A Meta Analysis of Pancreatic Microarray Datasets Yields New Targets as Cancer Genes and Biomarkers

The lack of specific symptoms at early tumor stages, together with a high biological aggressiveness of the tumor contribute to the high mortality rate for pancreatic cancer (PC), which has a five year survival rate of less than 5%. Improved screening for earlier diagnosis, through the detection of diagnostic and prognostic biomarkers provides the best hope of increasing the rate of curatively resectable carcinomas. Though many serum markers have been reported to be elevated in patients with PC, so far, most of these markers have not been implemented into clinical routine due to low sensitivity or specificity. In this study, we have identified genes that are significantly upregulated in PC, through a meta-analysis of large number of microarray datasets. We demonstrate that the biological functions ascribed to these genes are clearly associated with PC and metastasis, and that that these genes exhibit a strong link to pathways involved with inflammation and the immune response. This investigation has yielded new targets for cancer genes, and potential biomarkers for pancreatic cancer. The candidate list of cancer genes includes protein kinase genes, new members of gene families currently associated with PC, as well as genes not previously linked to PC. In this study, we are also able to move towards developing a signature for hypomethylated genes, which could be useful for early detection of PC. We also show that the significantly upregulated 800+ genes in our analysis can serve as an enriched pool for tissue and serum protein biomarkers in pancreatic cancer.

[1]  C. Rancourt,et al.  Characterization of the tumor marker muc16 (ca125) expressed by murine ovarian tumor cell lines and identification of a panel of cross-reactive monoclonal antibodies , 2009, Journal of ovarian research.

[2]  R. Tibshirani,et al.  Disease signatures are robust across tissues and experiments , 2009, Molecular systems biology.

[3]  H. Lee,et al.  A synergistic interaction between transcription factors nuclear factor-κB and signal transducers and activators of transcription 3 promotes gastric cancer cell migration and invasion , 2013, BMC Gastroenterology.

[4]  A. Matussek,et al.  DNA promoter methylation status and protein expression of interleukin-8 in human colorectal adenocarcinomas , 2011, International Journal of Colorectal Disease.

[5]  W. Jonat,et al.  Clinicopathological significance and molecular regulation of maspin expression in ductal adenocarcinoma of the pancreas. , 2003, Cancer letters.

[6]  F. Hsieh,et al.  Clinicopathologic Correlation of Up-regulated Genes Identified Using cDNA Microarray and Real-time Reverse Transcription-PCR in Human Colorectal Cancer , 2005, Cancer Epidemiology Biomarkers & Prevention.

[7]  Xin Lu,et al.  Imaging transforming growth factor-β signaling dynamics and therapeutic response in breast cancer bone metastasis , 2009, Nature Medicine.

[8]  Luis Serrano,et al.  Correlation of mRNA and protein in complex biological samples , 2009, FEBS letters.

[9]  Songying Zhang,et al.  Calcium-binding protein S100P and cancer: mechanisms and clinical relevance , 2011, Journal of Cancer Research and Clinical Oncology.

[10]  P. Scherle,et al.  Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. , 2010, Trends in molecular medicine.

[11]  Rainer Breitling,et al.  Rank products: a simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experiments , 2004, FEBS letters.

[12]  J. Diallo,et al.  Regulation of IkappaB kinase epsilon expression by the androgen receptor and the nuclear factor-kappaB transcription factor in prostate cancer. , 2007, Molecular cancer research : MCR.

[13]  N. McGranahan,et al.  The causes and consequences of genetic heterogeneity in cancer evolution , 2013, Nature.

[14]  E. Elinav,et al.  Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms , 2013, Nature Reviews Cancer.

[15]  Riccardo Colombo,et al.  Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors. , 2011, Bioorganic & medicinal chemistry letters.

[16]  G. Parmigiani,et al.  Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses , 2008, Science.

[17]  B. Christensen,et al.  The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma , 2011, Epigenetics.

[18]  A. Levitzki,et al.  Tyrphostins and other tyrosine kinase inhibitors. , 2006, Annual review of biochemistry.

[19]  K. Franssila,et al.  Hepatocyte growth factor receptor, matrix metalloproteinase-11, tissue inhibitor of metalloproteinase-1, and fibronectin are up-regulated in papillary thyroid carcinoma: a cDNA and tissue microarray study. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[20]  C. Heizmann,et al.  S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). , 2004, Biochemical and biophysical research communications.

[21]  Leonard J Foster,et al.  Pseudopodial actin dynamics control epithelial-mesenchymal transition in metastatic cancer cells. , 2010, Cancer research.

[22]  R. Hruban,et al.  Methylation of cyclin D2 is observed frequently in pancreatic cancer but is also an age-related phenomenon in gastrointestinal tissues. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[23]  K. Borden,et al.  Mechanisms and insights into drug resistance in cancer , 2013, Front. Pharmacol..

[24]  R. King,et al.  When 2+2=5: the origins and fates of aneuploid and tetraploid cells. , 2008, Biochimica et biophysica acta.

[25]  Aleksandar S. Dimovski,et al.  Association of GPX1 polymorphism, GPX activity and prostate cancer risk , 2012, Human & experimental toxicology.

[26]  D. Hunter,et al.  Gene × Gene interaction between MnSOD and GPX-1 and breast cancer risk: a nested case-control study , 2006, BMC Cancer.

[27]  Brian J. Smith,et al.  Suppression of the malignant phenotype in pancreatic cancer by overexpression of phospholipid hydroperoxide glutathione peroxidase. , 2006, Human gene therapy.

[28]  Rainer Breitling,et al.  A comparison of meta-analysis methods for detecting differentially expressed genes in microarray experiments , 2008, Bioinform..

[29]  S. Serra,et al.  The Use of Cytokeratin 19 (CK19) Immunohistochemistry in Lesions of the Pancreas, Gastrointestinal Tract, and Liver , 2010, Applied immunohistochemistry & molecular morphology : AIMM.

[30]  Laurent Lessard,et al.  Nuclear localisation of nuclear factor-kappaB transcription factors in prostate cancer: an immunohistochemical study , 2005, British Journal of Cancer.

[31]  S. Ishikawa,et al.  Claudin-18 Is an Early-Stage Marker of Pancreatic Carcinogenesis , 2011, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[32]  J. Pollack,et al.  LYN is a mediator of epithelial-mesenchymal transition and a target of dasatinib in breast cancer. , 2010, Cancer research.

[33]  S. Leivonen,et al.  Transforming growth factor‐β signaling in cancer invasion and metastasis , 2007, International journal of cancer.

[34]  R. Srinivasan,et al.  Major Molecular Markers in Pancreatic Ductal Adenocarcinoma and Their Roles in Screening, Diagnosis, Prognosis, and Treatment , 2011, Pancreas.

[35]  C. Marson,et al.  Histone deacetylase inhibitors: design, structure-activity relationships and therapeutic implications for cancer. , 2009, Anti-cancer agents in medicinal chemistry.

[36]  S. Miknyoczki,et al.  Discovery of small molecule c-Met inhibitors: Evolution and profiles of clinical candidates. , 2010, Anti-cancer agents in medicinal chemistry.

[37]  M. Goto,et al.  Mucins in human neoplasms: Clinical pathology, gene expression and diagnostic application , 2011, Pathology international.

[38]  H. Hua,et al.  Matrix metalloproteinases in tumorigenesis: an evolving paradigm , 2011, Cellular and Molecular Life Sciences.

[39]  Andrea Musacchio,et al.  Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine , 2010, The Journal of cell biology.

[40]  Martin A. Nowak,et al.  Genetic Progression and the Waiting Time to Cancer , 2007, PLoS Comput. Biol..

[41]  E. Motrescu,et al.  Cancer cells, adipocytes and matrix metalloproteinase 11: a vicious tumor progression cycle , 2008, Biological chemistry.

[42]  T. Barrette,et al.  ONCOMINE: a cancer microarray database and integrated data-mining platform. , 2004, Neoplasia.

[43]  T. Neumann,et al.  AHNAK1 and AHNAK2 are costameric proteins: AHNAK1 affects transverse skeletal muscle fiber stiffness. , 2010, Biochemical and biophysical research communications.

[44]  J. Habermann,et al.  Serum biomarkers for improved diagnostic of pancreatic cancer: a current overview , 2011, Journal of Cancer Research and Clinical Oncology.

[45]  F. Domann,et al.  Human pancreatic carcinoma cells activate maspin expression through loss of epigenetic control. , 2003, Neoplasia.

[46]  J. Neoptolemos,et al.  Comprehensive Analysis of Matrix Metalloproteinase and Tissue Inhibitor Expression in Pancreatic Cancer , 2004, Clinical Cancer Research.

[47]  S. Batra,et al.  Current status of molecular markers for early detection of sporadic pancreatic cancer. , 2011, Biochimica et biophysica acta.

[48]  J. Thiery Epithelial–mesenchymal transitions in tumour progression , 2002, Nature Reviews Cancer.

[49]  Gang Meng,et al.  Changes in genomic imprinting and gene expression associated with transformation in a model of human osteosarcoma. , 2008, Experimental and molecular pathology.

[50]  P. Slattum,et al.  Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors. , 2012, Bioorganic & medicinal chemistry letters.

[51]  William R Sellers,et al.  Linking somatic genetic alterations in cancer to therapeutics. , 2009, Current opinion in cell biology.

[52]  Y. Miao,et al.  The increase in the expression and hypomethylation of MUC4 gene with the progression of pancreatic ductal adenocarcinoma , 2011, Medical oncology.

[53]  J. Diallo,et al.  Regulation of IκB Kinase ε Expression by the Androgen Receptor and the Nuclear Factor-κB Transcription Factor in Prostate Cancer , 2007, Molecular Cancer Research.

[54]  J. Cameron,et al.  Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. , 2003, Cancer research.

[55]  K. D. Sørensen,et al.  Promoter hypomethylation and upregulation of trefoil factors in prostate cancer , 2010, International journal of cancer.

[56]  Shizuo Akira,et al.  Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. , 2011, Cancer cell.

[57]  D. Fisher,et al.  A new era: melanoma genetics and therapeutics , 2011, The Journal of pathology.

[58]  R. Flavell,et al.  The AHNAKs are a class of giant propeller-like proteins that associate with calcium channel proteins of cardiomyocytes and other cells , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[59]  N. Fausto Hepatocyte growth factor receptor and the c-met oncogene Bottaro DP, Rubin JS, Faletto DL, Chan AM-L, Kmiecik TE, Vande Woude GF, Aaronson SA. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 1991;251:802?804 , 1991 .

[60]  L. Buscail,et al.  [New molecular targets in pancreatic cancer]. , 2008, Bulletin du cancer.

[61]  Michele Magrane,et al.  UniProt Knowledgebase: a hub of integrated protein data , 2011, Database J. Biol. Databases Curation.

[62]  L. Tanoue Cancer Statistics, 2009 , 2010 .

[63]  Z. Werb,et al.  Matrix Metalloproteinases: Regulators of the Tumor Microenvironment , 2010, Cell.

[64]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

[65]  E. van Marck,et al.  Nuclear factor-kappaB signature of inflammatory breast cancer by cDNA microarray validated by quantitative real-time reverse transcription-PCR, immunohistochemistry, and nuclear factor-kappaB DNA-binding. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[66]  M. Park,et al.  Cell growth inhibition and induction of apoptosis by snake venom toxin in ovarian cancer cell via inactivation of nuclear factor κB and signal transducer and activator of transcription 3 , 2012, Archives of Pharmacal Research.

[67]  M. Stratton Exploring the Genomes of Cancer Cells: Progress and Promise , 2011, Science.

[68]  Andrew Menzies,et al.  The patterns and dynamics of genomic instability in metastatic pancreatic cancer , 2010, Nature.

[69]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[70]  Guido Jenster,et al.  Venn Mapping: clustering of heterologous microarray data based on the number of co-occurring differentially expressed genes , 2003, Bioinform..

[71]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[72]  A. Jimeno,et al.  Characterizing DNA methylation patterns in pancreatic cancer genome , 2009, Molecular oncology.

[73]  S. Erkeland,et al.  Retroviral insertion mutagenesis in mice as a comparative oncogenomics tool to identify disease genes in human leukemia. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[74]  H. Yoshioka,et al.  Epiplakin accelerates the lateral organization of keratin filaments during wound healing. , 2010, Journal of dermatological science.

[75]  K. Tanabe,et al.  Cancer immunosuppression and autoimmune disease: beyond immunosuppressive networks for tumour immunity , 2006, Immunology.

[76]  M. Reiss,et al.  Targeting the Transforming Growth Factor-β pathway inhibits human basal-like breast cancer metastasis , 2010, Molecular Cancer.

[77]  V. Regitz-Zagrosek,et al.  The FASEB Journal • Research Communication Ahnak is critical for cardiac Ca(v)1.2 calcium channel function and its �-adrenergic regulation , 2022 .

[78]  Rainer Breitling,et al.  RankProd: a bioconductor package for detecting differentially expressed genes in meta-analysis , 2006, Bioinform..

[79]  D. Goldenberg,et al.  Expression patterns of CEACAM5 and CEACAM6 in primary and metastatic cancers , 2007, BMC Cancer.

[80]  Jason Y. Park,et al.  Molecular signatures of pancreatic cancer. , 2011, Archives of pathology & laboratory medicine.

[81]  I. Salmon,et al.  S100A2 is a predictive biomarker of adjuvant therapy benefit in pancreatic adenocarcinoma. , 2013, European journal of cancer.

[82]  M. Nowak,et al.  Distant Metastasis Occurs Late during the Genetic Evolution of Pancreatic Cancer , 2010, Nature.

[83]  Christian Pilarsky,et al.  Meta-analysis of microarray data on pancreatic cancer defines a set of commonly dysregulated genes , 2005, Oncogene.

[84]  L. Griffiths,et al.  An Assessment of MMP and TIMP Gene Expression in Cell Lines and Stroma – Tumour Differences in MicrodissectedBreast Cancer Biopsies , 2003, Tumor Biology.

[85]  M. Hermanová,et al.  Expression of matrix metalloproteinases 3, 10 and 11 (stromelysins 1, 2 and 3) and matrix metalloproteinase 7 (matrilysin) by cancer cells in non-small cell lung neoplasms. Clinicopathologic studies. , 2006, Ceskoslovenska patologie.

[86]  Kenoki Ohuchida,et al.  S100P is a novel marker to identify intraductal papillary mucinous neoplasms. , 2010, Human pathology.

[87]  Jingde Zhu,et al.  CTHRC1 is upregulated by promoter demethylation and transforming growth factor‐β1 and may be associated with metastasis in human gastric cancer , 2012, Cancer science.

[88]  A. Kutikhin,et al.  Inherited variations in the SOD and GPX gene families and cancer risk , 2012, Free radical research.

[89]  John Quackenbush,et al.  Multiple-laboratory comparison of microarray platforms , 2005, Nature Methods.

[90]  William C Hahn,et al.  Oncogenic transformation and experimental models of human cancer. , 2008, Frontiers in bioscience : a journal and virtual library.

[91]  Peter A. Jones,et al.  A decade of exploring the cancer epigenome — biological and translational implications , 2011, Nature Reviews Cancer.

[92]  S. Ghosh,et al.  Signal transduction through NF-κB , 1998 .

[93]  T. Barrette,et al.  Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. , 2007, Neoplasia.

[94]  David M. Berman,et al.  Tissue repair and stem cell renewal in carcinogenesis , 2004, Nature.

[95]  C. Röcken,et al.  Proteomics of Pancreatic Cancer , 2008, Pancreas.

[96]  M. Hoenerhoff,et al.  Inhibition of transforming growth factor-β-activated kinase-1 blocks cancer cell adhesion, invasion, and metastasis , 2012, British Journal of Cancer.

[97]  G. Tortora,et al.  LY2109761, a novel transforming growth factor β receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis , 2008, Molecular Cancer Therapeutics.

[98]  V. Dymicka-Piekarska,et al.  Expression of matrix metalloproteinase 9 in pancreatic ductal carcinoma is associated with tumor metastasis formation. , 2007, Folia histochemica et cytobiologica.

[99]  M. May,et al.  Signal transduction through NF-kappa B. , 1998, Immunology today.

[100]  J. Rubin,et al.  Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. , 1991, Science.

[101]  G. Turashvili,et al.  Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis , 2007, BMC Cancer.

[102]  Douglas G Altman,et al.  Key Issues in Conducting a Meta-Analysis of Gene Expression Microarray Datasets , 2008, PLoS medicine.

[103]  T. Hubbard,et al.  A census of human cancer genes , 2004, Nature Reviews Cancer.

[104]  M. Moses,et al.  Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[105]  Taiping Zhang,et al.  Advances in early diagnosis and therapy of pancreatic cancer. , 2011, Hepatobiliary & pancreatic diseases international : HBPD INT.

[106]  S. Leivonen,et al.  Transforming growth factor-beta signaling in cancer invasion and metastasis. , 2007, International journal of cancer.

[107]  A. Siriwardena,et al.  Systematic review of carbohydrate antigen (CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer. , 2007, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[108]  A. Jemal,et al.  Cancer Statistics, 2009 , 2009, CA: a cancer journal for clinicians.

[109]  F. Jiang,et al.  The usefulness of S100P, mesothelin, fascin, prostate stem cell antigen, and 14‐3‐3 sigma in diagnosing pancreatic adenocarcinoma in cytological specimens obtained by endoscopic ultrasound guided fine‐needle aspiration , 2014, Diagnostic cytopathology.

[110]  A. Amon,et al.  Aneuploidy: cancer's fatal flaw? , 2009, Cancer research.

[111]  N. S. Thomas,et al.  Lck is a key target of imatinib and dasatinib in T-cell activation , 2010, Leukemia.

[112]  Richard D Kolodner,et al.  An overview of Cdk1-controlled targets and processes , 2010, Cell Division.

[113]  M. Noguchi,et al.  Tumorigenesis and Neoplastic Progression Aberrant Stratifin Overexpression Is Regulated by Tumor-Associated CpG Demethylation in Lung Adenocarcinoma , 2016 .

[114]  J. Yanagisawa,et al.  Global analysis of DNA methylation in early-stage liver fibrosis , 2012, BMC Medical Genomics.

[115]  J. Cameron,et al.  Overexpression of S100A4 in pancreatic ductal adenocarcinomas is associated with poor differentiation and DNA hypomethylation. , 2002, The American journal of pathology.

[116]  Emma Laing,et al.  RankProdIt: A web-interactive Rank Products analysis tool , 2010, BMC Research Notes.

[117]  Taebo Sim,et al.  Small Molecule Kinase Inhibitors Provide Insight into Mps1 Cell Cycle Function , 2010, Nature chemical biology.

[118]  Zhaoshen Li,et al.  Proteomics in Pancreatic Cancer Research , 2011, International journal of proteomics.

[119]  Paolo P. Provenzano,et al.  Collagen reorganization at the tumor-stromal interface facilitates local invasion , 2006, BMC medicine.

[120]  K. Ochi,et al.  Matrix Metalloproteinase-2 in Pancreatic Juice for Diagnosis of Pancreatic Cancer , 2002, Pancreas.

[121]  S. Ashley,et al.  Inhibition of tyrosine kinase Src suppresses pancreatic cancer invasiveness. , 2003, Surgery.

[122]  A. Jankowska,et al.  Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. , 2008, Blood.

[123]  M. Martinka,et al.  Aberrant Expression of Collagen Triple Helix Repeat Containing 1 in Human Solid Cancers , 2006, Clinical Cancer Research.

[124]  R. Andersson,et al.  Proteome-based biomarkers in pancreatic cancer. , 2011, World journal of gastroenterology.

[125]  Yang Song,et al.  Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery , 2011, Nucleic Acids Res..

[126]  S. S. Koh,et al.  Claudin-4 overexpression is associated with epigenetic derepression in gastric carcinoma , 2011, Laboratory Investigation.

[127]  B. Bauvois,et al.  New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. , 2012, Biochimica et biophysica acta.