow-up is the standard treatment. PJS and JP are reported to be characterized by hamartomatous polyps throughout the GI tract and germ-line mutations in the STK11 gene (PJS) and the DPC4/BMPR1A gene (JP).

A Case of Multiple Endocrine Neoplasia Associated with VIPoma / 대한내분비학회지

Multiple endocrine neoplasia I(MEN I) is a genetic disorder that consists of neoplasia of neuroendocrine type in the parathyroid glands, in the islets of Langerhans in the pancreas, and in the anterior pituitary gland. Primary hyperparathyroidism is the most common feature and occurs in approximately 95% of MEN I patients. Pancreatic islet cell tumors occur in 40% of MEN I patients. Most of these tumors produce excessive amounts of hormones, such as gastrin, insulin, glucagon and vasoactive intestinal polypeptide(VIP). VIP-producing pancreatic tumors(VIPoma) associated with MEN I are rare and so far only one has been reported in Korea. Recently, we came across a case of MEN I, associated VIPoma presented persistent hypercalcemia after a parathyroidectomy. A 70 year old man had suffered from large amount of watery diarrhea, severe general weakness and paralysis of lower limbs for 3 months which suggests symptoms of hypercalcemia. Before the patient visited our hospital, he underwent subtotal parathyroidectomy due to hyperparathyroidism. Even though he was operation, there was no subsidization of the symptoms and abnormal findings of blood chemistry such as hypercalcemia, hypocalemia were remained unchanged. However, the parathyroid hormone level was still within normal limits. Abdominal computerized tomography scan demonstrated a mass of 2.5cm diameter in tail of the pancreas. As serum level of VIP hormone was also elevated, distal pancreatectomy was carried out to performed. There was improvement in the symptoms towards the normal condition and the level of biochemical parameters such as serum potassium, calcium and VIP, were also within the normal limits. In a direct sequence analysis, GAC-->CAT(Asp-->His) point mutation, at codon 383 of exon 9 of the MEN I gene was identified in both the patient and his son. The authors report a rare case of VIPoma associated with MEN I with review of literature on MEN I.

A Case of Multiple Endocrine Neoplasia Type 1 with Mutation in MENIN Gene / 대한내분비학회지

Multiple endocrine neoplasia type 1(MEN 1) is an autosomal dominantly inherited syndrome, characterized by the combined occurrence of tumors of the parathyroid glands, endocrine pancreas, and anterior pituitary gland. The MENIN gene, which is a kind of tumor suppressor gene, is located at the chromosomal locus 11q13. It consists of one untranslated exon and nine exons encoding the menin protein. We report a case of a 22-yearss-old woman with MEN type 1, who was proven to have a mutation in the MENIN gene. The patient was admitted because of repeated hypoglycemia. The fasting plasma glucose level was 32mg/dL. Seventy two hours fasting test showed an the insulin/glucose ratio as 0.33. Endoscopic ultrasonography detected multiple masses on the pancreas. The arterial -stimulated venous sampling(ASVS) with calcium showed sudden step up of insulin at the head and tail portions of the pancreas. The sellar MRI showed a pituitary mass that produced prolactin. Instead of a pathologic diagnosis from operational specimen, the genetic analysis revealed a mutation in the MENIN 1 gene(exon 2, 200~201insAGCCC).

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.