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Jae-Gahb Park

Publications and source records attributed to Jae-Gahb Park.

At least 19 recordsLinked to original sources
PubMed2007

Correlation between hypermethylation of the RASSF2A promoter and K-ras/BRAF mutations in microsatellite-stable colorectal cancers.

Recently, RASSF2A was identified as a potential tumor suppressor epigenetically inactivated in human cancers. Here, we evaluated the methylation status of RASSF2A in colorectal cancer (CRC) and analyzed its correlation with K-ras/BRAF mutations, microsatellite instability status and other clinicopathological features. Using methylation-specific PCR and bisulfite sequencing, we analyzed the methylation status in primary CRC, adenomas and corresponding normal tissues and then compared it with the presence of K-ras and BRAF mutations. We also examined the expression and methylation status of RASSF2A in CRC cell lines. We found that aberrant methylation of RASSF2A promoter regions is associated with gene silencing in CRC cell lines. In primary CRC, the frequency of RASSF2A methylation was 72.6%, and it was found in 16 of 16 (100%) adenomas. In addition, there was a positive correlation between K-ras/BRAF mutations and RASSF2A methylation in primary CRC. Furthermore, a significant positive correlation between K-ras/BRAF mutations and RASSF2A methylation was also observed in microsatellite-stable (p = 0.033) and distal CRC (p = 0.025). These results show that RASSF2A methylation is a frequent event in colorectal tumorigenesis and positively correlates with K-ras/BRAF mutation in microsatellite-stable or distal CRC.

Adenoma↗
PubMed2007

Job loss and reemployment after a cancer diagnosis in Koreans - a prospective cohort study.

Patients undergoing treatment for cancer have reported a variety of work-related problems. The aim of this study was to investigate the impact of a cancer diagnosis on employment status, and to identify relevant associated factors. This prospective cohort study was conducted at the National Cancer Center in Korea. Male patients newly diagnosed with stomach, liver, or colorectal cancers were recruited. Patients were interviewed and asked to complete an employment questionnaire every 3 months for 24 months. Clinical, sociodemographic and work-related factors were assessed. There were 305 male patients who had a primary diagnosis of cancer and underwent appropriate treatment. Of the 305 male patients who were employed at the time of diagnosis, 53% lost their job, and of these 23% later reemployed. In a multivariate Cox regression analysis, job loss was significantly associated with years of education, job characteristics and disease stage. Reemployment was significantly associated with disease stage and cancer site. Change of employment was common among cancer patients in Korea. With an understanding of the factors involved, it should be possible to reduce unnecessary work cessation, and increase the rate of employment of cancer survivors.

Asian People↗
PubMed2006

Establishment and characterization of cell lines from three human thyroid carcinomas: responses to all-trans-retinoic acid and mutations in the BRAF gene.

We report the characteristics of three cell lines (designated, SNU-80, SNU-373 and SNU-790), which were established from two papillary carcinomas and one anaplastic carcinoma obtained from three Korean thyroid carcinoma patients. All cell lines grow as adherent cells. Electron microscopy characteristically showed cytoplasmic invaginations of nuclei and intranuclear cytoplasmic inclusions. SNU-80 and SNU-790 cells showed a positive reaction to anti-cytokeratin antibody, and SNU-790 cells positivity for CK-19. All lines were free of mycoplasma or bacteria and were proven unique by DNA fingerprinting analysis. The p15 and p16 genes are deleted in the SNU-790 line. Mutations of the p53 gene were found in two lines (SNU-80 and SNU-373), but no mutations in the RET or MEN1 genes were observed. Mutations of the BRAF gene were found in the SNU-80 (G468R) and the SNU-790 (V599E) cell lines, but no mutations in the K-ras gene were present. SNU-80 and SNU-790 cells showed a positive reaction to anti-cytokeratin antibody, and no evidence of the production of thyroglobulin or calcitonin was observed. The cell lines were unable to trap radioactive iodine but did not contain TSH receptor. In addition, we investigated the mRNA expression levels of Tg, TSHR, TTF-1, PAX-8, NIS, IL-6, and LIF, and of the alpha, beta and gamma retinoic acid receptors in these cell lines. IL-6 was down-regulated in all three cell lines by all-trans-retinoic acid treatment. RAR-alpha was expressed but RAR-beta was not expressed in the three cell lines, and RAR-gamma was not expressed in SNU-790. Interestingly, RAR-beta (SNU-80 and SNU-373) and RAR-gamma (SNU-790) was up-regulated by all-trans-retinoic acid treatment. We believe that these well-characterized thyroid carcinoma cell lines may be useful tools for investigations on the biological characteristics of thyroid carcinoma, particularly for investigations related to gene alterations, especially of the BRAF gene. These cell lines may also be useful for redifferentiation therapy studies on thyroid carcinoma using all-trans-retinoic acid.

Antineoplastic Agents↗
PubMed2006

Comparison of 5-fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer.

PURPOSE: To describe our experience with a bolus injection of 5-fluorouracil and leucovorin (FL) vs. capecitabine in terms of radiologic and pathologic findings in preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. METHODS: The study enrolled 278 patients scheduled for preoperative CRT using two protocols with different chemotherapeutic regimens. Pelvic radiotherapy (50.4 Gy) was delivered concurrently with FL (n = 145) or capecitabine (n = 133). Surgery was performed 6 weeks after CRT completion. Tumor responses to CRT were measured using both radiologic and pathologic examination. Magnetic resonance volumetry was performed at the initial workup and just before surgery after completion of preoperative CRT. Post-CRT pathology tests were used to determine tumor stage and regression. RESULTS: Radiologic examination showed that tumor volume decreased by 68.2% +/- 20.5% in the FL group and 68.3% +/- 22.3% in the capecitabine group (p = 0.970). Postoperative pathologic T stage determination showed that downstaging occurred in 44.3% of FL and 49.9% of capecitabine patients (p = 0.571). The tumor regression grades after CRT were Grade 1 (minimal response) in 22.6% and 21.0%, Grade 2 (moderate response) in 53.2% and 50.0%, Grade 3 (near-complete response) in 12.9% and 12.9%, and Grade 4 (complete response) in 11.3% and 16.1% of the FL and capecitabine groups, respectively (p = 0.758). CONCLUSION: In the present study, the radiologic and pathologic findings did not reveal significant differences in short-term tumor responses between preoperative FL and capecitabine CRT for locally advanced rectal cancer. Long-term results and a prospective randomized trial are needed.

Adult↗
PubMed2006

Analysis of microsatellite instability in stool DNA of patients with colorectal cancer using denaturing high performance liquid chromatography.

AIM: To evaluate the usefulness of denaturing high performance liquid chromatography (DHPLC) for analyzing microsatellite instability (MSI) status in stool DNA of patients with colorectal cancer. METHODS: A total of 80 cancer tissues from patients with primary sporadic colorectal tumor (proximal cancer: 27, distal cancer: 53) and matched stool (which were employed for comparison with the tissues) were analyzed for MSI status in BAT 26. DNA samples extracted from stool were evaluated by nested polymerase chain reaction (PCR) and DHPLC for MSI analysis. RESULTS: Six cases (7.5%) of MSI were identified in BAT 26 from 80 cancer tissues. All the stool DNA samples from patients whose cancer tissue showed MSI also displayed MSI in BAT 26. CONCLUSION: As MSI is one of the established fecal DNA markers to screen colorectal cancer, we propose to use DHPLC for the MSI analysis in fecal DNA.

Biomarkers, Tumor↗
PubMed2006

Promoter hypomethylation and reactivation of MAGE-A1 and MAGE-A3 genes in colorectal cancer cell lines and cancer tissues.

AIM: To verify the expression and methylation status of the MAGE-A1 and MAGE-A3 genes in colorectal cancer tissues and cancer cell lines. METHODS: We evaluated promoter demethylation status of the MAGE-A1 and MAGE-A3 genes by RT-PCR analysis and methylation-specific PCR (MS-PCR), as well as sequencing analysis, after sodium bisulfite modification in 32 colorectal cancer cell lines and 87 cancer tissues. RESULTS: Of the 32 cell lines, MAGE-A1 and MAGE-A3 expressions were observed in 59% and 66%, respectively. Subsequent to sodium bisulfite modification and MS-PCR analysis, the promoter hypomethylation of MAGE-A1 and MAGE-A3 was confirmed in both at 81% each. Promoter hypomethylation of MAGE-A1 and MAGE-A3 in colorectal cancer tissues was observed in 43% and 77%, respectively. Hypomethylation of MAGE-A1 and MAGE-A3 genes in corresponding normal tissues were observed in 2% and 6%, respectively. CONCLUSION: The promoter hypomethylation of MAGE genes up-regulates its expression in colorectal carcinomas as well as in gastric cancers and might play a significant role in the development and progression of human colorectal carcinomas.

Antigens, Neoplasm↗
PubMed2006

Genetic alterations of the TGF-beta signaling pathway in colorectal cancer cell lines: a novel mutation in Smad3 associated with the inactivation of TGF-beta-induced transcriptional activation.

To investigate genetic alterations involved in the TGF-beta signaling pathway in colorectal cancer, we assayed DNA synthesis rates after treating TGF-beta and checked for genetic alterations in TGF-betaRII, TGF-betaRI, Smad2, Smad3, and Smad4 in 12 colorectal cancer cell lines. Eleven lines, except SNU-61, show no significant change in DNA synthesis rate after TGF-beta treatment. In these 11 lines, several mutations were found in genes involved in the TGF-beta signaling pathway: (i) frameshift deletions in the poly(A)(10) tract of the TGF-betaRII gene in SNU-407, SNU-769A, SNU-769B, and SNU-1047 cell lines, (ii) a missense mutation of Smad2 (R321Q) in SNU-81, (iii) two missense mutations in TGF-betaRI (R487W in SNU-175 and A202V in SNU-1040), and (iv) a monoallelic loss at the Smad4 locus in three cell lines. Interestingly, a missense mutation (R373H) in Smad3 gene was found in SNU-769A. To our knowledge, this is the first report of Smad3 mutation in human malignancy. This mutation was found to result in the inhibition of translocation of Smad3 protein to the nucleus and a reduction in the activity of Smad3 during TGF-beta-induced transcriptional activation. These results indicate that the majority of cell lines, which are insensitive to TGF-beta, have alterations in genes involved in the TGF-beta signaling pathway in colorectal cancer cell lines.

Base Sequence↗
PubMed2006

Novel polymorphisms in the SUV39H2 histone methyltransferase and the risk of lung cancer.

Histone H3 lysine 9 (H3-K9) methylation and DNA methylation are important features of mammalian heterochromatin. Suppressor of variegation 3-9 homolog 2 (SUV39H2) is the histone methyltransferase that is required to methylate H3-K9, leading to transcriptional repression or silencing of target genes. In this study, we investigated the association of SUV39H2 polymorphisms and the risk of lung cancer. From the results of PCR direct sequencing, eight single nucleotide polymorphisms (SNPs) of SUV39H2 were identified in Korean population. In a hospital-based study of 346 lung cancer patients and 423 healthy controls, a novel SNP in the 3'-UTR of SUV39H2 (1624 G-->C) was associated with a statistically significant increase in lung cancer risk. Compared to the G/G genotype, genotypes with 1624C allele (G/C + C/C) significantly increased the susceptibility to lung cancer with adjusted odds ratio (AOR) of 2.63 (95% confidence interval (CI)= 1.10-6.29) for ever-smokers, especially in the older age group (age >or=55 years). Specifically, the variant genotype of 1624SNP was significantly associated with an increased risk of squamous cell carcinoma (AOR, 3.52; 95% CI = 1.13-9.45) in the older age group, while no significant association was found in patients with other histology. This study provided the first evidence that a novel SUV39H2 polymorphism may be an important predictive marker for lung cancer susceptibility for the smokers.

3' Untranslated Regions↗
PubMed2006

Germ line mutations of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients with small bowel cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study.

PURPOSE: The aim of study was to determine the clinical characteristics and mutational profiles of the mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients with small bowel cancer (SBC). EXPERIMENTAL DESIGN: A questionnaire was mailed to 55 members of the International Society for Gastrointestinal Hereditary Tumours, requesting information regarding patients with HNPCC-associated SBC and germ line mismatch repair gene mutations. RESULTS: The study population consisted of 85 HNPCC patients with identified mismatch repair gene mutations and SBCs. SBC was the first HNPCC-associated malignancy in 14 of 41 (34.1%) patients for whom a personal history of HNPCC-associated cancers was available. The study population harbored 69 different germ line mismatch repair gene mutations, including 31 mutations in MLH1, 34 in MSH2, 3 in MSH6, and 1 in PMS2. We compared the distribution of the mismatch repair mutations in our study population with that in a control group, including all pathogenic mismatch repair mutations of the International Society for Gastrointestinal Hereditary Tumours database (excluding those in our study population). In patients with MSH2 mutations, patients with HNPCC-associated SBCs had fewer mutations in the MutL homologue interaction domain (2.9% versus 19.9%, P = 0.019) but an increased frequency of mutations in codons 626 to 733, a domain that has not previously been associated with a known function, versus the control group (26.5% versus 2.8%, P < 0.001). CONCLUSIONS: In HNPCC patients, SBC can be the first and only cancer and may develop as soon as the early teens. The distribution of MSH2 mutations found in patients with HNPCC-associated SBCs significantly differed from that found in the control group (P < 0.001).

Adaptor Proteins, Signal Transducing↗
PubMed2006

Gastric cancer patients at high-risk of having synchronous cancer.

AIM: To identify patients with a high-risk of having a synchronous cancer among gastric cancer patients. METHODS: We retrospectively analyzed the prospective gastric cancer database at the National Cancer Center, Korea from December 2000 to December 2004. The clinicopathological characteristics of patients with synchronous cancers and those of patients without synchronous cancers were compared. Multivariate analysis was performed to identify the risk factors for the presence of a synchronous cancer in gastric cancer patients. RESULTS: 111 of 3291 gastric cancer patients (3.4%) registered in the database had a synchronous cancer. Among these 111 patients, 109 had a single synchronous cancer and 2 patients had two synchronous cancers. The most common form of synchronous cancer was colorectal cancer (42 patients, 37.2%) followed by lung cancer (21 patients, 18.6%). Multivariate analyses revealed that elderly patients with differentiated early gastric cancer have a higher probability of a synchronous cancer. CONCLUSION: Synchronous cancers in gastric cancer patients are not infrequent. The physicians should try to find synchronous cancers in gastric cancer patients, especially in the elderly with a differentiated early gastric cancer.

Adult↗
PubMed2006

Regulation of MDK expression in human cancer cells modulates sensitivities to various anticancer drugs: MDK overexpression confers to a multi-drug resistance.

MDK is a heparin-binding growth factor associated with cancer development. Here, we sought to examine the association of MDK expression with resistance and sensitivity to different chemotherapeutic agents. We established stable HeLa cell transfectants (HeLa-MDK) and tested for decreased sensitivity to chemotherapeutic agents (5-FU, doxorubicin, and cisplatin). In addition, we used siRNA to block MDK expression in SNU-638 human gastric cancer cells and examined the chemosensitizing effect. HeLa-MDK cells treated with 5-FU, doxorubicin, and cisplatin showed a fold increase in the average IC(50) and an increased cell survival. siRNA-based knockdown of MDK expression in SNU-638 cells decreased the average IC(50) by 18-44% in cells treated with three drugs. Further investigations on the molecular mechanism should be clarified, but these results indicate that MDK up- and down-regulation appears to be capable of changing the chemosensitivities of cancer cells and MDK may have possible importance as a candidate therapeutic molecule.

Antineoplastic Agents↗
PubMed2006

Is T classification still correlated with lymph node status after preoperative chemoradiotherapy for rectal cancer?

BACKGROUND: It is well known that the risk of lymph node involvement increases according to pathologic T classification in rectal cancers, but to the authors' knowledge, the correlation between risk of lymph node involvement and ypT classification in rectal cancers treated with preoperative chemoradiotherapy (CRT) remains unclear. The current study investigated the correlation between tumor involvement in regional lymph nodes and rectal mural tumor status in patients who underwent preoperative CRT for rectal cancer. METHODS: Between October 2001 and February 2005, 282 patients underwent preoperative CRT followed by proctectomy for locally advanced rectal adenocarcinoma. Correlations between lymph node status and ypT classification, Dworak regression grade, and magnetic resonance (MR) volumetry findings were explored. RESULTS: Lymph nodes harboring tumors were found in 87 of 282 (30.9%) patients. The rate of lymph node involvement was found to be correlated with ypT-classification (P < .001); positive lymph nodes were detected in 1 of 45 (2.2%) ypT0 patients, 1 of 13 (7.7%) ypT1 patients, 13 of 77 (16.9%) ypT2 patients, 69 of 140 (49.3%) ypT3 patients, and 3 of 7 (42.9%) ypT4 patients. The rate of lymph node involvement decreased as Dworak regression grade increased (P < .001); tumor-harboring lymph nodes were found in 62.3% of Grade 1 patients, 31.4% of Grade 2 patients, 16.1% of Grade 3 patients, and 2.2% of Grade 4 patients. There were no differences noted with regard to MR volumetry findings, including mean volume of pre- or post-CRT tumor and the tumor volume reduction rate between lymph node-negative and lymph node-positive patients. CONCLUSIONS: Pathologic T classification is still the most reliable predictor of lymph node metastasis in rectal cancer patients who have undergone preoperative CRT. The risk of lymph node metastasis was found to be 3.4% in rectal cancer that had regressed to ypT0 or ypT1.

Adenocarcinoma↗
PubMed2006

Isolated tumor cells in lymph nodes are not a prognostic marker for patients with stage I and stage II colorectal cancer.

BACKGROUND AND OBJECTIVES: Lymph node metastasis is an important prognostic factor for colorectal cancer (CRC). The relationship between isolated tumor cells (ITC) in lymph nodes and the prognosis is controversial. The aim of this study is to evaluate the prognostic importance of ITC in lymph nodes from patients with stage I and II CRC. METHODS: We examined all the lymph nodes obtained during surgery from 121 consecutive patients with stage I and II CRC after a curative resection in 1999 by using monoclonal antibody against cytokeratin (MNF116). Clinicopathologic data and follow-up information were obtained from all patients. The mean follow up duration was 57 months. RESULTS: ITC were found in 50% (60/121) of the patients. The mean number of examined lymph node was 19.3 +/- 9.4. The presence of ITC was not related to clinicopathologic factors such as age, sex, location of tumor, tumor size, tumor depth, differentiation, lymphovascular invasion, and the preoperative CEA level, except for the tumor gross type (P = 0.002). There were no statistically significant differences for the recurrence rate (10/60 = 16.7% and 9/61 = 14.8%, respectively), and disease-free survival (P = 0.809) between the ITC positive group and ITC negative group. CONCLUSIONS: The presence of ITC detected by immunohistochemical staining does not have an influence on the prognosis of patients with stage I and II CRC.

Adult↗
PubMed2005

Oligonucleotide microarray analysis of distinct gene expression patterns in colorectal cancer tissues harboring BRAF and K-ras mutations.

Various types of human cancers harbor BRAF somatic mutations, leading researchers to seek molecular targets for BRAF inhibitors. A mutually exclusive relationship has been observed between the BRAF-V600E mutation and K-ras mutations, suggesting that the BRAF-V600E mutation may differ from the other BRAF mutant types. Here, we used microarray analysis to examine differences between the BRAF and K-ras mutant colorectal samples and within the BRAF group (V600E versus non-V600E), in the hope that the identified gene sets could form the basis for new target development. Eleven colorectal cancers (CRCs) with BRAF mutations and nine with K-ras mutations were examined by high-density microarray analysis. We also tested whether other significant genetic or clinical status involved in CRC development, such as APC and TP53 mutations, MSI and TNM-Duke's staging, were related with the observed BRAF- or K-ras associated expression profiles. Unsupervised two-way hierarchical clustering and multidimensional scaling revealed that the differentially expressed genes clustered according to the mutation status of BRAF and K-ras, and that samples with the BRAF-V600E and non-V600E mutants could be distinguished from each other by gene profiling. Examination of TNM-Duke's staging, MSI and mutations in APC and TP53 revealed that these significant mutations could not account for the hierarchical clustering results observed in our study. We herein identified distinct gene expression patterns and gene sets that may form the basis for identification of BRAF-targeting molecules or provide researchers with a better understanding of the molecular pathogenesis underlying RAS-RAF signaling.

Colorectal Neoplasms↗
PubMed2005

Usefulness of magnetic resonance volumetric evaluation in predicting response to preoperative concurrent chemoradiotherapy in patients with resectable rectal cancer.

PURPOSE: We performed magnetic resonance (MR) volumetry before and after neoadjuvant chemoradiation for evaluating response to therapy in T3 and T4 rectal cancer. To investigate the utility of MR volumetry for predicting the response to neoadjuvant chemoradiation, we compared results from MR volumetry before chemoradiation with those after chemoradiation. METHODS AND MATERIALS: A total 112 patients with T3 or T4 rectal cancer who successfully underwent MR volumetry and completed neoadjuvant chemoradiation followed by radical resection for cure were identified. MR volumetries were performed before and after chemoradiation. We compared pre- and postchemoradiation tumor volume and % volume reduction rates of patients whose tumors were down-staged with those of patients that were not down-staged. The same analyses were also performed between those patients having a complete histologic regression and those with residual disease in the operative specimen. We assessed the difference of % volume reduction rate according to Dworak's rectal cancer regression grades. RESULTS: Fifty-seven patients (50.9%) demonstrated a tumor down-staging after chemoradiation therapy. Both pre- and posttreatment MR tumor volumes were significantly less in patients whose tumors were down-staged than in patients that were not down-staged (p = 0.04, 0.031), and % volume reduction rates were significantly higher in patients whose tumors were down-staged (p = 0.024). Sixteen patients (14.3%) showed pathologically complete tumor regression. The differences of MR tumor volumes before and after chemoradiation and % volume reduction rates were not significantly different between patients having a complete histologic regression and those with residual disease (p = 0.688, 0.451, and 0.480). The differences of % volume reduction rates according to Dworak's grades were statistically significant (p = 0.03). CONCLUSION: The MR volumetric examinations before and after chemoradiation demonstrated the significant difference of tumor volume and % volume reduction rate between patients whose tumors were down-staged and those that were not down-staged. The volume reduction rates were significantly different among groups according to Dworak's grades. However, the MR volumetric evaluation could not identify any differences between those patients having a complete histologic regression and those with residual disease.

Adult↗