The B-type Raf kinase (BRAF) protein is a serine/threonine kinase that has an important role in cellular proliferation, differentiation, and programmed cell death. The BRAF gene has been recently found to be mutated in human carcinomas, predominantly in malignant melanoma. The aim of this study was to investigate the frequency of the BRAF mutation in papillary thyroid carcinoma (PTC) of Koreans through direct DNA sequencing of the polymerase chain reaction (PCR)- amplified exon 15 with clinicopathological features. Seventy paraffin-embedded conventional papillary carcinomas in the thyroid gland were evaluated. The BRAF missense mutation at V599E was found in 58 of 70 PTCs (83%). The frequency of our series was much higher than the frequencies of other PTC series (36 - 69%). The frequency of nodal metastasis was also significantly higher in the BRAF mutation group (p= 0.048). These results suggest that the BRAF mutation is involved in the carcinogenesis in most conventional PTCs, especially those occurring in Koreans, and this is a potentially valuable marker for the evaluation of prognosis of patients with PTC. These findings support the specific inhibitors of BRAF being promising targets for the disease outcome.

Seven hundred forty seven cases of gastrointestinal stromal tumors (GISTs) in Koreans who were diagnosed between 2001 and 2002 were analyzed to evaluate their occurrence and their clinical, pathologic and immunohistochemical findings. The most frequent location of tumor was in the stomach (63%), followed by the small intestine (30%), the colorectum (5%), and the esophagus (2%). c-kit expression was found in 93.6% of the cases, while CD34, SMA and S-100 protein was positive in 80.1%, 28.2%, and 20.2%, respectively. c-kit positivity was high in the stomach (94.2%) and small intestine (94.6%), while it was relatively low in the colorectum (85.0%), and esophagus (81.2%). The positivity for CD34 was correlated with the higher risk of GISTs (p=0.04). Follow up of the patients showed that 58 primary GISTs patients died and 20 of these patients were recurrent or metastatic at the time of diagnosis. The pathologic diagnosis to predict the risk of aggressive behavior of GISTs was correlated with the numbers of tumor, clinical stage, epithelioid histologic type, cellularity, cellular atypia, necrosis, and mucosal invasion (p=0.00). GISTs with a poor prognosis were closely related to the clinical stage at presentation, the locations of the tumor, and the ages of the patients.

Gastrointestinal stromal tumor is characterized by a gain of function mutation of KIT gene and the expression of c-kit protein, but in 5% of cases, c-kit expression is negative although histological findings of gastrointestinal stromal tumor are most suspicious. The existence of c-kit-negative gastrointestinal stromal tumors points to the need of additional markers for making the diagnosis. In this study, we studied the expression of PKCh and correlated their expression with other immunohistochemical profiles of gastrointestinal stromal tumors and evaluated their usability as a diagnostic marker. For this purpose, 220 gastrointestinal stromal tumors were immunohistochemically stained for PKCh, c-kit, CD34, a-smooth muscle actin and S-100 protein. Additionally, genetic studies of KIT and PDGFRA genes were performed using c-kit-negative or PKCh-negative cases. All the 220 masses were either PKCh-positive or c-kit-positive. PKCh was positive in 212 (96%) cases and c-kit was positive in 216 (98%) cases in the cytoplasm of tumor cells with a diffuse staining pattern. Out of 212 PKChpositive GISTs, 208 (98%) cases were c-kit-positive, 174 (82%) cases were CD34-positive, 62 (29%) cases were SMA-positive and S-100 protein was positive in 54 cases (26%). Genetic analyses on eight PKCh-negative cases showed exon 11 mutations of KIT gene in four cases. Two PKCh-positive and c-kit-negative GISTs showed mutations of PDGFRA gene. Our study shows that PKCh is a useful marker and it may play a role in the development of gastrointestinal stromal tumors. Together with c-kit, PKCh immunostaining can be used as an important diagnostic tool in the pathologic diagnosis of gastrointestinal stromal tumors with its high specificity and sensitivity.

Colorectal cancer (CRC), which was the fourth most common cancer in Korea at the time, is now the second most common cancer in Korea. Meanwhile, there have been many changes in the pathologic diagnosis of CRC, such as the diagnostic criteria for carcinoma, and pathologic findings included in the pathology report [1,2]. Molecular pathology tests for CRC have also become necessary tests, as targeted therapy and immunotherapy were introduced into the treatment of CRC. The existing standardization report does not reflect the recent changes in colon cancer diagnosis. There has been considerable demand for the revision of the

A transgenic mouse line that expresses iCre under regulation of the Cytochrome P 450 17α-hydroxylase/17, 20-lyase (Cyp17) promoter was developed as a novel transgenic mouse model for the conditional deletion of genes specifically in the theca/interstitial cells of the ovary and Leydig cells of the testis. In this report we describe the development of Cyp17iCre mice and the application of these mice for conditional deletion of the estrogen receptor alpha (Esr1) gene in the theca/ interstitial and Leydig cells of the female and male gonad, respectively. These mice will prove a powerful tool to inactivate genes in the gonad in a cell-specific manner.Targeted gene deletion has become a powerful tool in the study of gene function with the utilization of this technology leading to marked progress in our understanding of both physiological and pathophysiological systems. The ovary is one organ where targeted genetic deletion has proven fruitful with the establishment of transgenic mice with Cre expression targeted to granulosa cells (Lécureuil et al., 2002), somatic cells (Bingham et al., 2006) and the oocyte (Lan et al., 2004;Lewandoski et al., 1997). However, our understanding of ovarian function cannot advance at optimal pace without a tool to specifically delete genes of interest from the other major endocrine cell population of the ovary, the theca/interstitial cells. Hence, our primary goal was to develop the mice necessary to allow the specific deletion of genes in the theca/interstitial cells of the ovary and in this report we describe the generation of such a line of transgenic mice, with codon-improved Cre (iCre) driven by the promoter to Cytochrome P 450 17α-hydroxylase/17, 20-lyase (Cyp17).Cytochrome P 450 17α-hydroxylase/17, 20-lyase, the product of Cyp17 gene expression, plays a major role in the control of sex steroid hormone synthesis by mediating the17α-hydroxylation of pregnenolone or progesterone to dehydroepiandrostenedione or androstenedione, respectively. In the female mouse, Cyp17 expression is primarily restricted to the ovary and placenta (Su et al., 2002) and within the ovary, Cyp17 is abundant in the gonadotropin-primed theca/interstitial cell population, but not the granulosa cells or oocyte (Zhang et al., 2001), making it ideal for iCre targeting. Furthermore, coincident to the need of a transgenic mouse line with iCre targeted to the theca/interstitial cells, is one also designed to allow the deletion of Leydig cell specific genes from the male gonad. Fortunately, the specificity of Cyp17 expression to the Leydig cells of the testis (Zhang et al., 2001) makes this line of mice also ideal as a tool to inactive genes specifically within that endocrine population of cells. Hence, this report was widened as a functional characterization of these mice inclusive to both the sexes.Three lines of Cyp17iCre founder mice were generated (A, B and C) by pronuclear injection of a KpnI/SalI DNA fragment derived from a Cyp17iCre expression plasmid (Figure 1). Then, to facilitate expression analys...