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1.  Diagnostic Value of MDM2 and DDIT3 Fluorescence In Situ Hybridization in Liposarcoma Classification: A Single-Institution Experience 
Korean Journal of Pathology  2012;46(2):115-122.
The amplification of murine double minutes (MDM2) is the primary feature of well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas (DDLPS), while DDIT3 rearrangement is the main one of myxoid liposarcomas (MLPS). Our aim was to evaluate the added value of MDM2 amplification and DDIT3 rearrangement in making a diagnosis and classifying lipogenic tumors.
Eighty-two cases of liposarcoma and 60 lipomas diagnosed between 1995 and 2010 were analysed for MDM2 amplification and DDIT3 rearrangement using a fluorescence in situ hybridization (FISH). The subtypes of liposarcoma were reclassified according to the molecular results, whose results were reviewed with an analysis of the relevant histologic and immunohistochemical findings.
One case of lipoma (1.67%) was reclassified as a WDLPS. Of the liposarcomas, 13.4% (16/82) were reclassified after the molecular testing. Five cases of MLPS were reclassified as four cases of DDLPS and one case of myxoid lipoma. Two cases of WDLPS were reclassified as one case of spindle cell lipoma and another case of myxofibrosarcoma. Four cases of DDLPS were reclassified as two cases of leiomyosarcoma, one case of angiomyolipoma and another case of fibroinflammatory lesion. Of the six cases of pleomorphic liposarcoma, five were reclassified as DDLPS.
In our series, a critical revision of diagnosis was found at a rate of 3.5% (5/142) after a review of the lipomatous lesions. The uses of molecular testing by MDM2 and DDIT3 FISH were valuable to make an accurate subtyping of liposarcomas as well as to differentiate WDLPS from benign lipomatous tumor.
PMCID: PMC3479776  PMID: 23109990
Liposarcoma; MDM2; DDIT3; In situ hybridization, fluorescence
2.  Aberrant CDK4 Amplification in Refractory Rhabdomyosarcoma as Identified by Genomic Profiling 
Scientific Reports  2014;4:3623.
Rhabdomyosarcoma (RMS) is the most commonly occurring type of soft tissue tumor in children. However, it is rare in adults, and therefore, very little is known about the most appropriate treatment strategy for adult RMS patients. We performed genomic analysis of RMS cells derived from a 27-year-old male patient whose disease was refractory to treatment. A peritoneal seeding nodule from the primary tumor, pleural metastases, malignant pleural effusion, and ascites obtained during disease progression, were analyzed. Whole exome sequencing revealed 23 candidate variants, and 10 of 23 mutations were validated by Sanger sequencing. Three of 10 mutations were present in both primary and metastatic tumors, and 3 mutations were detected only in metastatic specimens. Comparative genomic hybridization array analysis revealed prominent amplification in the 12q13–14 region, and more specifically, the CDK4 proto-oncogene was highly amplified. ALK overexpression was observed at both protein and RNA levels. However, an ALK fusion assay using NanoString technology failed to show any ALK rearrangements. Little genetic heterogeneity was observed between primary and metastatic RMS cells. We propose that CDK4, located at 12q14, is a potential target for drug development for RMS treatment.
PMCID: PMC3887377  PMID: 24406431
3.  Comparison of Three BRAF Mutation Tests in Formalin-Fixed Paraffin Embedded Clinical Samples 
Korean Journal of Pathology  2013;47(4):348-354.
Recently, BRAF inhibitors showed dramatic treatment outcomes in BRAF V600 mutant melanoma. Therefore, the accuracy of BRAF mutation test is critical.
BRAF mutations were tested by dual-priming oligonucleotide-polymerase chain reaction (DPO-PCR), direct sequencing and subsequently retested with a real-time PCR assay, cobas 4800 V600 mutation test. In total, 64 tumors including 34 malignant melanomas and 16 papillary thyroid carcinomas were analyzed. DNA was extracted from formalin-fixed paraffin embedded tissue samples and the results of cobas test were directly compared with those of DPO-PCR and direct sequencing.
BRAF mutations were found in 23 of 64 (35.9%) tumors. There was 9.4% discordance among 3 methods. Out of 6 discordant cases, 4 cases were melanomas; 3 cases were BRAF V600E detected only by cobas test, but were not detected by DPO-PCR and direct sequencing. One melanoma patient with BRAF mutation detected only by cobas test has been on vemurafenib treatment for 6 months and showed a dramatic response to vemurafenib. DPO-PCR failed to detect V600K mutation in one case identified by both direct sequencing and cobas test.
In direct comparison of the currently available DPO-PCR, direct sequencing and real-time cobas test for BRAF mutation, real-time PCR assay is the most sensitive method.
PMCID: PMC3759634  PMID: 24009630
BRAF mutation; Melanoma; Real-time polymerase chain reaction; Sanger sequencing; Dual-priming oligonucleotide-PCR
4.  Peripheral Primitive Neuroectodermal Tumor with Osseous Component of the Small Bowel Mesentery: A Case Study 
Korean Journal of Pathology  2013;47(1):77-81.
A case of peripheral primitive neuroectodermal tumor of the small bowel mesentery with osseous component is reported. A 23-year-old man was admitted to our hospital because of acute severe abdominal pain. Abdominal computed tomography revealed a large solid and cystic, oval shaped mass, measuring 11.0×6.0 cm in the pelvic cavity. Histologically the resected lesion consisted of sheets of undifferentiated small round cells forming Homer-Wright rosettes and perivascular pseudorosettes, and showed areas of osteoid and bone formation. Immunohistochemical studies revealed that tumor cells expressed positivity against CD99 (MIC2), CD57, neuron-specific enolase, and vimentin. Fluorescence in situ hybridization study revealed Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangement on chromosome 22q12. To the authors' knowledge this is the first documentation of a peripheral neuroectodermal tumor with osteoid and bone formation of the small bowel mesentery.
PMCID: PMC3589613  PMID: 23482293
Neuroectodermal tumor, primitive, peripheral; Intestine, small; Osteogenesis; Metaplasia; EWSR1
5.  Prognostic implications of tumor volume response and COX-2 expression change during radiotherapy in cervical cancer patients 
Radiation Oncology Journal  2012;30(4):218-225.
The relationship between treatment outcomes, alteration of the expression of biological markers, and tumor volume response during radiotherapy (RT) in patients with uterine cervical cancer was analyzed.
Materials and Methods
Twenty patients with cervical squamous cell carcinoma received definitive RT with (n = 17) or without (n = 3) concurrent chemotherapy. Tumor volumes were measured by three serial magnetic resonance imaging scans at pre-, mid-, and post-RT. Two serial punch biopsies were performed at pre- and mid-RT, and immunohistochemical staining for cyclooxygenase (COX)-2 and epidermal growth factor receptor was performed. The median follow-up duration was 60 months.
The median tumor volume response at mid-RT (V2R) was 0.396 (range, 0.136 to 0.983). At mid-RT, an interval increase in the distribution of immunoreactivity for COX-2 was observed in 8 patients, and 6 of them showed poor mid-RT tumor volume response (V2R ≥ 0.4). Four (20%) patients experienced disease progression after 10 to 12 months (median, 11 months). All 4 patients had poor mid-RT tumor volume response (p = 0.0867) and 3 of them had an interval increase in COX-2 expression. Overall survival (OS) and progression-free survival (PFS) decreased in patients with V2R ≥ 0.4 (p = 0.0291 for both). An interval increase in COX-2 expression at mid-RT was also associated with a decreased survival (p = 0.1878 and 0.1845 for OS and PFS, respectively).
Poor tumor volume response and an interval increase in COX-2 expression at mid-RT decreased survival outcomes in patients with uterine cervical cancer.
PMCID: PMC3546291  PMID: 23346542
Uterine cervical neoplasms; Radiotherapy; Volume response; Cyclooxygenase-2
6.  A Proposal for Creating a Guideline for Cancer Registration of the Fibromatosis, PEComa Group, Malignant Lymphoma In Situ and Dendritic Cell Tumors (III) 
Korean Journal of Pathology  2012;46(5):436-442.
Understanding the biologic behavior of a tumor is a prerequisite for tumor registration code assignment. The aim of this report was to propose appropriate behavior codes of the International Classification of Disease Oncology 3 (ICD-O3) to rare, yet pathologically interesting hematopoietic and soft tissue tumors.
The Study Group for Hematopathology, the Bone and Soft Tissue Pathology Study Group, and the Cancer Registration Committee prepared the questionnaire containing provisional behavior codes of selected diseases.
In situ lesions of mantle cell and follicular lymphomas, dendritic cell tumors, and neoplasms with perivascular epithelioid cell differentiation (PEComa), not otherwise specified were classified as malignant (-/3). The fibromatosis group, with the exception of lipofibromatosis, was proposed as benign (-/0). Lipofibromatosis and several diseases that belong to the PEComa group were proposed as uncertain malignant potential (-/1). For the hematologic and soft tissue tumors, 274 and 288 members of the Korean Society of Pathologists, respectively, provided opinions through questionnaire, and most responders showed agreement with the provisional behavior code proposed.
The determination of behavior codes for the rare diseases described in this study, especially those of the PEComa group or malignant lymphoma, could be viewed as impractical and premature, but this study provides the basis for future research on this topic.
PMCID: PMC3490119  PMID: 23136570
ICD-O3; Behavior code; Hematologic malignancy; Soft tissue neoplasms
7.  Tob1 induces apoptosis and inhibits proliferation, migration and invasion of gastric cancer cells by activating Smad4 and inhibiting β-catenin signaling 
International Journal of Oncology  2012;41(3):839-848.
Transducer of ErbB-2.1 (Tob1), a tumor suppressor protein, is inactivated in a variety of cancers including stomach cancer. However, the role of Tob1 in gastric carcinogenesis remains elusive. The present study aimed to investigate whether Tob1 could inhibit gastric cancer progression in vitro, and to elucidate its underlying molecular mechanisms. We found differential expression of Tob1 in human gastric cancer (MKN28, AGS and MKN1) cells. The overexpression of Tob1 induced apoptosis in MKN28 and AGS cells, which was associated with sub-G1 arrest, activation of caspase-3, induction of Bax, inhibition of Bcl-2 and cleavage of poly (ADP-ribose) polymerase (PARP). In addition, Tob1 inhibited proliferation, migration and invasion, which were reversed in MKN1 and AGS cells transfected with Tob1 siRNA. Overexpression of Tob1 in MKN28 and AGS cells induced the expression of Smad4, leading to the increased expression and the promoter activity of p15, which was diminished by silencing of Tob1 using specific siRNA. Tob1 decreased the phosphorylation of Akt and glycogen synthase kinase-3β (GSK3β) in MKN28 and AGS cells, resulting in the reduced protein expression and the transcriptional activity of β-catenin, which in turn decreased the expression of cyclin D1, cyclin-dependent kinase-4 (CDK4), urokinase plasminogen activator receptor (uPAR) and peroxisome proliferator and activator receptor-δ (PPARδ). Conversely, silencing of Tob1 induced the phosphorylation of Akt and GSK-3β, and increased the expression of β-catenin and its target genes. Collectively, our study demonstrates that the overexpression of Tob1 inhibits gastric cancer progression by activating Smad4- and inhibiting β-catenin-mediated signaling pathways.
PMCID: PMC3582759  PMID: 22710759
transducer of ErbB-2; gastric cancer; cell migration; invasion; Smad4; β-catenin
8.  Extranodal Follicular Dendritic Cell Sarcoma with Rapid Growth in Parapharynx: A Case Report 
Korean Journal of Pathology  2012;46(3):306-310.
Follicular dendritic cell sarcoma (FDCS) is a rare malignancy arising from the antigen-presenting cells in the lymph node and extranodal tissue. We describe a 31-year-old male patient who presented with a swelling of the left parapharynx. The radiologic findings showed a 4.7×4.5×1.9 cm-sized, ill-defined mass in the left parapharyngeal space. A fine-needle aspiration cytology was performed and it showed scattered, irregular, cohesive clusters of tumor cells with a spindle-to-ovoid shape with irregular contours in a background of lymphocytes. Based on these findings, a diagnosis of spindle cell neoplasm was made. The surgically resected tumor was composed of elongated, ovoid or polygonal cells showing positive immunohistochemistry for CD21, CD23, and CD35. Postoperatively, the residual tumor was observed to undergo a rapidly growth. There is an overlap in the cytologic and histologic findings between FDCS of the parapharynx and other tumors. Pathologists should therefore be aware of its characteristics not only to provide an accurate diagnosis but also to recommend the appropriate clinical management.
PMCID: PMC3479760  PMID: 23110021
Dendritic cell sarcoma, follicular; Extranodal; Parapharynx
9.  Identification of prognostic biomarkers for glioblastomas using protein expression profiling 
International Journal of Oncology  2011;40(4):1122-1132.
A set of proteins reflecting the prognosis of patients have clinical significance since they could be utilized as predictive biomarkers and/or potential therapeutic targets. With the aim of finding novel diagnostic and prognostic markers for glioblastoma (GBM), a tissue microarray (TMA) library consisting of 62 GBMs and 28 GBM-associated normal spots was constructed. Immunohistochemistry against 78 GBM-associated proteins was performed. Expression levels of each protein for each patient were analyzed using an image analysis program and converted to H-score [summation of the intensity grade of staining (0–3) multiplied by the percentage of positive cells corresponding to each grade]. Based on H-score and hierarchical clustering methods, we divided the GBMs into two groups (n=19 and 37) that had significantly different survival lengths (p<0.05). In the two groups, expression of nine proteins (survivin, cyclin E, DCC, TGF-β, CDC25B, histone H1, p-EGFR, p-VEGFR2/3, p16) was significantly changed (q<0.05). Prognosis-predicting potential of these proteins were validated with another independent library of 82 GBM TMAs and a public GBM DNA microarray dataset. In addition, we determined 32 aberrant or mislocalized subcellular protein expression patterns in GBMs compared with relatively normal brain tissues, which could be useful for diagnostic biomarkers of GBM. We therefore suggest that these proteins can be used as predictive biomarkers and/or potential therapeutic targets for GBM.
PMCID: PMC3584590  PMID: 22179774
biomarker; therapeutic target; glioblastoma; tissue micro-array; bioinformatics; automated image analysis
10.  Molecular profiles of EGFR, K-ras, c-met, and FGFR in pulmonary pleomorphic carcinoma, a rare lung malignancy 
Pulmonary pleomorphic carcinoma (PPC) is a rare type of lung cancer characterized by the poor response to conventional chemotherapy and subsequent disappointing outcomes. Therefore, it is paramount to delineate the molecular characteristics of this disease entity.
In this study, we retrospectively examined the surgical specimens of 61 patients who underwent lung surgery. Mutational or gene amplification statuses of epidermal growth factor receptor (EGFR), k-ras, c-kit, c-met, and fibroblast growth factor receptor (FGFR) were examined using genomic DNA sequencing, real-time PCR and/or fluorescence in situ hybridization (FISH).
The median age was 61 years, and 50 patients were men and 11 were women. In the histologic review of epithelial component, adenocarcinoma were in 44 cases (72%), squamous cell carcinoma in 15 (25%) and large cell carcinoma in 2 patients (3%). Overall, 30 cases (49%) had any molecular alterations. Nine patients (15%) possessed EGFR deletion in exon 19 (n = 8) or L858R mutations in exon 21 (n = 1), while 3 other cases having atypical EGFR mutations. Six patients (9.8%) had k-ras mutations in exon 12, and 3 had c-kit mutations. High gene copy number of c-met was found in 11 patients (18.0%) and that of FGFR was in 6 patients (9.8%). No significant relationships were identified among the occurrence and type of mutations and patient survival or any other clinicopathological variables.
Given the diverse repertoire of mutational profiles observed in PPC samples, clinical trials based on accurate cancer-genotyping should be considered as a legitimate treatment scheme for this rare disease entity in the future.
PMCID: PMC3133705  PMID: 21626008
Lung cancer; Pulmonary pleomorphic carcinoma; EGFR; k-ras; c-kit; c-met; FGFR
11.  LYN is a mediator of epithelial-mesenchymal transition and target of dasatinib in breast cancer 
Cancer research  2010;70(6):2296-2306.
Epithelial-mesenchymal transition (EMT), a switch of polarized epithelial cells to a migratory, fibroblastoid phenotype, is considered a key process driving tumor cell invasiveness and metastasis. Using breast cancer cell lines as a model system, we sought to discover gene-expression signatures of EMT with clinical and mechanistic relevance. A supervised comparison of epithelial and mesenchymal breast cancer lines defined a 200-gene EMT signature that was prognostic across multiple breast cancer cohorts. Immunostaining of LYN, a top-ranked EMT signature gene and Src-family tyrosine kinase, was associated with significantly shorter overall survival (P=0.02), and correlated with the basal-like (“triple-negative”) phenotype. In mesenchymal breast cancer lines, RNAi-mediated knockdown of LYN inhibited cell migration and invasion, but not proliferation. Dasatinib, a dual-specificity tyrosine kinase inhibitor, also blocked invasion (but not proliferation) at nanomolar concentrations that inhibit LYN kinase activity, suggesting that LYN is a likely target and invasion a relevant endpoint for dasatinib therapy. Our findings define a prognostically-relevant EMT signature in breast cancer, and identify LYN as a mediator of invasion and possible new therapeutic target (and theranostic marker for dasatinib response), with particular relevance to clinically-aggressive basal-like breast cancer.
PMCID: PMC2869247  PMID: 20215510
Breast cancer; epithelial-mesenchymal transition; transcriptional profiling; LYN; dasatinib
12.  AGR2, a mucinous ovarian cancer marker, promotes cell proliferation and migration 
Ovarian cancer is a leading cause of death in women. Early detection of ovarian cancer is essential to decrease mortality. However, the early diagnosis of ovarian cancer is difficult due to a lack of clinical symptoms and suitable molecular diagnostic markers. Thus, identification of meaningful tumor biomarkers with potential clinical application is clearly needed. To search for a biomarker for the early detection of ovarian cancer, we identified human anterior gradient 2 (AGR2) from our systematic analysis of paired normal and ovarian tumor tissue cDNA microarray. We noted a marked overexpression of AGR2 mRNA and protein in early stage mucinous ovarian tumors compared to normal ovarian tissues and serous type ovarian tumors by Western blot analysis and immunohistochemistry. To further elucidate the role of AGR2 in ovarian tumorigenesis, stable 2774 human ovarian cancer cell lines overexpressing AGR2 were established. Forced expression of AGR2 in 2774 cells enhanced the growth and migration of ovarian cancer cells. AGR2 protein was detected in the serum of mucinous ovarian cancer patients by Western blot and ELISA analysis. Thus, AGR2 is a potential biomarker for the diagnosis of mucinous ovarian cancer and an ELISA assay may facilitate the early detection of mucinous ovarian cancer using patient serum.
PMCID: PMC3047197  PMID: 21200134
AGR2 protein, human; biological markers; ovarian neoplasms
13.  Comparative Profiling of Primary Colorectal Carcinomas and Liver Metastases Identifies LEF1 as a Prognostic Biomarker 
PLoS ONE  2011;6(2):e16636.
We sought to identify genes of clinical significance to predict survival and the risk for colorectal liver metastasis (CLM), the most common site of metastasis from colorectal cancer (CRC).
Patients and Methods
We profiled gene expression in 31 specimens from primary CRC and 32 unmatched specimens of CLM, and performed Significance Analysis of Microarrays (SAM) to identify genes differentially expressed between these two groups. To characterize the clinical relevance of two highly-ranked differentially-expressed genes, we analyzed the expression of secreted phosphoprotein 1 (SPP1 or osteopontin) and lymphoid enhancer factor-1 (LEF1) by immunohistochemistry using a tissue microarray (TMA) representing an independent set of 154 patients with primary CRC.
Supervised analysis using SAM identified 963 genes with significantly higher expression in CLM compared to primary CRC, with a false discovery rate of <0.5%. TMA analysis showed SPP1 and LEF1 protein overexpression in 60% and 44% of CRC cases, respectively. Subsequent occurrence of CLM was significantly correlated with the overexpression of LEF1 (chi-square p = 0.042), but not SPP1 (p = 0.14). Kaplan Meier analysis revealed significantly worse survival in patients with overexpression of LEF1 (p<0.01), but not SPP1 (p = 0.11). Both univariate and multivariate analyses identified stage (p<0.0001) and LEF1 overexpression (p<0.05) as important prognostic markers, but not tumor grade or SPP1.
Among genes differentially expressed between CLM and primary CRC, we demonstrate overexpression of LEF1 in primary CRC to be a prognostic factor for poor survival and increased risk for liver metastasis.
PMCID: PMC3044708  PMID: 21383983
15.  Triple-negative, basal-like, and quintuple-negative breast cancers: better prediction model for survival 
BMC Cancer  2010;10:507.
Triple-negative breast cancers (TNBCs) and basal-like breast cancers (BLBCs) are known as poor outcome subtypes with a lack of targeted therapy. Previous studies have shown conflicting results regarding the difference of prognostic significance between TNBCs and BLBCs. In this study, we aimed to characterize the prognostic features of TNBCs, in view of BLBCs and quintuple-negative breast cancers (QNBC/5NPs).
Using tissue microarray-based immunohistochemical analysis, we categorized 951 primary breast cancers into four or five subtypes according to the expression of ER, PR, HER2, and basal markers (CK5/6, EGFR).
The results of this study showed that both TNBCs and BLBCs were associated with high histological and/or nuclear grades. When the TNBCs are divided into two subtypes by the presence of basal markers, the clinicopathologic characteristics of TNBCs were mainly maintained in the BLBCs. The 5-subgrouping was the better prediction model for both disease free and overall survival in breast cancers than the 4-subgrouping. After multivariate analysis of TNBCs, the BLBCs did not have a worse prognosis than the QNBC/5NPs. Interestingly, the patients with BLBCs showed significant adjuvant chemotherapy benefit. In addition, QNBC/5NPs comprised about 6~8% of breast cancers in publicly available breast cancer datasets
The QNBC/5NP subtype is a worse prognostic subgroup of TNBCs, especially in higher stage and this result may be related to adjuvant chemotherapy benefit of BLBCs, calling for caution in the identification of subgroups of patients for therapeutic classification.
PMCID: PMC2957395  PMID: 20860845
16.  Derepression of CLDN3 and CLDN4 during ovarian tumorigenesis is associated with loss of repressive histone modifications 
Carcinogenesis  2010;31(6):974-983.
Unlike epigenetic silencing of tumor suppressor genes, the role of epigenetic derepression of cancer-promoting genes or oncogenes in carcinogenesis remains less well understood. The tight junction proteins claudin-3 and claudin-4 are frequently overexpressed in ovarian cancer and their overexpression was previously reported to promote the migration and invasion of ovarian epithelial cells. Here, we show that the expression of claudin-3 and claudin-4 is repressed in ovarian epithelial cells in association with promoter ‘bivalent’ histone modifications, containing both the activating trimethylated histone H3 lysine 4 (H3K4me3) mark and the repressive mark of trimethylated histone H3 lysine 27 (H3K27me3). During ovarian tumorigenesis, derepression of CLDN3 and CLDN4 expression correlates with loss of H3K27me3 in addition to trimethylated histone H4 lysine 20 (H4K20me3), another repressive histone modification. Although CLDN4 repression was accompanied by both DNA hypermethylation and repressive histone modifications, DNA methylation was not required for CLDN3 repression in immortalized ovarian epithelial cells. Moreover, activation of both CLDN3 and CLDN4 in ovarian cancer cells was associated with simultaneous changes in multiple histone modifications, whereas H3K27me3 loss alone was insufficient for their derepression. CLDN4 repression was robustly reversed by combined treatment targeting both DNA demethylation and histone acetylation. Our study strongly suggests that in addition to the well-known chromatin-associated silencing of tumor suppressor genes, epigenetic derepression by the conversely related loss of repressive chromatin modifications also contributes to ovarian tumorigenesis via activation of cancer-promoting genes or candidate oncogenes.
PMCID: PMC2878357  PMID: 20053926
17.  The Effect of Cyclooxygenase-2 Expression on Tumor Volume Response in Patients Treated with Radiotherapy for Uterine Cervical Cancer 
Journal of Korean Medical Science  2009;24(6):1170-1176.
We investigated the correlation between Cyclooxygenase-2 (COX-2) expression and the tumor response in patients with cervical cancer that were treated with curative radiotherapy (RT). Fifty-seven patients with squamous cell carcinoma were treated with concurrent radiochemotherapy (CRCT, n=29) or RT alone (n=28). The response of each patient was evaluated by three serial Magnetic Resonance Imaging examinations: before the start of RT, at four weeks after the start of RT (mid-RT) and at four weeks after the completion of RT (post-RT). Forty-three patients had positive COX-2 expression. The COX-2 negative patients achieved a higher rate of complete response (CR) at mid-RT than did the COX-2 positive patients (28.6% vs. 7.0%, P=0.054), but not at post-RT (64.3% vs. 69.8%). The initial tumor volume was a significant predictor of CR at mid-RT (P=0.003) and post-RT (P=0.004). The multivariate analysis showed that the initial tumor volume (at mid-RT and post-RT) and CRCT (at post-RT) were significant predictors of CR; however, the COX-2 expression was not. In conclusion, the COX-2 expression status has no significant correlation with the tumor response. Further studies on the changes in COX-2 expression levels during RT may be helpful for determination of its role in the tumor response to treatment and patient prognosis.
PMCID: PMC2775869  PMID: 19949677
Uterine Cervical Neoplasms; Cyclooxygenase 2; Radiotherapy; Tumor Burden; Tumor Response
18.  Correlation between tumor volume response to radiotherapy and expression of biological markers in patients with cervical squamous cell carcinoma 
Journal of Gynecologic Oncology  2009;20(4):215-220.
To determine the factors associated with tumor volume response to radiotherapy (RT) in cervical cancer patients, and the relationship between the tumor volume response and alteration of the expression of biological markers during RT.
Twenty consecutive patients with cervical squamous cell carcinoma who received definitive RT were enrolled. Tumor volumes were calculated by MRI examinations performed at the start of RT (pre-RT), at the fourth week of RT (mid-RT), and 1 month after RT completion (post-RT). Two serial punch biopsies were performed at pre- and mid-RT, and immunohistochemical staining was performed for cyclooxygenase (COX)-2 and epidermal growth factor receptor (EGFR).
For the pre-RT evaluation, fourteen (70%) and eleven (55%) patients showed positive immunoreactivity for COX-2 and EGFR, respectively. Among the seven patients whose median percentage residual tumor at mid-RT (V2R) was greater than 0.5, seven (100%, p=0.0515) and five (71.4%, p=0.3742) patients showed positive immunoreactivity for COX-2 and EGFR, respectively. The logistic regression analysis showed that positive immunoreactivity for both COX-2 and EGFR at pre-RT were associated with V2R (p=0.0782). For the mid-RT evaluation, eight cases showed an interval increase in the distribution of immunoreactivity for COX-2, and six out of the eight patients had a V2R greater than 0.5 (p=0.2222).
The poor mid-RT tumor response was associated with the coexpression of COX-2 and EGFR.
PMCID: PMC2799019  PMID: 20041097
Cervical cancer; Radiotherapy; Volume response; Cyclooxygenase-2; Epidermal growth factor receptor
19.  Centrosomal PKCβII and pericentrin are critical for human prostate cancer growth and angiogenesis 
Cancer research  2008;68(16):6831-6839.
Angiogenesis is critical in the progression of prostate cancer. However, the interplay between the proliferation kinetics of tumor endothelial cells (angiogenesis) and tumor cells has not been investigated. Also, protein kinase C (PKC) regulates various aspects of tumor cell growth but its role in prostate cancer has not been investigated in detail. Here, we found that the proliferation rates of endothelial and tumor cells oscillate asynchronously during the growth of human prostate cancer xenografts. Furthermore, our analyses suggest that PKCβII was activated during increased angiogenesis and that PKCβII plays a key role in the proliferation of endothelial cells and tumor cells in human prostate cancer; treatment with a PKCβII-selective inhibitor, βIIV5-3, reduced angiogenesis and tumor cell proliferation. We also find a unique effect of PKCβII inhibition on normalizing pericentrin (a protein regulating cytokinesis), especially in endothelial cells as well as in tumor cells. PKCβII inhibition reduced the level and mislocalization of pericentrin and normalized microtubule organization in the tumor endothelial cells. Although pericentrin has been known to be upregulated in epithelial cells of prostate cancers, its level in tumor endothelium has not been studied in detail. We found that pericentrin is upregulated in human tumor endothelium compared with endothelium adjacent to normal glands in tissues from prostate cancer patients. Our results suggest that a PKCβII inhibitor such as βIIV5-3 may be used to reduce prostate cancer growth by targeting both angiogenesis and tumor cell growth.
PMCID: PMC2597632  PMID: 18701509
20.  Correction: Identification of Novel Reference Genes Using Multiplatform Expression Data and Their Validation for Quantitative Gene Expression Analysis 
PLoS ONE  2009;4(8):10.1371/annotation/695436c7-3329-4bdc-9832-f427ecc33698.
PMCID: PMC2727537
21.  Identification of candidate prostate cancer genes through comparative expression-profiling of seminal vesicle 
The Prostate  2008;68(11):1248-1256.
Prostate cancer is the most frequently diagnosed cancer among men in the United States. In contrast, cancer of the seminal vesicle is exceedingly rare, despite that the prostate and seminal vesicle share similar histology, secretory function, androgen dependency, blood supply, and (in part) embryonic origin. We hypothesized that gene-expression differences between prostate and seminal vesicle might inform mechanisms underlying the higher incidence of prostate cancer.
Whole-genome DNA microarrays were used to profile gene expression of 11 normal prostate and 7 seminal vesicle specimens (including 6 matched pairs) obtained from radical prostatectomy. Supervised analysis was used to identify genes differentially expressed between normal prostate and seminal vesicle, and this list was then cross-referenced to genes differentially expressed between normal and cancerous prostate. Expression patterns of selected genes were confirmed by immunohistochemistry using a tissue microarray.
We identified 32 genes that displayed a highly statistically-significant expression pattern with highest levels in seminal vesicle, lower levels in normal prostate, and lowest levels in prostate cancer. Among these genes was the known candidate prostate tumor suppressor GSTP1 (involved in xenobiotic detoxification). The expression pattern of GSTP1 and four other genes, ABCG2 (xenobiotic transport), CRABP2 (retinoic acid signaling), GATA3 (lineage-specific transcription) and SLPI (immune response), was confirmed by immunohistochemistry.
Our findings identify candidate prostate cancer genes whose reduced expression in prostate (compared to seminal vesicle) may be permissive to prostate cancer initiation. Such genes and their pathways may inform mechanisms of prostate carcinogenesis, and suggest new opportunities for prostate cancer prevention.
PMCID: PMC2516917  PMID: 18500686
prostate cancer; seminal vesicle; expression profiling; microarray
22.  Identification of Novel Reference Genes Using Multiplatform Expression Data and Their Validation for Quantitative Gene Expression Analysis 
PLoS ONE  2009;4(7):e6162.
Normalization of mRNA levels using endogenous reference genes (ERGs) is critical for an accurate comparison of gene expression between different samples. Despite the popularity of traditional ERGs (tERGs) such as GAPDH and ACTB, their expression variability in different tissues or disease status has been reported. Here, we first selected candidate housekeeping genes (HKGs) using human gene expression data from different platforms including EST, SAGE, and microarray, and 13 novel ERGs (nERGs) (ARL8B, CTBP1, CUL1, DIMT1L, FBXW2, GPBP1, LUC7L2, OAZ1, PAPOLA, SPG21, TRIM27, UBQLN1, ZNF207) were further identified from these HKGs. The mean coefficient variation (CV) values of nERGs were significantly lower than those of tERGs and the expression level of most nERGs was relatively lower than high expressing tERGs in all dataset. The higher expression stability and lower expression levels of most nERGs were validated in 108 human samples including formalin-fixed paraffin-embedded (FFPE) tissues, frozen tissues and cell lines, through quantitative real-time RT-PCR (qRT-PCR). Furthermore, the optimal number of nERGs required for accurate normalization was as few as two, while four genes were required when using tERGs in FFPE tissues. Most nERGs identified in this study should be better reference genes than tERGs, based on their higher expression stability and fewer numbers needed for normalization when multiple ERGs are required.
PMCID: PMC2703796  PMID: 19584937
23.  Molecular Profiling of Breast Cancer Cell Lines Defines Relevant Tumor Models and Provides a Resource for Cancer Gene Discovery 
PLoS ONE  2009;4(7):e6146.
Breast cancer cell lines have been used widely to investigate breast cancer pathobiology and new therapies. Breast cancer is a molecularly heterogeneous disease, and it is important to understand how well and which cell lines best model that diversity. In particular, microarray studies have identified molecular subtypes–luminal A, luminal B, ERBB2-associated, basal-like and normal-like–with characteristic gene-expression patterns and underlying DNA copy number alterations (CNAs). Here, we studied a collection of breast cancer cell lines to catalog molecular profiles and to assess their relation to breast cancer subtypes.
Whole-genome DNA microarrays were used to profile gene expression and CNAs in a collection of 52 widely-used breast cancer cell lines, and comparisons were made to existing profiles of primary breast tumors. Hierarchical clustering was used to identify gene-expression subtypes, and Gene Set Enrichment Analysis (GSEA) to discover biological features of those subtypes. Genomic and transcriptional profiles were integrated to discover within high-amplitude CNAs candidate cancer genes with coordinately altered gene copy number and expression.
Transcriptional profiling of breast cancer cell lines identified one luminal and two basal-like (A and B) subtypes. Luminal lines displayed an estrogen receptor (ER) signature and resembled luminal-A/B tumors, basal-A lines were associated with ETS-pathway and BRCA1 signatures and resembled basal-like tumors, and basal-B lines displayed mesenchymal and stem/progenitor-cell characteristics. Compared to tumors, cell lines exhibited similar patterns of CNA, but an overall higher complexity of CNA (genetically simple luminal-A tumors were not represented), and only partial conservation of subtype-specific CNAs. We identified 80 high-level DNA amplifications and 13 multi-copy deletions, and the resident genes with concomitantly altered gene-expression, highlighting known and novel candidate breast cancer genes.
Overall, breast cancer cell lines were genetically more complex than tumors, but retained expression patterns with relevance to the luminal-basal subtype distinction. The compendium of molecular profiles defines cell lines suitable for investigations of subtype-specific pathobiology, cancer stem cell biology, biomarkers and therapies, and provides a resource for discovery of new breast cancer genes.
PMCID: PMC2702084  PMID: 19582160
24.  Liposarcoma: exploration of clinical prognostic factors for risk based stratification of therapy 
BMC Cancer  2009;9:205.
Prognosis and optimal treatment strategies of liposarcoma have not been fully defined. The purpose of this study is to define the distinctive clinical features of liposarcomas by assessing prognostic factors.
Between January 1995 and May 2008, 94 liposarcoma patients who underwent surgical resection with curative intent were reviewed.
Fifty patients (53.2%) presented with well differentiated, 22 (23.4%) myxoid, 15 (16.0%) dedifferentiated, 5 (5.3%) round cell, and 2 (2.1%) pleomorphic histology. With the median 14 cm sized of tumor burden, about half of the cases were located in the retroperitoneum (46.8%). Seventy two (76.6%) patients remained alive with 78.1%, and 67.5% of the 5- and 10-year overall survival (OS) rates, respectively. Low grade liposarcoma (well differentiated and myxoid) had a significantly prolonged OS and disease free survival (DFS) with adjuvant radiotherapy when compared with those without adjuvant radiotherapy (5-year OS, 100% vs 66.3%, P = 0.03; 1-year DFS, 92.9% vs 50.0%, respectively, P = 0.04). Independent prognostic factors for OS were histologic variant (P = 0.001; HR, 5.1; 95% CI, 2.0 – 12.9), and margin status (P = 0.005; HR, 4.1; 95% CI, 1.6–10.5). We identified three different risk groups: group 1 (n = 66), no adverse factors; group 2, one or two adverse factors (n = 28). The 5-year OS rate for group 1, and 2 were 91.9%, 45.5%, respectively.
The histologic subtype, and margin status were independently associated with OS, and adjuvant radiotherapy seems to confer survival benefit in low grade tumors. Our prognostic model for primary liposarcoma demonstrated distinct three groups of patients with good prognostic discrimination.
PMCID: PMC2711972  PMID: 19558664
25.  Comparison of Her-2, EGFR and Cyclin D1 in Primary Breast Cancer and Paired Metastatic Lymph Nodes: An Immunohistochemical and Chromogenic In Situ Hybridization Study 
Journal of Korean Medical Science  2008;23(6):1053-1061.
The significant advance in the development of molecular-targeting drugs has made an evaluation of Her-2, EGFR, and cyclin D1 an important clinical issue in breast cancer patients. This study compared the Her-2, EGFR, and cyclin D1 status of primary tumors as well as their matching lymph node metastases using immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) in 73 breast cancer patients. Her-2, EGFR, and cyclin D1 protein showed a concordance between the primary lesion and the metastatic regional lymph nodes in 82%, 90%, and 63%, respectively. CISH also revealed 92%, 93%, and 85% concordance in the gene amplification status of Her-2, EGFR, and cyclin D1, showing a reasonable agreement between primary tumors and metastatic regional lymph nodes. Although a statistically significant agreement was found in Her-2 expression, a relatively high discordance rate (18%) raises a little concern. Our findings suggest that the Her-2 status can be reliably assessed on primary tumor but a possible difference can be found in Her-2, EGFR, and cyclin D1 status between the primary and the metastatic sites and this possibility should be concerned in patients considering molecular targeted therapy or patients with progress of disease.
PMCID: PMC2610643  PMID: 19119452
CISH; Her-2; EGFR; Cyclin D1; Immunohistochemistry

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