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1.  Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients 
Journal of Clinical Oncology  2013;32(2):121-128.
Purpose
Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer, largely because of a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SCC, we probed somatic genome alterations of lung SCC by using samples from Korean patients.
Patients and Methods
We performed whole-exome sequencing of DNA from 104 lung SCC samples from Korean patients and matched normal DNA. In addition, copy-number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated.
Results
This cancer cohort is characterized by a high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of exposure to cigarette smoke. Seven genes demonstrated statistical enrichment for mutation: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA). Comparative analysis between Korean and North American lung SCC samples demonstrated a similar spectrum of alterations in these two populations in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SCC.
Conclusion
These findings provide new steps toward the identification of genomic target candidates for precision medicine in lung SCC, a disease with significant unmet medical needs.
doi:10.1200/JCO.2013.50.8556
PMCID: PMC4062710  PMID: 24323028
2.  KRAS Mutation Detection in Non-small Cell Lung Cancer Using a Peptide Nucleic Acid-Mediated Polymerase Chain Reaction Clamping Method and Comparative Validation with Next-Generation Sequencing 
Korean Journal of Pathology  2014;48(2):100-107.
Background
KRAS is one of commonly mutated genetic "drivers" in non-small cell lung cancers (NSCLCs). Recent studies indicate that patients with KRAS-mutated tumors do not benefit from adjuvant chemotherapy, so there is now a focus on targeting KRAS-mutated NSCLCs. A feasible mutation detection method is required in order to accurately test for KRAS status.
Methods
We compared direct Sanger sequencing and the peptide nucleic acid (PNA)-mediated polymerase chain reaction (PCR) clamping method in 134 NSCLCs and explored associations with clinicopathological factors. Next-generation sequencing (NGS) was used to validate the results of discordant cases. To increase the resolution of low-level somatic mutant molecules, PNA-mediated PCR clamping was used for mutant enrichment prior to NGS.
Results
Twenty-one (15.7%) cases were found to have the KRAS mutations using direct sequencing, with two additional cases by the PNA-mediated PCR clamping method. The frequencies of KRAS mutant alleles were 2% and 4%, respectively, using conventional NGS, increasing up to 90% and 89%, using mutant-enriched NGS. The KRAS mutation occurs more frequently in the tumors of smokers (p=.012) and in stage IV tumors (p=.032).
Conclusions
Direct sequencing can accurately detect mutations, but, it is not always possible to obtain a tumor sample with sufficient volume. The PNA-mediated PCR clamping can rapidly provide results with sufficient sensitivity.
doi:10.4132/KoreanJPathol.2014.48.2.100
PMCID: PMC4026800  PMID: 24868222
Lung neoplasms; KRAS; Mutation; Peptide nucleic acids
3.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.4132/KoreanJPathol.2012.46.2.115
PMCID: PMC3479776  PMID: 23109990
Liposarcoma; MDM2; DDIT3; In situ hybridization, fluorescence
4.  Synovial sarcoma of the spine: a case involving paraspinal muscle with extensive calcification and the surgical consideration in treatment 
European Spine Journal  2013;23(1):27-31.
Introduction
Synovial sarcoma is a rare malignant tumor of the spine. This tumor may present as a painless mass of the spine or slowly enlarge, causing pain or neurologic deficits. As it is difficult to differentiate this lesion from other soft tissue tumors, synovial sarcoma requires histologic confirmation for definite diagnosis. Thus, the treatment strategy is often planned in the final step depending on the pathologic results. Despite its rare incidence, a few cases of primary or metastatic synovial sarcoma involving the spinal cord, foramen, vertebral body, or paraspinal muscles have been reported in the literature.
Materials and methods
We present the case of a 29-year-old man with a synovial sarcoma in the paraspinal muscle of the cervical spine. The patient was evaluated radiologically and histologically. Plain radiography, computed tomography, and magnetic resonance imaging were performed as part of the preoperative workup, and immunohistochemical and cytogenetic studies were additionally performed to identify the histologic features of the tumor. The patient underwent marginal resection followed by adjuvant radiation therapy. The patient has been followed up for 2 years.
Conclusions
This article highlights the features of synovial sarcoma of the spine via a comprehensive review. Synovial sarcoma of the spine is uncommon, but it is a challenging issue in both diagnostic and therapeutic aspects. The currently available evidence suggests the use of a multidisciplinary approach in the treatment of synovial sarcoma, which includes complete resection and radiation therapy.
doi:10.1007/s00586-013-3034-8
PMCID: PMC3897827  PMID: 24121750
Synovial sarcoma; Cervical spine; Paraspinal muscle
5.  Gankyrin is a predictive and oncogenic factor in well-differentiated and dedifferentiated liposarcoma 
Oncotarget  2014;5(19):9065-9078.
Liposarcoma is one of the most common histologic types of soft tissue sarcoma and is frequently an aggressive cancer with poor outcome. Hence, alternative approaches other than surgical excision are necessary to improve treatment of well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS).
For this reason, we performed a two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry/mass spectrometry (MALDI-TOF/MS) analysis to identify new factors for WDLPS and DDLPS. Among the selected candidate proteins, gankyrin, known to be an oncoprotein, showed a significantly high level of expression pattern and inversely low expression of p53/p21 in WDLPS and DDLPS tissues, suggesting possible utility as a new predictive factor. Moreover, inhibition of gankyrin not only led to reduction of in vitro cell growth ability including cell proliferation, colony-formation, and migration, but also in vivo DDLPS cell tumorigenesis, perhaps via downregulation of the p53 tumor suppressor gene and its p21 target and also reduction of AKT/mTOR signal activation. This study identifies gankyrin, for the first time, as new potential predictive and oncogenic factor of WDLPS and DDLPS, suggesting the potential for service as a future LPS therapeutic approach.
PMCID: PMC4253419  PMID: 25238053
Liposarcoma; 2-DE; Gankyrin; Predictive factor; Tumorigenesis
6.  Successful use of pazopanib for treatment of refractory metastatic hemangiopericytoma 
Hemangiopericytoma is a rare disease entity of soft-tissue sarcoma (STS) that can be cured with surgical resection. In cases of inoperable recurrence or metastasis, palliative chemotherapy is indicated, though there is currently no approved chemotherapy regimen. Therefore new treatment regimens are needed.
We describe three cases of metastatic hemangiopericytoma. In the first case, five lines of chemotherapeutic agents were used unsuccessfully in a patient with a 12-year history of metastatic hemangiopericytoma. After one cycle of pazopanib therapy, however, chest radiography showed a decrease in tumor volume of more than 30%. A marked decrease in FDG uptake on PET CT was also noted, and the patient is now on her 5th month of pazopanib therapy. The second case is a patient with a brain hemangiopericytoma with multiple liver, lung, and bone metastases. Pazopanib induced radiologic stabilization of metastatic disease over the course of 8 months. The third case is a patient with a retroperitoneal hemangiopericytoma with pleural and peri-renal metastases. For more than 8 months, he has exhibited stable disease with pazopanib treatment.
Pazopanib may be useful for treatment of metastatic hemangiopericytoma, though further studies are needed to confirm the efficacy of this medication and to investigate its molecular mechanism of action.
doi:10.1186/2045-3329-4-13
PMCID: PMC4179434  PMID: 25276340
Hemangiopericytoma; Pazopanib; Anti-angiogenic agent
7.  The forkhead transcription factor FOXM1 promotes endocrine resistance and invasiveness in estrogen receptor–positive breast cancer by expansion of stem-like cancer cells 
Introduction
The forkhead transcription factor FOXM1 coordinates expression of cell cycle–related genes and plays a pivotal role in tumorigenesis and cancer progression. We previously showed that FOXM1 acts downstream of 14-3-3ζ signaling, the elevation of which correlates with a more aggressive tumor phenotype. However, the role that FOXM1 might play in engendering resistance to endocrine treatments in estrogen receptor–positive (ER+) patients when tumor FOXM1 is high has not been clearly defined yet.
Methods
We analyzed FOXM1 protein expression by immunohistochemistry in 501 ER-positive breast cancers. We also mapped genome-wide FOXM1, extracellular signal-regulated kinase 2 and ERα binding events by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in hormone-sensitive and resistant breast cancer cells after tamoxifen treatment. These binding profiles were integrated with gene expression data derived from cells before and after FOXM1 knockdown to highlight specific FOXM1 transcriptional networks. We also modulated the levels of FOXM1 and newly discovered FOXM1-regulated genes and examined their impact on the cancer stem-like cell population and on cell invasiveness and resistance to endocrine treatments.
Results
FOXM1 protein expression was high in 20% of the tumors, which correlated with significantly reduced survival in these patients (P = 0.003 by logrank Mantel-Cox test). ChIP-seq analyses revealed that FOXM1 binding sites were enriched at the transcription start site of genes involved in cell-cycle progression, maintenance of stem cell properties, and invasion and metastasis, all of which are associated with a poor prognosis in ERα-positive patients treated with tamoxifen. Integration of binding profiles with gene expression highlighted FOXM1 transcriptional networks controlling cell proliferation, stem cell properties, invasion and metastasis. Increased expression of FOXM1 was associated with an expansion of the cancer stem-like cell population and with increased cell invasiveness and resistance to endocrine treatments. Use of a selective FOXM1 inhibitor proved very effective in restoring endocrine therapy sensitivity and decreasing breast cancer aggressiveness.
Conclusions
Collectively, our findings uncover novel roles for FOXM1 and FOXM1-regulated genes in promoting cancer stem-like cell properties and therapy resistance. They highlight the relevance of FOXM1 as a therapeutic target to be considered for reducing invasiveness and enhancing breast cancer response to endocrine treatments.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0436-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0436-4
PMCID: PMC4303117  PMID: 25213081
8.  Synchronous Triple Primary Lung Cancers: A Case Report 
Korean Journal of Radiology  2014;15(5):646-650.
Synchronous primary lung cancers are relatively rare. The accurate diagnosis remains challenging, despite of the routine use of bronchoscopy and computed tomography (CT) of the chest. Herein we report a case of synchronous triple primary cancers of the right lung in a 72-year-old male patient in whom each tumor presented distinct CT imaging findings.
doi:10.3348/kjr.2014.15.5.646
PMCID: PMC4170167  PMID: 25246827
Neoplasms, multiple primary; Lung; Multidetector computed tomography
9.  CDK4 Amplification Predicts Recurrence of Well-Differentiated Liposarcoma of the Abdomen 
PLoS ONE  2014;9(8):e99452.
Background
The absence of CDK4 amplification in liposarcomas is associated with favorable prognosis. We aimed to identify the factors associated with tumor recurrence in patients with well-differentiated (WD) and dedifferentiated (DD) liposarcomas.
Methods
From 2000 to 2010, surgical resections for 101 WD and DD liposarcomas were performed. Cases in which complete surgical resections with curative intent were carried out were selected. MDM2 and CDK4 gene amplification were analyzed by quantitative real-time polymerase chain reaction (Q-PCR).
Results
There were 31 WD and 17 DD liposarcomas. Locoregional recurrence was observed in 11 WD and 3 DD liposarcomas. WD liposarcomas showed better patient survival compared to DD liposarcomas (P<0.05). Q-PCR analysis of the liposarcomas revealed the presence of CDK4 amplification in 44 cases (91.7%) and MDM2 amplification in 46 cases (95.8%). WD liposarcomas with recurrence after surgical resection had significantly higher levels of CDK4 amplification compared to those without recurrence (P = 0.041). High level of CDK4 amplification (cases with CDK4 amplification higher than the median 7.54) was associated with poor recurrence-free survival compared to low CDK4 amplification in both univariate (P = 0.012) and multivariate analyses (P = 0.020).
Conclusions
Level of CDK4 amplification determined by Q-PCR was associated with the recurrence of WD liposarcomas after surgical resection.
doi:10.1371/journal.pone.0099452
PMCID: PMC4133208  PMID: 25121597
10.  Extrapulmonary Lymphangioleiomyoma: Clinicopathological Analysis of 4 Cases 
Korean Journal of Pathology  2014;48(3):188-192.
Background
Lymphangioleiomyomatosis (LAM) is a slowly progressive neoplastic disease that predominantly affects females. Usually, LAM affects the lung; it can also affect extrapulmonary sites, such as the mediastinum, the retroperitoneum, or the lymph nodes, although these locations are rare. A localized form of LAM can manifest as extrapulmonary lesions; this form is referred to as extrapulmonary lymphangioleiomyoma (E-LAM). Due to the rare occurrence of E-LAM and its variable, atypical location, E-LAM is often difficult to diagnose. Herein, we report the clinicopathological information from four E-LAM cases, and also review previous articles investigating this disease.
Methods
Four patients with E-LAM were identified at the Samsung Medical Center (Seoul, Korea) from 1995 to 2012. All E-LAM lesions underwent surgical excision.
Results
All patients were females within the age range of 43 to 47 years. Two patients had para-aortic retroperitoneal masses, while the other two patients had pelvic lesions; two out of the four patients also had accompanying pulmonary LAM. In addition, no patient displayed any evidence of tuberous sclerosis. Histologically, two patients exhibited nuclear atypism with cytologic degeneration.
Conclusions
E-LAM should be considered in the differential diagnosis of patients presenting with pelvic or para-aortic masses. We also conclude that further clinical and pathological evaluation is needed in patients with E-LAM and nuclear atypism.
doi:10.4132/KoreanJPathol.2014.48.3.188
PMCID: PMC4087131  PMID: 25013416
Lymphangioleiomyomatosis; Abdomen; Pelvis; Lymph nodes; Recurrence
11.  Polyostotic Fibrous Dysplasia Mimicking Multiple Bone Metastases in a Patient with Ductal Carcinoma In Situ 
Journal of Breast Cancer  2014;17(1):83-87.
Whole-body bone scans and whole body 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic scans are sensitive for detecting bone metastasis in patients with breast cancer. However, it is often difficult to discriminate between bone metastasis and other nonmalignant bone lesions. Polyostotic fibrous dysplasia is a rare disorder characterized by the osteoid medullary cavity filling with fibrous tissue causing bony expansion. We report the case of a 42-year-old female patient with ductal carcinoma in situ, which appeared to have multiple bone metastases on initial work-up images. Subsequently, the bone metastases were identified as polyostotic fibrous dysplasia. The patient underwent modified radical mastectomy and subsequently visited for a second opinion regarding the bony metastases. She underwent right ilium computed tomography-guided biopsy. Pathology was consistent with fibrous dysplasia. This patient received only adjuvant tamoxifen, and 1.5 years later, there was no evidence of recurrence.
doi:10.4048/jbc.2014.17.1.83
PMCID: PMC3988348  PMID: 24744802
Breast neoplasms; Fibrous dysplasia of bone; Neoplasm metastasis; Positron-emission tomography; Whole body imaging
12.  Quantitative CT Variables Enabling Response Prediction in Neoadjuvant Therapy with EGFR-TKIs: Are They Different from Those in Neoadjuvant Concurrent Chemoradiotherapy? 
PLoS ONE  2014;9(2):e88598.
Background and Purpose
To correlate changes of various CT parameters after the neoadjuvant treatment in patients with lung adenocarcinoma with pathologic responses, focused on their relationship with different therapeutic options, particularly of EGFR-TKI and concurrent chemoradiation therapy (CCRT) settings.
Materials and Methods
We reviewed pre-operative CT images of primary tumors and surgical specimens obtained after neoadjuvant therapy (TKI, n = 23; CCRT, n = 28) from 51 patients with lung adenocarcinoma. Serial changes in tumor volume, density, mass, skewness/kurtosis, and size-zone variability/intensity variability) were assessed from CT datasets. The changes in CT parameters were correlated with histopathologic responses, and the relationship between CT variables and histopathologic responses was compared between TKI and CCRT groups.
Results
Tumor volume, mass, kurtosis, and skewness were significant predictors of pathologic response in CCRT group in univariate analysis. Using multivariate analysis, kurtosis was found to be independent predictor. In TKI group, intensity variability and size-zone variability were significantly decreased in pathologic responder group. Intensity variability was found to be an independent predictor for pathologic response on multivariate analysis.
Conclusions
Quantitative CT variables including histogram or texture analysis have potential as a predictive tool for response evaluation, and it may better reflect treatment response than standard response criteria based on size changes.
doi:10.1371/journal.pone.0088598
PMCID: PMC3935840  PMID: 24586348
13.  Targeted Inhibition of FAK, PYK2 and BCL-XL Synergistically Enhances Apoptosis in Ovarian Clear Cell Carcinoma Cell Lines 
PLoS ONE  2014;9(2):e88587.
Ovarian clear cell carcinoma (OCCC) displays a higher resistance to first line chemotherapy, requiring the development of new therapeutics. We previously identified a frequent chromosomal gain at 8q24 that harbors the focal-adhesion kinase (FAK) gene; the potential of this gene as a therapeutic target remains to be evaluated in OCCCs. We first examined the dependence of OCCCs on FAK and the PI3K/AKT signaling pathway. FAK was overexpressed in 20% of 67 OCCC samples, and this overexpression was correlated with its copy number gain. FAK copy number gains and mutations in PIK3CA accounted for about 40% of OCCC samples, suggesting that the FAK/PI3K/AKT axis is an attractive candidate for targeted therapeutics. We, therefore, treated ovarian cancer cell lines, including OCCC subtypes, with the FAK inhibitors PF-562,271 (PF271), and PF-573,228 (PF228). Ovarian cancer cells were more sensitive to PF271 than PF228. We then searched for single agents that exhibited a synergistic effect on cell death in combination with PF271. We found that co-treatment of PF271 with ABT-737, a BCL-2/BCL-XL antagonist, was profoundly effective at inducing apoptosis. RMGI and OVISE cells were more sensitive to ABT-737 than OVMANA and SKOV3 cells, which have PIK3CA mutations. Mechanistically, PF271 treatment resulted in the transient down-regulation of the anti-apoptotic protein MCL1 via the PI3K/AKT pathway. Therefore, PF271/ABT-737 treatment led to the inhibition of the anti-apoptotic proteins MCL1 and BCL-XL/BCL-2. We suggest that pharmacological inhibition of BCL-XL and FAK/PYK2 can be a potential therapeutic strategy for the treatment of OCCC.
doi:10.1371/journal.pone.0088587
PMCID: PMC3921183  PMID: 24523919
14.  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.
doi:10.1038/srep03623
PMCID: PMC3887377  PMID: 24406431
15.  Comparison of Three BRAF Mutation Tests in Formalin-Fixed Paraffin Embedded Clinical Samples 
Korean Journal of Pathology  2013;47(4):348-354.
Background
Recently, BRAF inhibitors showed dramatic treatment outcomes in BRAF V600 mutant melanoma. Therefore, the accuracy of BRAF mutation test is critical.
Methods
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.
Results
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.
Conclusions
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.
doi:10.4132/KoreanJPathol.2013.47.4.348
PMCID: PMC3759634  PMID: 24009630
BRAF mutation; Melanoma; Real-time polymerase chain reaction; Sanger sequencing; Dual-priming oligonucleotide-PCR
16.  EGFR Mutation Testing in Patients with Advanced Non-Small Cell Lung Cancer: A Comprehensive Evaluation of Real-World Practice in an East Asian Tertiary Hospital 
PLoS ONE  2013;8(2):e56011.
Introduction
Guidelines for management of non-small cell lung cancer (NSCLC) strongly recommend EGFR mutation testing. These recommendations are particularly relevant in Asians that have higher EGFR mutation prevalence. This study aims to explore current testing practices, logistics of testing, types of EGFR mutation, and prevalence of EGFR mutations in patients with advanced NSCLC in a large comprehensive cancer center in Korea.
Methods
Our retrospective cohort included 1,503 NSCLC patients aged ≥18 years, with stage IIIB/IV disease, who attended the Samsung Medical Center in Seoul, Korea, from January 2007 through July 2010. Trained oncology nurses reviewed and abstracted data from electronic medical records.
Results
This cohort had a mean age (SD) of 59.6 (11.1) years, 62.7% were males, and 52.9% never-smokers. The most common NSCLC histological types were adenocarcinoma (70.5%) and squamous cell carcinoma (18.0%). Overall, 39.5% of patients were tested for EGFR mutations. The proportion of patients undergoing EGFR testing during January 2007 through July 2008, August 2008 through September 2009, and October 2009 through July 2010 were 23.3%, 38.3%, and 63.5%, respectively (P<0.001). The median time elapsed between cancer diagnoses and receiving EGFR testing results was 21 days. EGFR testing was most frequently ordered by oncologists (57.7%), pulmonologists (31.9%), and thoracic surgeons (6.6%). EGFR testing was more commonly requested for women, younger patients, stage IV disease, non-smokers, and adenocarcinoma histology. Of 586 cases successfully tested for EGFR mutations, 209 (35.7%) were positive, including 118 cases with exon 19 deletions and 62 with L858R mutations. EGFR mutation positive patients were more likely to be female, never-smokers, never-drinkers and to have adenocarcinoma.
Conclusions
In a large cancer center in Korea, the proportion of EGFR testing increased from 2007 through 2010. The high frequency of EGFR mutation positive cases warrants the need for generalized testing in Asian NSCLC patients.
doi:10.1371/journal.pone.0056011
PMCID: PMC3585299  PMID: 23468851
17.  Low SP1 Expression Differentially Affects Intestinal-Type Compared with Diffuse-Type Gastric Adenocarcinoma 
PLoS ONE  2013;8(2):e55522.
Specificity protein 1 (SP1) is an essential transcription factor that regulates multiple cancer-related genes. Because aberrant expression of SP1 is related to cancer development and progression, we focused on SP1 expression in gastric carcinoma and its correlation with disease outcomes. Although patient survival decreased as SP1 expression increased (P<0.05) in diffuse-type gastric cancer, the lack of SP1 expression in intestinal-type gastric cancer was significantly correlated with poor survival (P<0.05). The knockdown of SP1 in a high SP1-expressing intestinal-type gastric cell line, MKN28, increased migration and invasion but decreased proliferation. Microarray data in SP1 siRNA-transfected MKN28 revealed that the genes inhibiting migration were downregulated, whereas the genes negatively facilitating proliferation were increased. However, both migration and invasion were decreased by forced SP1 expression in a low SP1-expressing intestinal-type gastric cell line, AGS. Unlike the intestinal-type, in a high SP1-expressing diffuse-type gastric cell line, SNU484, migration and invasion were decreased by SP1 siRNA. In contrast to previous studies that did not identify differences between the 2 histological types, our results reveal that low expression of SP1 is involved in cancer progression and metastasis and differentially affects intestinal-type compared with diffuse-type gastric adenocarcinoma.
doi:10.1371/journal.pone.0055522
PMCID: PMC3577840  PMID: 23437057
18.  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.
doi:10.4132/KoreanJPathol.2013.47.1.77
PMCID: PMC3589613  PMID: 23482293
Neuroectodermal tumor, primitive, peripheral; Intestine, small; Osteogenesis; Metaplasia; EWSR1
19.  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.
Purpose
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.
Results
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).
Conclusion
Poor tumor volume response and an interval increase in COX-2 expression at mid-RT decreased survival outcomes in patients with uterine cervical cancer.
doi:10.3857/roj.2012.30.4.218
PMCID: PMC3546291  PMID: 23346542
Uterine cervical neoplasms; Radiotherapy; Volume response; Cyclooxygenase-2
20.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.4132/KoreanJPathol.2012.46.5.436
PMCID: PMC3490119  PMID: 23136570
ICD-O3; Behavior code; Hematologic malignancy; Soft tissue neoplasms
21.  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.
doi:10.3892/ijo.2012.1517
PMCID: PMC3582759  PMID: 22710759
transducer of ErbB-2; gastric cancer; cell migration; invasion; Smad4; β-catenin
22.  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.
doi:10.4132/KoreanJPathol.2012.46.3.306
PMCID: PMC3479760  PMID: 23110021
Dendritic cell sarcoma, follicular; Extranodal; Parapharynx
23.  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.
doi:10.3892/ijo.2011.1302
PMCID: PMC3584590  PMID: 22179774
biomarker; therapeutic target; glioblastoma; tissue micro-array; bioinformatics; automated image analysis
24.  Molecular profiles of EGFR, K-ras, c-met, and FGFR in pulmonary pleomorphic carcinoma, a rare lung malignancy 
Background
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1007/s00432-011-0986-0
PMCID: PMC3133705  PMID: 21626008
Lung cancer; Pulmonary pleomorphic carcinoma; EGFR; k-ras; c-kit; c-met; FGFR
25.  Cancer-Associated Splicing Variant of Tumor Suppressor AIMP2/p38: Pathological Implication in Tumorigenesis 
PLoS Genetics  2011;7(3):e1001351.
Although ARS-interacting multifunctional protein 2 (AIMP2, also named as MSC p38) was first found as a component for a macromolecular tRNA synthetase complex, it was recently discovered to dissociate from the complex and work as a potent tumor suppressor. Upon DNA damage, AIMP2 promotes apoptosis through the protective interaction with p53. However, it was not demonstrated whether AIMP2 was indeed pathologically linked to human cancer. In this work, we found that a splicing variant of AIMP2 lacking exon 2 (AIMP2-DX2) is highly expressed by alternative splicing in human lung cancer cells and patient's tissues. AIMP2-DX2 compromised pro-apoptotic activity of normal AIMP2 through the competitive binding to p53. The cells with higher level of AIMP2-DX2 showed higher propensity to form anchorage-independent colonies and increased resistance to cell death. Mice constitutively expressing this variant showed increased susceptibility to carcinogen-induced lung tumorigenesis. The expression ratio of AIMP2-DX2 to normal AIMP2 was increased according to lung cancer stage and showed a positive correlation with the survival of patients. Thus, this work identified an oncogenic splicing variant of a tumor suppressor, AIMP2/p38, and suggests its potential for anti-cancer target.
Author Summary
Lung cancer is one of the most common cancers and a leading cause of death resulting from cancer. Despite intensive investigation, effective therapeutic targets and reliable biomarkers are still limited. Here we found that a tumor suppressor, AIMP2 (MSC p38), produces a variant lacking a part of its structure in cancer tissues. We designated it AIMP2-DX2. This smaller version of AIMP2 compromises the normal tumor suppressive activity of AIMP2 and induces tumor formation. We also found that the expression of AIMP2-DX2 was increased according to cancer progression. In addition, the patients with higher expression of AIMP2-DX2 showed lower survival than those with lower levels of this variant. Suppression of AIMP2-DX2 slowed tumor growth, suggesting it as a new therapeutic target. In summary, this work newly identified a tumor-inducing factor, AIMP2-DX2, that can be used as a therapeutic target and biomarker associated with lung cancer.
doi:10.1371/journal.pgen.1001351
PMCID: PMC3069106  PMID: 21483803

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