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author:("Lee, Ju-seg")
1.  Comprehensive molecular characterization of gastric adenocarcinoma 
Bass, Adam J. | Thorsson, Vesteinn | Shmulevich, Ilya | Reynolds, Sheila M. | Miller, Michael | Bernard, Brady | Hinoue, Toshinori | Laird, Peter W. | Curtis, Christina | Shen, Hui | Weisenberger, Daniel J. | Schultz, Nikolaus | Shen, Ronglai | Weinhold, Nils | Kelsen, David P. | Bowlby, Reanne | Chu, Andy | Kasaian, Katayoon | Mungall, Andrew J. | Robertson, A. Gordon | Sipahimalani, Payal | Cherniack, Andrew | Getz, Gad | Liu, Yingchun | Noble, Michael S. | Pedamallu, Chandra | Sougnez, Carrie | Taylor-Weiner, Amaro | Akbani, Rehan | Lee, Ju-Seog | Liu, Wenbin | Mills, Gordon B. | Yang, Da | Zhang, Wei | Pantazi, Angeliki | Parfenov, Michael | Gulley, Margaret | Piazuelo, M. Blanca | Schneider, Barbara G. | Kim, Jihun | Boussioutas, Alex | Sheth, Margi | Demchok, John A. | Rabkin, Charles S. | Willis, Joseph E. | Ng, Sam | Garman, Katherine | Beer, David G. | Pennathur, Arjun | Raphael, Benjamin J. | Wu, Hsin-Ta | Odze, Robert | Kim, Hark K. | Bowen, Jay | Leraas, Kristen M. | Lichtenberg, Tara M. | Weaver, Stephanie | McLellan, Michael | Wiznerowicz, Maciej | Sakai, Ryo | Getz, Gad | Sougnez, Carrie | Lawrence, Michael S. | Cibulskis, Kristian | Lichtenstein, Lee | Fisher, Sheila | Gabriel, Stacey B. | Lander, Eric S. | Ding, Li | Niu, Beifang | Ally, Adrian | Balasundaram, Miruna | Birol, Inanc | Bowlby, Reanne | Brooks, Denise | Butterfield, Yaron S. N. | Carlsen, Rebecca | Chu, Andy | Chu, Justin | Chuah, Eric | Chun, Hye-Jung E. | Clarke, Amanda | Dhalla, Noreen | Guin, Ranabir | Holt, Robert A. | Jones, Steven J.M. | Kasaian, Katayoon | Lee, Darlene | Li, Haiyan A. | Lim, Emilia | Ma, Yussanne | Marra, Marco A. | Mayo, Michael | Moore, Richard A. | Mungall, Andrew J. | Mungall, Karen L. | Nip, Ka Ming | Robertson, A. Gordon | Schein, Jacqueline E. | Sipahimalani, Payal | Tam, Angela | Thiessen, Nina | Beroukhim, Rameen | Carter, Scott L. | Cherniack, Andrew D. | Cho, Juok | Cibulskis, Kristian | DiCara, Daniel | Frazer, Scott | Fisher, Sheila | Gabriel, Stacey B. | Gehlenborg, Nils | Heiman, David I. | Jung, Joonil | Kim, Jaegil | Lander, Eric S. | Lawrence, Michael S. | Lichtenstein, Lee | Lin, Pei | Meyerson, Matthew | Ojesina, Akinyemi I. | Pedamallu, Chandra Sekhar | Saksena, Gordon | Schumacher, Steven E. | Sougnez, Carrie | Stojanov, Petar | Tabak, Barbara | Taylor-Weiner, Amaro | Voet, Doug | Rosenberg, Mara | Zack, Travis I. | Zhang, Hailei | Zou, Lihua | Protopopov, Alexei | Santoso, Netty | Parfenov, Michael | Lee, Semin | Zhang, Jianhua | Mahadeshwar, Harshad S. | Tang, Jiabin | Ren, Xiaojia | Seth, Sahil | Yang, Lixing | Xu, Andrew W. | Song, Xingzhi | Pantazi, Angeliki | Xi, Ruibin | Bristow, Christopher A. | Hadjipanayis, Angela | Seidman, Jonathan | Chin, Lynda | Park, Peter J. | Kucherlapati, Raju | Akbani, Rehan | Ling, Shiyun | Liu, Wenbin | Rao, Arvind | Weinstein, John N. | Kim, Sang-Bae | Lee, Ju-Seog | Lu, Yiling | Mills, Gordon | Laird, Peter W. | Hinoue, Toshinori | Weisenberger, Daniel J. | Bootwalla, Moiz S. | Lai, Phillip H. | Shen, Hui | Triche, Timothy | Van Den Berg, David J. | Baylin, Stephen B. | Herman, James G. | Getz, Gad | Chin, Lynda | Liu, Yingchun | Murray, Bradley A. | Noble, Michael S. | Askoy, B. Arman | Ciriello, Giovanni | Dresdner, Gideon | Gao, Jianjiong | Gross, Benjamin | Jacobsen, Anders | Lee, William | Ramirez, Ricardo | Sander, Chris | Schultz, Nikolaus | Senbabaoglu, Yasin | Sinha, Rileen | Sumer, S. Onur | Sun, Yichao | Weinhold, Nils | Thorsson, Vésteinn | Bernard, Brady | Iype, Lisa | Kramer, Roger W. | Kreisberg, Richard | Miller, Michael | Reynolds, Sheila M. | Rovira, Hector | Tasman, Natalie | Shmulevich, Ilya | Ng, Santa Cruz Sam | Haussler, David | Stuart, Josh M. | Akbani, Rehan | Ling, Shiyun | Liu, Wenbin | Rao, Arvind | Weinstein, John N. | Verhaak, Roeland G.W. | Mills, Gordon B. | Leiserson, Mark D. M. | Raphael, Benjamin J. | Wu, Hsin-Ta | Taylor, Barry S. | Black, Aaron D. | Bowen, Jay | Carney, Julie Ann | Gastier-Foster, Julie M. | Helsel, Carmen | Leraas, Kristen M. | Lichtenberg, Tara M. | McAllister, Cynthia | Ramirez, Nilsa C. | Tabler, Teresa R. | Wise, Lisa | Zmuda, Erik | Penny, Robert | Crain, Daniel | Gardner, Johanna | Lau, Kevin | Curely, Erin | Mallery, David | Morris, Scott | Paulauskis, Joseph | Shelton, Troy | Shelton, Candace | Sherman, Mark | Benz, Christopher | Lee, Jae-Hyuk | Fedosenko, Konstantin | Manikhas, Georgy | Potapova, Olga | Voronina, Olga | Belyaev, Smitry | Dolzhansky, Oleg | Rathmell, W. Kimryn | Brzezinski, Jakub | Ibbs, Matthew | Korski, Konstanty | Kycler, Witold | ŁaŸniak, Radoslaw | Leporowska, Ewa | Mackiewicz, Andrzej | Murawa, Dawid | Murawa, Pawel | Spychała, Arkadiusz | Suchorska, Wiktoria M. | Tatka, Honorata | Teresiak, Marek | Wiznerowicz, Maciej | Abdel-Misih, Raafat | Bennett, Joseph | Brown, Jennifer | Iacocca, Mary | Rabeno, Brenda | Kwon, Sun-Young | Penny, Robert | Gardner, Johanna | Kemkes, Ariane | Mallery, David | Morris, Scott | Shelton, Troy | Shelton, Candace | Curley, Erin | Alexopoulou, Iakovina | Engel, Jay | Bartlett, John | Albert, Monique | Park, Do-Youn | Dhir, Rajiv | Luketich, James | Landreneau, Rodney | Janjigian, Yelena Y. | Kelsen, David P. | Cho, Eunjung | Ladanyi, Marc | Tang, Laura | McCall, Shannon J. | Park, Young S. | Cheong, Jae-Ho | Ajani, Jaffer | Camargo, M. Constanza | Alonso, Shelley | Ayala, Brenda | Jensen, Mark A. | Pihl, Todd | Raman, Rohini | Walton, Jessica | Wan, Yunhu | Demchok, John A. | Eley, Greg | Mills Shaw, Kenna R. | Sheth, Margi | Tarnuzzer, Roy | Wang, Zhining | Yang, Liming | Zenklusen, Jean Claude | Davidsen, Tanja | Hutter, Carolyn M. | Sofia, Heidi J. | Burton, Robert | Chudamani, Sudha | Liu, Jia
Nature  2014;513(7517):202-209.
Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.
doi:10.1038/nature13480
PMCID: PMC4170219  PMID: 25079317
2.  Significant Association of oncogene YAP1 with Poor Prognosis and Cetuximab Resistance in Colorectal Cancer Patients 
Purpose
Activation of YAP1, novel oncogene in Hippo pathway, has been observed in many cancers including colorectal cancer (CRC). We investigated if activation of YAP1 is significantly associated with prognosis or treatment outcomes in CRC
Experimental Design
A gene expression signature reflecting YAP1 activation was identified in CRC cells, and CRC patients were stratified into two groups according to this signature: activated YAP1 CRC (AYCC) or inactivated YAP1 CRC (IYCC). Stratified patients in five test cohorts were evaluated to determine the effect of the signature on CRC prognosis and response to cetuximab treatment.
Results
The activated YAP1 signature was associated with poor prognosis for CRC in four independent patient cohorts with stage I–III disease (total n = 1,028). In a multivariate analysis, the impact of the YAP1 signature on the disease-free survival was independent of other clinical variables [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.25–2.13; P < 0.001]. In patients with stage IV CRC and wild-type KRAS, IYCC patients had a better disease control rate and progression-free survival (PFS) after cetuximab monotherapy than did AYCC patients; however, in patients with KRAS mutations, PFS duration after cetuximab monotherapy was not different between IYCC and AYCC patients. In multivariate analysis, the effect of YAP1 activation on PFS was independent of KRAS mutation status and other clinical variables (HR, 1.82; 95% CI, 1.05–3.16; P = 0.03).
Conclusions
Activation of YAP1 is highly associated with poor prognosis for CRC and may be useful in identifying patients with metastatic CRC resistant to cetuximab.
doi:10.1158/1078-0432.CCR-14-1374
PMCID: PMC4513664  PMID: 25388162
3.  Impact of Intratumoral Expression Levels of Fluoropyrimidine-Metabolizing Enzymes on Treatment Outcomes of Adjuvant S-1 Therapy in Gastric Cancer 
PLoS ONE  2015;10(3):e0120324.
We analyzed the expression levels of fluoropyrimidine-metabolizing enzymes (thymidylate synthase [TS], dihydropyrimidine dehydrogenase [DPD], thymidine phosphorylase [TP] and orotate phosphoribosyltransferase [OPRT]) to identify potential biomarkers related to treatment outcomes in gastric cancer (GC) patients receiving adjuvant S-1 chemotherapy. In this study, 184 patients who received curative gastrectomy (D2 lymph node dissection) and adjuvant S-1 were included. Immunohistochemistry and quantitative reverse transcription polymerase chain reaction were performed to measure the protein and mRNA levels of TS, DPD, TP, and OPRT in tumor tissue. In univariate analysis, low intratumoral DPD protein expression was related to poorer 5-year disease-free survival (DFS; 78% vs. 88%; P = 0.068). Low intratumoral DPD mRNA expression (1st [lowest] quartile) was also related to poorer DFS (69% vs. 90%; P < 0.001) compared to high intratumoral DPD expression (2nd to 4th quartiles). In multivariate analyses, low intratumoral DPD protein or mRNA expression was related to worse DFS (P < 0.05), irrespective of other clinical variables. TS, TP, and OPRT expression levels were not related to treatment outcomes. Severe non-hematologic toxicities (grade ≥ 3) had a trend towards more frequent development in patients with low intratumoral DPD mRNA expression (29% vs. 16%; P = 0.068). In conclusion, GC patients with high intratumoral DPD expression did not have inferior outcome following adjuvant S-1 therapy compared with those with low DPD expression. Instead, low intratumoral DPD expression was related to poor DFS.
doi:10.1371/journal.pone.0120324
PMCID: PMC4368508  PMID: 25793299
4.  Activation of YAP1 Is Associated with Poor Prognosis and Response to Taxanes in Ovarian Cancer 
Anticancer research  2014;34(2):811-817.
Aim
We aimed to investigate the clinical significance of the activation of Yes-Associated Protein 1 (YAP1), a key downstream effector of Hippo tumor-suppressor pathway, in ovarian cancer.
Patients and Methods
A gene expression signature reflecting activation of YAP1 was developed from gene expression data of 267 samples from patients with ovarian cancer. A refined ovarian cancer YAP1 signature was validated in an independent ovarian cancer cohort (n=185). Associations between the YAP1 signature and prognosis were assessed using Kaplan–Meier plots, the log-rank test, and a Cox proportional hazards model.
Results
We identified a 612-gene expression signature reflecting YAP1 activation in ovarian cancer. In multivariate analysis, the signature was an independent predictor of overall survival (hazard ratio=1.66; 95% confidence interval=1.1 to 2.53; p=0.01). In subset analysis, the signature identified patients likely to benefit from taxane-based adjuvant chemotherapy.
Conclusion
Activation of YAP1 is significantly associated with prognosis and the YAP1 signature can predict response to taxane-based adjuvant chemotherapy in patients with ovarian cancer.
PMCID: PMC4082822  PMID: 24511017
DNA microarrays; ovarian cancer; prognosis; taxane; YAP1
5.  65-gene–based risk score classifier predicts overall survival in hepatocellular carcinoma 
Hepatology (Baltimore, Md.)  2012;55(5):1443-1452.
Clinical application of the prognostic gene expression signature has been delayed due to the large number of genes and complexity of prediction algorithms. In current study, we aim to develop an easy-to-use risk score with a limited number of genes that can robustly predict prognosis of patients with HCC. The risk score was developed by using Cox coefficient values of 65 genes in the training set (n=139) and its robustness was validated in test sets (n=292). The risk score was a highly significant predictor of overall survival (OS) in the first test cohort (P = 5.6 × 10-5, n = 100) and the second test cohort (P = 5.0 × 10-5, n = 192). In multivariate analysis, the risk score was significant risk factor among clinical variables examined together (hazard ratio [HR], 1.36; 95% confidential interval [CI], 1.13-1.64; P = 0.001 for OS).
Conclusion
The risk score classifier we have developed can identify two clinically distinct HCC subtypes at early and late stage of the disease in a simple and highly reproducible manner across multiple data sets.
doi:10.1002/hep.24813
PMCID: PMC4060518  PMID: 22105560
Hepatocellular Carcinoma; Gene expression signature; Microarrays; Prognostic biomarkers
6.  Epigenetic silencing of the non-coding RNA nc886 provokes oncogenes during human esophageal tumorigenesis 
Oncotarget  2014;5(11):3472-3481.
nc886 (= vtRNA2-1 or pre-miR-886) is a recently discovered noncoding RNA that is a cellular PKR (Protein Kinase RNA-activated) ligand and repressor. nc886 has been suggested to be a tumor suppressor, solely based on its expression pattern and genomic locus. In this report, we have provided sufficient evidence that nc886 is a putative tumor suppressor in esophageal squamous cell carcinoma (ESCC). In 84 paired specimens from ESCC patients, nc886 expression is significantly lower in tumors than their normal adjacent tissues. More importantly, decreased expression of nc886 is significantly associated with shorter recurrence-free survival of the patients. Suppression of nc886 is mediated by CpG hypermethylation of its promoter, as evidenced by its significant negative correlation to nc886 expression in ESCC tumors and by induced expression of nc886 upon demethylation of its promoter. Knockdown of nc886 and consequent PKR activation induce FOS and MYC oncogenes as well as some inflammatory genes including oncogenic NF-κB. When ectopically expressed, nc886 inhibits proliferation of ESCC cells, further demonstrating that nc886 could be a tumor suppressor. All these findings implicate nc886 as a novel, putative tumor suppressor that is epigenetically silenced and regulates the expression of oncogenes in ESCC.
PMCID: PMC4116496  PMID: 25004084
nc886; ESCC; CpG DNA methylation; tumor suppressor
7.  Overexpression of miR-196b and HOXA10 characterize a poor-prognosis gastric cancer subtype 
AIM: To identify molecular biologic differences between two gastric adenocarcinoma subgroups presenting different prognoses through the analysis of microRNA and protein expression.
METHODS: Array technologies were used to generate 1146 microRNAs and 124 proteins expression profiles of samples from 60 patients with gastric cancer. For the integrative analysis, we used established mRNA expression data published in our previous study. Whole mRNA expression levels were acquired from microarray data for 60 identical gastric cancer patients. Two gastric adenocarcinoma subgroups with distinct mRNA expression profiles presented distinctly different prognoses. MicroRNA and protein expression patterns were compared between gastric cancer tissue and normal gastric tissue and between two different prognostic groups. Aberrantly expressed microRNA, associated mRNA, and protein in patients with poor-prognosis gastric cancer were validated by quantitative reverse transcription polymerase chain reaction and immunochemistry in independent patients.
RESULTS: We obtained the expression data of 1146 microRNAs and 124 cancer-related proteins. Four microRNAs were aberrantly expressed in the two prognostic groups and in cancer vs non-cancer tissues (P < 0.05). In the poor-prognosis group, miR-196b, miR-135b, and miR-93 were up-regulated and miR-29c* was down-regulated. miR-196b expression positively correlated with Homeobox A10 (HOXA10) expression (r = 0.726, P < 0.001), which was significantly increased in poor-prognosis patients (P < 0.001). Comparing gastric cancer with non-cancer tissues, 46/124 proteins showed differential expression (P < 0.05); COX2 (P < 0.001) and cyclin B1 (P = 0.017) were clearly over-expressed in the poor-prognosis group.
CONCLUSION: Co-activation of miR-196b and HOXA10 characterized a poor-prognosis subgroup of patients with gastric cancer. Elucidation of the biologic function of miR-196b and HOXA10 is warranted.
doi:10.3748/wjg.v19.i41.7078
PMCID: PMC3819543  PMID: 24222951
Gastric cancer; Gene expression; Microarray; MicroRNA; miR-196b; Homeobox A10
8.  Prognostic gene expression signature associated with two molecularly distinct subtypes of colorectal cancer 
Gut  2011;61(9):1291-1298.
Aims
Despite continual efforts to develop prognostic and predictive models of colorectal cancer by using clinicopathological and genetic parameters, a clinical test that can discriminate between patients with good or poor outcome after treatment has not been established. Thus, the authors aim to uncover subtypes of colorectal cancer that have distinct biological characteristics associated with prognosis and identify potential biomarkers that best reflect the biological and clinical characteristics of subtypes.
Methods
Unsupervised hierarchical clustering analysis was applied to gene expression data from 177 patients with colorectal cancer to determine a prognostic gene expression signature. Validation of the signature was sought in two independent patient groups. The association between the signature and prognosis of patients was assessed by Kaplan–Meier plots, log-rank tests and the Cox model.
Results
The authors identified a gene signature that was associated with overall survival and disease-free survival in 177 patients and validated in two independent cohorts of 213 patients. In multivariate analysis, the signature was an independent risk factor (HR 3.08; 95% CI 1.33 to 7.14; p=0.008 for overall survival). Subset analysis of patients with AJCC (American Joint Committee on Cancer) stage III cancer revealed that the signature can also identify the patients who have better outcome with adjuvant chemotherapy (CTX). Adjuvant chemotherapy significantly affected disease-free survival in patients in subtype B (3-year rate, 71.2% (CTX) vs 41.9% (no CTX); p=0.004). However, such benefit of adjuvant chemotherapy was not significant for patients in subtype A.
Conclusion
The gene signature is an independent predictor of response to chemotherapy and clinical outcome in patients with colorectal cancer.
doi:10.1136/gutjnl-2011-300812
PMCID: PMC3419333  PMID: 21997556
9.  Gene expression signature–based prognostic risk score in gastric cancer 
Purpose
Despite continual efforts to develop a prognostic model of gastric cancer by using clinical and pathological parameters, a clinical test that can discriminate patients with good outcomes from those with poor outcomes after gastric cancer surgery has not been established. We aim to develop practical biomarker-based risk score that can predict relapse of gastric cancer after surgical treatment.
Experimental Design
Using microarray technologies, we generated and analyzed gene expression profiling data from 65 gastric cancer patients to identify biomarker genes associated with relapse. The association of expression patterns of identified genes with relapse and overall survival was validated in independent gastric cancer patients.
Results
We uncovered two subgroups of gastric cancer that were strongly associated with the prognosis. For the easy translation of our findings into practice, we developed a scoring system based on the expression of six genes that predicted the likelihood of relapse after curative resection. In multivariate analysis, the risk score was an independent predictor of relapse in a cohort of 96 patients. We were able to validate the robustness of the 6-gene signature in an additional independent cohort.
Conclusions
The risk score derived from the 6-gene set successfully prognosticated the relapse of gastric cancer patients after gastrectomy.
doi:10.1158/1078-0432.CCR-10-2180
PMCID: PMC3078023  PMID: 21447720
10.  Systems Biology Approaches to Decoding the Genome of Liver Cancer 
Molecular classification of cancers has been significantly improved patient outcomes through the implementation of treatment protocols tailored to the abnormalities present in each patient's cancer cells. Breast cancer represents the poster child with marked improvements in outcome occurring due to the implementation of targeted therapies for estrogen receptor or human epidermal growth factor receptor-2 positive breast cancers. Important subtypes with characteristic molecular features as potential therapeutic targets are likely to exist for all tumor lineages including hepatocellular carcinoma (HCC) but have yet to be discovered and validated as targets. Because each tumor accumulates hundreds or thousands of genomic and epigenetic alterations of critical genes, it is challenging to identify and validate candidate tumor aberrations as therapeutic targets or biomarkers that predict prognosis or response to therapy. Therefore, there is an urgent need to devise new experimental and analytical strategies to overcome this problem. Systems biology approaches integrating multiple data sets and technologies analyzing patient tissues holds great promise for the identification of novel therapeutic targets and linked predictive biomarkers allowing implementation of personalized medicine for HCC patients.
doi:10.4143/crt.2011.43.4.205
PMCID: PMC3253861  PMID: 22247704
Oligonucleotide array sequence analysis; Gene expression profiling; Hepatocellular carcinoma; Genomics; Systems biology; Proteomics
11.  Sulfatase 2 Up-Regulates Glypican 3, Promotes Fibroblast Growth Factor Signaling, and Decreases Survival in Hepatocellular Carcinoma 
Hepatology (Baltimore, Md.)  2008;47(4):1211-1222.
It has been shown that the heparin-degrading endosulfatase, sulfatase 1 (SULF1), functions as a liver tumor suppressor, but the role of the related sulfatase, sulfatase 2 (SULF2), in liver carcinogenesis remains to be elucidated. We investigated the effect of SULF2 on liver tumorigenesis. Expression of SULF2 was increased in 79 (57%) of 139 hepatocellular carcinomas (HCCs) and 8 (73%) of 11 HCC cell lines. Forced expression of SULF2 increased HCC cell growth and migration, whereas knockdown of SULF2 using short hairpin RNA targeting SULF2 abrogated HCC cell proliferation and migration in vitro. Because SULF1 and SULF2 desulfate heparan sulfate proteoglycans (HSPGs) and the HSPG glypican 3 (GPC3) is up-regulated in HCC, we investigated the effects of SULF2 on GPC3 expression and the association of SULF2 with GPC3. SULF2-mediated cell growth was associated with increased binding of fibroblast growth factor 2 (FGF2), phosphorylation of extracellular signal-regulated kinase and AKT, and expression of GPC3. Knockdown of GPC3 attenuated FGF2 binding in SULF2-expressing HCC cells. The effects of SULF2 on up-regulation of GPC3 and tumor growth were confirmed in nude mouse xenografts. Moreover, HCC patients with increased SULF2 expression in resected HCC tissues had a worse prognosis and a higher rate of recurrence after surgery.
Conclusion
In contrast to the tumor suppressor effect of SULF1, SULF2 has an oncogenic effect in HCC mediated in part through up-regulation of FGF signaling and GPC3 expression.
doi:10.1002/hep.22202
PMCID: PMC2536494  PMID: 18318435
12.  Decoding Human Liver Cancer Signatures 
Gastrointestinal Cancer Research : GCR  2008;2(4 Suppl 2):S31-S34.
Because alterations of expression patterns and genomic copy numbers of thousands of genes are fundamental properties of cancer cells, and the application of high-throughput microarray-based genomic technologies for the analysis of cancer inevitably generate many false-positive results, it is rarely possible to select a reasonable number of candidate genes for therapeutic targets and/or biomarkers for diagnosis and prognosis. Therefore, it will be necessary to devise new experimental and analytical strategies to overcome this problem. This review summarizes recent advances in gene expression profiling of hepatocellular carcinoma and discusses future strategies for analyzing large and complicated data sets from microarray studies and how to integrate these with diverse genomic data.
PMCID: PMC2661555  PMID: 19343146
13.  An expression signature of phenotypic resistance to hepatocellular carcinoma identified by cross-species gene expression analysis 
Cellular oncology (Dordrecht)  2012;35(3):163-173.
Background and aims
Hepatocarcinogenesis is under polygenic control. We analyzed gene expression patterns of dysplastic liver nodules (DNs) and hepatocellular carcinomas (HCCs) chemically-induced in F344 and BN rats, respectively susceptible and resistant to hepatocarcinogenesis.
Methods
Expression profiles were performed by microarray and validated by quantitative RT-PCR and Western blot.
Results
Cluster analysis revealed two distinctive gene expression patterns, the first of which included normal liver of both strains and BN nodules, and the second one F344 nodules and HCC of both strains. We identified a signature predicting DN and HCC progression, characterized by highest expression of oncosuppressors Csmd1, Dmbt1, Dusp1, and Gnmt, in DNs, and Bhmt, Dmbt1, Dusp1, Gadd45g, Gnmt, Napsa, Pp2ca, and Ptpn13 in HCCs of resistant rats. Integrated gene expression data revealed highest expression of proliferation-related CTGF, c-MYC, and PCNA, and lowest expression of BHMT, DMBT1, DUSP1, GADD45g, and GNMT, in more aggressive rat and human HCC. BHMT, DUSP1, and GADD45g expression predicted patients’ survival.
Conclusions
Our results disclose, for the first time, a major role of oncosuppressor genes as effectors of genetic resistance to hepatocarcinogenesis. Comparative functional genomic analysis allowed discovering an evolutionarily conserved gene expression signature discriminating HCC with different propensity to progression in rat and human.
doi:10.1007/s13402-011-0067-z
PMCID: PMC4517440  PMID: 22434528
Hepatocarcinogenesis; Genetic predisposition; Gene expression profiling; Oncosuppressor genes; Prognostic markers
14.  Hematogenous metastasis of ovarian cancer: Rethinking mode of spread 
Cancer cell  2014;26(1):77-91.
SUMMARY
Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer impaired omental metastasis. Our results highlight hematogenous metastasis as an important mode of ovarian cancer metastasis. These findings have implications for designing alternative strategies aimed at preventing and treating ovarian cancer metastasis.
doi:10.1016/j.ccr.2014.05.002
PMCID: PMC4100212  PMID: 25026212
15.  Notch3 Pathway Alterations in Ovarian Cancer 
Cancer research  2014;74(12):3282-3293.
Notch pathway plays an important role in the growth of high-grade serous ovarian (HGS-OvCa) and other cancers, but its clinical and biological mechanisms are not well understood. Here, we found that the Notch pathway alterations are prevalent and significantly related to poor clinical outcome in patients with ovarian cancer. Particularly, Notch3 alterations, including amplification and upregulation, were highly associated with poor patient survival. Targeting Notch3 inhibited OvCa growth and induced apoptosis. Importantly, we found that DNM-mediated endocytosis was required for selectively activating Jagged-1-mediated Notch3 signaling. Cleaved Notch3 expression was the critical determinant of response to Notch-targeted therapy. Collectively, these data identify previously unknown mechanisms underlying Notch3 signaling and identify new, biomarker-driven approaches for therapy.
doi:10.1158/0008-5472.CAN-13-2066
PMCID: PMC4058356  PMID: 24743243
16.  Targeting Poly (ADP-Ribose) Polymerase and the c-Myb-TopBP1-ATR-Chk1 Signaling Pathway in Castration-Resistant Prostate Cancer 
Science signaling  2014;7(326):ra47.
Androgen deprivation is the standard systemic treatment for advanced prostate cancer (PCa), but most patients ultimately develop castration-resistance. We show here that MYB is transcriptionally activated by androgen deprivation or impairment of androgen receptor (AR) signaling. MYB gene silencing significantly inhibited PCa growth in vitro and in vivo. Microarray data revealed that c-Myb shares a substantial subset of DNA damage response (DDR) target genes with AR, suggesting that c-Myb may replace AR for the dominant role in the regulation of their common DDR target genes in AR inhibition-resistant or AR-negative PCa. Gene signatures comprising AR, MYB, and their common DDR target genes are significantly correlated with metastasis, castration-resistance, recurrence, and shorter overall survival in PCa patients. We demonstrated in vitro that silencing of MYB, BRCA1 or TOPBP1 synergized with poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (OLA) to increase cytotoxicity to PCa cells. We further demonstrated that targeting the c-Myb-TopBP1-ATR-Chk1 pathway by using the Chk1 inhibitor AZD7762 synergizes with OLA to increase PCa cytotoxicity. Our results reveal new mechanism-based therapeutic approaches for PCa by targeting PARP and the c-Myb-TopBP1-ATR-Chk1 pathway.
doi:10.1126/scisignal.2005070
PMCID: PMC4135429  PMID: 24847116
17.  Biological effects of platelet-derived growth factor receptor α blockade in uterine cancer 
Purpose
Platelet-derived growth factor receptor alpha (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biological significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer.
Experimental Design
Expression of PDGFRα was examined in uterine cancer clinical samples and cell lines, and biological effects of PDGFRα inhibition were evaluated using in vitro (cell viability, apoptosis, and invasion) and in vivo (orthotopic) models of uterine cancer.
Results
PDGFRα was highly expressed and activated in uterine cancer samples and cell lines. Treatment with 3G3 resulted in substantial inhibition of PDGFRα phosphorylation and of downstream signaling molecules AKT and MAPK. Cell viability and invasive potential of uterine cancer cells were also inhibited by 3G3 treatment. In orthotopic mouse models of uterine cancer, 3G3 monotherapy had significant antitumor effects in PDGFRα-positive models (Hec-1A, Ishikawa, Spec-2), but not in PDGFRα-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in the PDGFRα-positive models. The anti-tumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis.
Conclusions
These findings identify PDGFRα as an attractive target for therapeutic development in uterine cancer.
doi:10.1158/1078-0432.CCR-13-2507
PMCID: PMC4024372  PMID: 24634380
PDGFRα; 3G3; uterine cancer
18.  The Orphan Nuclear Receptor NR4A1 (Nur77) Regulates Oxidative and Endoplasmic Reticulum Stress in Pancreatic Cancer Cells 
Molecular cancer research : MCR  2014;12(4):527-538.
NR4A1 (Nur77, TR3) is an orphan nuclear receptor that is overexpressed in pancreatic cancer and exhibits pro-oncogenic activity. RNAi interference of NR4A1 expression in Panc-1 cells induced apoptosis and subsequent proteomic analysis revealed the induction of several markers of endoplasmic reticulum (ER) stress including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), and activating transcription factor-4 (ATF-4). Treatment of pancreatic cancer cells with the NR4A1 antagonist 1,1-bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH), gave similar results. Moreover, both NR4A1 knockdown and DIM-C-pPhOH induced reactive oxygen species (ROS), and induction of ROS and ER stress by these agents was attenuated after co-treatment with antioxidants. Manipulation of NR4A1 expression coupled with gene expression profiling identified a number of ROS metabolism transcripts regulated by NR4A1. Knockdown of one of these transcripts, thioredoxin domain containing 5 (TXNDC5), recapitulated the elevated ROS and ER stress; thus, demonstrating that NR4A1 regulates levels of ER stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Finally, inactivation of NR4A1 by knockdown or DIM-C-pPhOH decreased TXNDC5, resulting in activation of ROS/ER stress and pro-apoptotic pathways.
doi:10.1158/1541-7786.MCR-13-0567
PMCID: PMC4407472  PMID: 24515801
NR4A1; TR3; Nur77; pancreatic cancer; oxidative stress; endoplasmic stress; apoptosis; TXNDC5
19.  Reassessing Hepatocellular Carcinoma Staging in a Changing Patient Population 
Oncology  2014;86(2):63-71.
Objective
Hepatocellular carcinoma (HCC) staging systems were developed using data predominantly from patients who had hepatitis and cirrhosis. Given the recent change in prevalence of viral hepatitis and cirrhosis at Oncology centers which altered the natural history of HCC, we aimed at comparing the accuracy of HCC staging systems in patients with or without hepatitis and cirrhosis.
Methods
438 patients were enrolled. Baseline clinicopathologic parameters, Barcelona Clinic Liver Cancer stage, Cancer of the Liver Italian Program score, TNM (6th edition) stage, Okuda stage, and Chinese University Prognostic Index score, were prospectively obtained for all patients, and retrospectively analyzed. Kaplan-Meier was used to determine overall survival (OS), Cox regression analyses were performed, and Harrell’s index compared the staging systems’ ability to predict OS duration. Subgroup analyses of patients with or without hepatitis or cirrhosis were performed.
Results
Patients’ median OS was 13.9 months. 165 patients (37.7%) had no cirrhosis, and 256 patients (58.4%) had no hepatitis. Overall, all staging systems were significantly less predictive of OS in patients who did not have cirrhosis or hepatitis.
Conclusion
Our results advocate for the need to further stratify HCC based on cirrhosis and hepatitis status, which may change patients’ risk-stratification and ultimately treatment decisions.
doi:10.1159/000356573
PMCID: PMC4060614  PMID: 24401634
hepatocellular carcinoma; staging; prognosis; cirrhosis; hepatitis
20.  Genomic Predictors for Recurrence Patterns of Hepatocellular Carcinoma: Model Derivation and Validation 
PLoS Medicine  2014;11(12):e1001770.
In this study, Lee and colleagues develop a genomic predictor that can identify patients at high risk for late recurrence of hepatocellular carcinoma (HCC) and provided new biomarkers for risk stratification.
Background
Typically observed at 2 y after surgical resection, late recurrence is a major challenge in the management of hepatocellular carcinoma (HCC). We aimed to develop a genomic predictor that can identify patients at high risk for late recurrence and assess its clinical implications.
Methods and Findings
Systematic analysis of gene expression data from human liver undergoing hepatic injury and regeneration revealed a 233-gene signature that was significantly associated with late recurrence of HCC. Using this signature, we developed a prognostic predictor that can identify patients at high risk of late recurrence, and tested and validated the robustness of the predictor in patients (n = 396) who underwent surgery between 1990 and 2011 at four centers (210 recurrences during a median of 3.7 y of follow-up). In multivariate analysis, this signature was the strongest risk factor for late recurrence (hazard ratio, 2.2; 95% confidence interval, 1.3–3.7; p = 0.002). In contrast, our previously developed tumor-derived 65-gene risk score was significantly associated with early recurrence (p = 0.005) but not with late recurrence (p = 0.7). In multivariate analysis, the 65-gene risk score was the strongest risk factor for very early recurrence (<1 y after surgical resection) (hazard ratio, 1.7; 95% confidence interval, 1.1–2.6; p = 0.01). The potential significance of STAT3 activation in late recurrence was predicted by gene network analysis and validated later. We also developed and validated 4- and 20-gene predictors from the full 233-gene predictor. The main limitation of the study is that most of the patients in our study were hepatitis B virus–positive. Further investigations are needed to test our prediction models in patients with different etiologies of HCC, such as hepatitis C virus.
Conclusions
Two independently developed predictors reflected well the differences between early and late recurrence of HCC at the molecular level and provided new biomarkers for risk stratification.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Primary liver cancer—a tumor that starts when a liver cell acquires genetic changes that allow it to grow uncontrollably—is the second-leading cause of cancer-related deaths worldwide, killing more than 600,000 people annually. If hepatocellular cancer (HCC; the most common type of liver cancer) is diagnosed in its early stages, it can be treated by surgically removing part of the liver (resection), by liver transplantation, or by local ablation, which uses an electric current to destroy the cancer cells. Unfortunately, the symptoms of HCC, which include weight loss, tiredness, and jaundice (yellowing of the skin and eyes), are vague and rarely appear until the cancer has spread throughout the liver. Consequently, HCC is rarely diagnosed before the cancer is advanced and untreatable, and has a poor prognosis (likely outcome)—fewer than 5% of patients survive for five or more years after diagnosis. The exact cause of HCC is unclear, but chronic liver (hepatic) injury and inflammation (caused, for example, by infection with hepatitis B virus [HBV] or by alcohol abuse) promote tumor development.
Why Was This Study Done?
Even when it is diagnosed early, HCC has a poor prognosis because it often recurs. Patients treated for HCC can experience two distinct types of tumor recurrence. Early recurrence, which usually happens within the first two years after surgery, arises from the spread of primary cancer cells into the surrounding liver that left behind during surgery. Late recurrence, which typically happens more than two years after surgery, involves the development of completely new tumors and seems to be the result of chronic liver damage. Because early and late recurrence have different clinical courses, it would be useful to be able to predict which patients are at high risk of which type of recurrence. Given that injury, inflammation, and regeneration seem to prime the liver for HCC development, might the gene expression patterns associated with these conditions serve as predictive markers for the identification of patients at risk of late recurrence of HCC? Here, the researchers develop a genomic predictor for the late recurrence of HCC by examining gene expression patterns in tissue samples from livers that were undergoing injury and regeneration.
What Did the Researchers Do and Find?
By comparing gene expression data obtained from liver biopsies taken before and after liver transplantation or resection and recorded in the US National Center for Biotechnology Information Gene Expression Omnibus database, the researchers identified 233 genes whose expression in liver differed before and after liver injury (the hepatic injury and regeneration, or HIR, signature). Statistical analyses indicate that the expression of the HIR signature in archived tissue samples was significantly associated with late recurrence of HCC in three independent groups of patients, but not with early recurrence (a significant association between two variables is one that is unlikely to have arisen by chance). By contrast, a tumor-derived 65-gene signature previously developed by the researchers was significantly associated with early recurrence but not with late recurrence. Notably, as few as four genes from the HIR signature were sufficient to construct a reliable predictor for late recurrence of HCC. Finally, the researchers report that many of the genes in the HIR signature encode proteins involved in inflammation and cell death, but that others encode proteins involved in cellular growth and proliferation such as STAT3, a protein with a well-known role in liver regeneration.
What Do These Findings Mean?
These findings identify a gene expression signature that was significantly associated with late recurrence of HCC in three independent groups of patients. Because most of these patients were infected with HBV, the ability of the HIR signature to predict late occurrence of HCC may be limited to HBV-related HCC and may not be generalizable to HCC related to other causes. Moreover, the predictive ability of the HIR signature needs to be tested in a prospective study in which samples are taken and analyzed at baseline and patients are followed to see whether their HCC recurs; the current retrospective study analyzed stored tissue samples. Importantly, however, the HIR signature associated with late recurrence and the 65-gene signature associated with early recurrence provide new insights into the biological differences between late and early recurrence of HCC at the molecular level. Knowing about these differences may lead to new treatments for HCC and may help clinicians choose the most appropriate treatments for their patients.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001770.
The US National Cancer Institute provides information about all aspects of cancer, including detailed information for patients and professionals about primary liver cancer (in English and Spanish)
The American Cancer Society also provides information about liver cancer (including information on support programs and services; available in several languages)
The UK National Health Service Choices website provides information about primary liver cancer (including a video about coping with cancer)
Cancer Research UK (a not-for-profit organization) also provides detailed information about primary liver cancer (including information about living with primary liver cancer)
MD Anderson Cancer Center provides information about symptoms, diagnosis, treatment, and prevention of primary liver cancer
MedlinePlus provides links to further resources about liver cancer (in English and Spanish)
doi:10.1371/journal.pmed.1001770
PMCID: PMC4275163  PMID: 25536056
21.  Profiling of Exome Mutations Associated with Progression of HBV-Related Hepatocellular Carcinoma 
PLoS ONE  2014;9(12):e115152.
Recent advances in sequencing technology have allowed us to profile genome-wide mutations of various cancer types, revealing huge heterogeneity of cancer genome variations. However, its heterogeneous landscape of somatic mutations according to liver cancer progression is not fully understood. Here, we profiled the mutations and gene expressions of early and advanced hepatocellular carcinoma (HCC) related with Hepatitis B-viral infection. Integrative analysis was performed with whole-exome sequencing and gene expression profiles of the 12 cases of early and advanced HCCs and paired non-tumoral adjacent liver tissues. A total of 293 tumor-specific somatic variants and 202 non-tumoral variants were identified. The tumor-specific variants were found to be enriched at chromosome 1q particularly in the advanced HCC, compared to the non-tumoral variants. Functional enrichment analysis revealed frequent mutations at the genes encoding cytoskeleton organization, cell adhesion, and cell cycle-related genes. In addition, to elucidate actionable somatic mutations, we performed an integrative analysis of gene mutations and gene expression profiles together. This revealed the 48 mutated genes which were differentially mutated with concomitant gene expression enrichment. Of these, CTNNB1 was found to have a pivotal role in the differential progression of the HCC subgroup. In conclusion, our integrative analysis of whole-exome sequencing and transcriptome profiles could provide actionable mutations which might play pivotal roles in the heterogeneous progression of HCC.
doi:10.1371/journal.pone.0115152
PMCID: PMC4270755  PMID: 25521761
22.  HIG2 promotes colorectal cancer progression via hypoxia-dependent and independent pathways 
Cancer letters  2013;341(2):159-165.
HIG2 (hypoxia-inducible gene 2) is a biomarker of hypoxia and elevated in several cancers. Here, we show that HIG2 also upregulated HIF-1α expression under hypoxic conditions and enhanced AP-1 expression under normoxic conditions, which affects colorectal cancer cell survival. Importantly, over-expression of HIG2 promoted tumor growth by suppressing apoptosis in a mouse orthotopic model. These results are likely relevant to human disease since we found that the expression of HIG2 is gradually elevated as tumors progress. Collectively, these findings suggest that HIG2 plays an important role in promoting colorectal cancer growth in hypoxia-dependent and independent manners.
doi:10.1016/j.canlet.2013.07.028
PMCID: PMC3928010  PMID: 23916472
hypoxia; normoxia; HIG2; HIF-1α; colorectal cancer; survival
23.  Sex hormone pathway gene polymorphisms are associated with risk of advanced hepatitis C-related liver disease in males 
Background: Males have excess advanced liver disease and cirrhosis risk including from chronic hepatitis C virus (HCV) infection though the reasons are unclear. Goal: To examine the role variants in genes involved in androgen and estrogen biosynthesis and metabolism play in HCV-related liver disease risk in males. Methods: We performed a cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 16 candidate genes involved in androgen and estrogen ligand and receptor synthesis and risk of advanced hepatic fibrosis (F3/F4-F4) and inflammation (A2/A3-A3). We calculated adjusted odds ratios (ORs) using logistic regression and used multifactor dimensionality reduction (MDR) analysis to assess for gene-environment interaction. Results: Among 466 chronically HCV-infected males, 59% (n = 274) had advanced fibrosis and 54% (n = 252) had advanced inflammation. Nine of 472 SNPs were significantly associated with fibrosis risk; 4 in AKR1C3 (e.g., AKR1C3 rs2186174: ORadj = 2.04, 95% CI 1.38-3.02), 1 each in AKR1C2 and ESR1, and 1 in HSD17B6. Four SNPs were associated with inflammation risk, 2 in SRD5A1 (e.g., SRD5A1 rs248800: ORadj = 1.86, 95% CI 1.20-2.88) and 1 each in AKR1C2 and AKR1C3. MDR analysis identified a single AKR1C3 locus (rs2186174) as the best model for advanced fibrosis; while a 4-locus model with diabetes, AKR1C2 rs12414884, SRD5A1 rs6555406, and SRD5A1 rs248800 was best for inflammation. Conclusions: The consistency of our findings suggests AKR1C isoenzymes 2 and 3, and potentially SRD5A1, may play a role in progression of HCV-related liver disease in males. Future studies are needed to validate these findings and to assess if similar associations exist in females.
PMCID: PMC4214264  PMID: 25379136
Epidemiology; hepatology; endocrinology; infectious diseases; digestive system; carcinogenesis; genetics
24.  2’f-OMe-phosphorodithioate modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity 
Nature communications  2014;5:3459.
Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2’-O-Methyl (2’-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2’-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM Domain Containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumors following MePS2-modified siRNA treatment, leading to a synergistic anti-tumor effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.
doi:10.1038/ncomms4459
PMCID: PMC4112501  PMID: 24619206
25.  Integrative analysis of proteomic signatures, mutations and drug responsiveness in the NCI 60 cancer cell line set 
Molecular cancer therapeutics  2010;9(2):257-267.
Aberrations in oncogenes and tumor suppressors frequently affect the activity of critical signal transduction pathways. To analyze systematically the relationship between the activation status of protein networks and other characteristics of cancer cells, we performed reverse phase protein array (RPPA) profiling of the NCI60 cell lines for total protein expression and activation-specific markers of critical signaling pathways. To extend the scope of the study, we merged those data with previously published RPPA results for the NCI60. Integrative analysis of the expanded RPPA data set revealed 5 major clusters of cell lines and 5 principal proteomic signatures. Comparison of mutations in the NCI60 cell lines with patterns of protein expression demonstrated significant associations for PTEN, PIK3CA, BRAF and APC mutations with proteomic clusters. PIK3CA and PTEN mutation enrichment were not cell lineage-specific but were associated with dominant yet distinct groups of proteins. The five RPPA-defined clusters were strongly associated with sensitivity to standard anti-cancer agents. RPPA analysis identified 27 protein features significantly associated with sensitivity to paclitaxel. The functional status of those proteins was interrogated in a paclitaxel whole genome siRNA library synthetic lethality screen, and confirmed the predicted associations with drug sensitivity. These studies expand our understanding of the activation status of protein networks in the NCI60 cancer cell lines, demonstrate the importance of the direct study of protein expression and activation, and provide a basis for further studies integrating the information with other molecular and pharmacological characteristics of cancer.
doi:10.1158/1535-7163.MCT-09-0743
PMCID: PMC4085051  PMID: 20124458
NCI60; reverse phase protein arrays; signal transduction

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