Tumor antigens as proteogenomic biomarkers in invasive ductal carcinomas

BackgroundThe majority of genetic biomarkers for human cancers are defined by statistical screening of high-throughput genomics data. While a large number of genetic biomarkers have been proposed for diagnostic and prognostic applications, only a small number have been applied in the clinic. Similarly, the use of proteomics methods for the discovery of cancer biomarkers is increasing. The emerging field of proteogenomics seeks to enrich the value of genomics and proteomics approaches by studying the intersection of genomics and proteomics data. This task is challenging due to the complex nature of transcriptional and translation regulatory mechanisms and the disparities between genomic and proteomic data from the same samples. In this study, we have examined tumor antigens as potential biomarkers for breast cancer using genomics and proteomics data from previously reported laser capture microdissected ER+ tumor samples.ResultsWe applied proteogenomic analyses to study the genetic aberrations of 32 tumor antigens determined in the proteomic data. We found that tumor antigens that are aberrantly expressed at the genetic level and expressed at the protein level, are likely involved in perturbing pathways directly linked to the hallmarks of cancer. The results found by proteogenomic analysis of the 32 tumor antigens studied here, capture largely the same pathway irregularities as those elucidated from large-scale screening of genomics analyses, where several thousands of genes are often found to be perturbed.ConclusionTumor antigens are a group of proteins recognized by the cells of the immune system. Specifically, they are recognized in tumor cells where they are present in larger than usual amounts, or are physiochemically altered to a degree at which they no longer resemble native human proteins. This proteogenomic analysis of 32 tumor antigens suggests that tumor antigens have the potential to be highly specific biomarkers for different cancers.

[1]  Tsviya Olender,et al.  GeneCards Version 3: the human gene integrator , 2010, Database J. Biol. Databases Curation.

[2]  E. Wiemer,et al.  The spliceosome as target for anticancer treatment , 2008, British Journal of Cancer.

[3]  María Martín,et al.  Activities at the Universal Protein Resource (UniProt) , 2013, Nucleic Acids Res..

[4]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[5]  J. Wharton,et al.  Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines , 1995, The Journal of experimental medicine.

[6]  Xiao-Jun Ma,et al.  Gene expression profiling of the tumor microenvironment during breast cancer progression , 2009, Breast Cancer Research.

[7]  M. Mottolese,et al.  The Cytoskeleton Regulatory Protein hMena (ENAH) Is Overexpressed in Human Benign Breast Lesions with High Risk of Transformation and Human Epidermal Growth Factor Receptor-2–Positive/Hormonal Receptor–Negative Tumors , 2006, Clinical Cancer Research.

[8]  M. Klymkowsky,et al.  Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe. , 2009, The American journal of pathology.

[9]  Roy Garcia,et al.  STATs in oncogenesis , 2000, Oncogene.

[10]  T. Speed,et al.  Summaries of Affymetrix GeneChip probe level data. , 2003, Nucleic acids research.

[11]  I. Pollack,et al.  Increased expression of tumor-associated antigens in pediatric and adult ependymomas: implication for vaccine therapy , 2012, Journal of Neuro-Oncology.

[12]  L. V. van't Veer,et al.  Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. , 2006, Journal of the National Cancer Institute.

[13]  R. Salunga,et al.  Gene expression profiles of human breast cancer progression , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[14]  M. Hung,et al.  β-Catenin, a novel prognostic marker for breast cancer: Its roles in cyclin D1 expression and cancer progression , 2000 .

[15]  Louise R Howe,et al.  Wnt Signaling and Breast Cancer , 2004, Cancer biology & therapy.

[16]  M. Weller,et al.  Phosphoglycerate kinase 1 a promoting enzyme for peritoneal dissemination in gastric cancer , 2010, International journal of cancer.

[17]  G. P. Beardsley,et al.  The Human purH Gene Product, 5-Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase , 1996, The Journal of Biological Chemistry.

[18]  H. Rammensee,et al.  The repertoire of human tumor-associated epitopes--identification and selection of antigens and their application in clinical trials. , 2013, Current opinion in immunology.

[19]  M. Skolnick,et al.  BRCA1 mutations in primary breast and ovarian carcinomas. , 1994, Science.

[20]  S. Signoretti,et al.  Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. , 2005, Cancer research.

[21]  L. Coussens,et al.  Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity , 2010, Cancer and Metastasis Reviews.

[22]  angesichts der Corona-Pandemie,et al.  UPDATE , 1973, The Lancet.

[23]  M. Imieliński,et al.  In Situ Proteomic Analysis of Human Breast Cancer Epithelial Cells Using Laser Capture Microdissection: Annotation by Protein Set Enrichment Analysis and Gene Ontology* , 2010, Molecular & Cellular Proteomics.

[24]  M. Oshimura,et al.  PI3K-Akt pathway: Its functions and alterations in human cancer , 2004, Apoptosis.

[25]  Sanjeeva Srivastava,et al.  Proteomic databases and tools to decipher post-translational modifications. , 2011, Journal of proteomics.

[26]  C. Burge,et al.  Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. , 2008, RNA.

[27]  T. Waldmann,et al.  Serum alpha fetoprotein and human chorionic gonadotropin in the diagnosis and management of nonseminomatous germ-cell testicular cancer. , 1976, The New England journal of medicine.

[28]  E. Montgomery,et al.  The Diagnostic Value of β-Catenin Immunohistochemistry , 2005, Advances in anatomic pathology.

[29]  V. P. Collins,et al.  Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics , 2013, Proceedings of the National Academy of Sciences.

[30]  S. Dhanasekaran,et al.  Delineation of prognostic biomarkers in prostate cancer , 2001, Nature.

[31]  G Weber,et al.  Enzymes of purine metabolism in cancer. , 1983, Clinical biochemistry.

[32]  E. Diamandis,et al.  The failure of protein cancer biomarkers to reach the clinic: why, and what can be done to address the problem? , 2012, BMC Medicine.

[33]  P. Hogg,et al.  Secretion of phosphoglycerate kinase from tumour cells is controlled by oxygen-sensing hydroxylases. , 2004, Biochimica et biophysica acta.

[34]  Lloyd J. Old,et al.  New Paths in Human Cancer Serology , 1998, The Journal of experimental medicine.

[35]  M. Hung,et al.  Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Thomas M. Schmitt,et al.  Cyclin-A1 represents a new immunogenic targetable antigen expressed in acute myeloid leukemia stem cells with characteristics of a cancer-testis antigen. , 2012, Blood.

[37]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[38]  W. Oyen,et al.  Targeting of a CCK(2) receptor splice variant with (111)In-labelled cholecystokinin-8 (CCK8) and (111)In-labelled minigastrin. , 2008, European journal of nuclear medicine and molecular imaging.

[39]  M. Nieto,et al.  The Snail genes as inducers of cell movement and survival: implications in development and cancer , 2005, Development.

[40]  B. Garcia,et al.  Proteomics , 2011, Journal of biomedicine & biotechnology.

[41]  Martin A. Nowak,et al.  Evolution of genetic redundancy , 1997, Nature.

[42]  P. Glazer,et al.  Genetic instability induced by the tumor microenvironment. , 1996, Cancer research.

[43]  K. Arihiro,et al.  Tumor-driven evolution of immunosuppressive networks during malignant progression. , 2006, Cancer research.

[44]  Marie Joseph,et al.  Gene expression signature with independent prognostic significance in epithelial ovarian cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  K. Khazaie,et al.  Tumor STAT1 Transcription Factor Activity Enhances Breast Tumor Growth and Immune Suppression Mediated by Myeloid-derived Suppressor Cells* , 2013, The Journal of Biological Chemistry.

[46]  P. Bottoni,et al.  Revisiting the Warburg effect in cancer cells with proteomics. The emergence of new approaches to diagnosis, prognosis and therapy , 2010, Proteomics. Clinical applications.

[47]  Michael R Stratton,et al.  Genomics and the continuum of cancer care. , 2011, The New England journal of medicine.

[48]  W Godolphin,et al.  Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. , 1989, Science.

[49]  F. Pontén,et al.  Correlations between RNA and protein expression profiles in 23 human cell lines , 2009, BMC Genomics.

[50]  E. Pauwels,et al.  Positron-emission tomography with [18F]fluorodeoxyglucose , 2000, Journal of Cancer Research and Clinical Oncology.

[51]  P. Chomez,et al.  A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. , 1991, Science.

[52]  G. Shore,et al.  Caspase-Resistant BAP31 Inhibits Fas-Mediated Apoptotic Membrane Fragmentation and Release of Cytochrome cfrom Mitochondria , 2000, Molecular and Cellular Biology.

[53]  M. Sarwal,et al.  The proteogenomic path towards biomarker discovery , 2008, Pediatric transplantation.

[54]  M. Karin,et al.  Immunity, Inflammation, and Cancer , 2010, Cell.

[55]  K. Khazaie,et al.  Tumor STAT 1 transcription factor activity enhances breast tumor growth and immune suppression mediated by myeloid-derived suppressor cells , 2013 .

[56]  R. Weichselbaum,et al.  Molecular Pathways Molecular Pathways : Interferon / Stat 1 Pathway : Role in the Tumor Resistance to Genotoxic Stress and Aggressive Growth , 2012 .

[57]  Christian von Mering,et al.  STRING: known and predicted protein–protein associations, integrated and transferred across organisms , 2004, Nucleic Acids Res..

[58]  Alan F. Scott,et al.  McKusick's Online Mendelian Inheritance in Man (OMIM®) , 2008, Nucleic Acids Res..

[59]  R. Skotheim,et al.  Alternative splicing in cancer: noise, functional, or systematic? , 2007, The international journal of biochemistry & cell biology.

[60]  R. Weichselbaum,et al.  COOPERATIVITY OF THE MUC1 ONCOPROTEIN AND STAT1 PATHWAY IN POOR PROGNOSIS HUMAN BREAST CANCER , 2009, Oncogene.

[61]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[62]  D. Kufe,et al.  Oncogenic MUC1-C Promotes Tamoxifen Resistance in Human Breast Cancer , 2013, Molecular Cancer Research.

[63]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[64]  M. Gerstein,et al.  Comparing protein abundance and mRNA expression levels on a genomic scale , 2003, Genome Biology.

[65]  T. Stamey,et al.  Prostate-Specific Antigen as a Serum Marker for Adenocarcinoma of the Prostate , 1987 .

[66]  Gerhard Christofori,et al.  EMT, the cytoskeleton, and cancer cell invasion , 2009, Cancer and Metastasis Reviews.

[67]  P. Bruggen,et al.  T cell defined tumor antigens , 1997 .

[68]  Hua Yu,et al.  Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells , 2004, Nature Medicine.

[69]  K. Robertson.  DNA methylation and human disease , 2005, Nature Reviews Genetics.

[70]  E. Lundberg,et al.  Towards a knowledge-based Human Protein Atlas , 2010, Nature Biotechnology.

[71]  Hua Yu,et al.  Tumour immunology: Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment , 2007, Nature Reviews Immunology.

[72]  Yibang Chen,et al.  Toll-like receptors on tumor cells facilitate evasion of immune surveillance. , 2005, Cancer research.

[73]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[74]  J. Massagué,et al.  TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. , 2005, Cancer cell.

[75]  S. Biffo,et al.  Translation factors and ribosomal proteins control tumor onset and progression: how? , 2014, Oncogene.

[76]  K. Gunsalus,et al.  Network modeling links breast cancer susceptibility and centrosome dysfunction. , 2007, Nature genetics.

[77]  C. Bailly,et al.  Selective Inhibition of Topoisomerase I and Various Steps of Spliceosome Assembly by Diospyrin Derivatives , 2005, Molecular Pharmacology.

[78]  Y. Kawasaki,et al.  Wnt signalling and the actin cytoskeleton , 2006, Oncogene.

[79]  G. Parmiani,et al.  Unique Human Tumor Antigens: Immunobiology and Use in Clinical Trials1 , 2007, The Journal of Immunology.

[80]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[81]  Daniel F Hayes,et al.  OMICS-based personalized oncology: if it is worth doing, it is worth doing well! , 2013, BMC Medicine.

[82]  L. Foulds.  The experimental study of tumor progression: a review. , 1954, Cancer research.

[83]  S. Ye,et al.  BST-2 is a potential activator of invasion and migration in tamoxifen-resistant breast cancer cells. , 2013, Biochemical and biophysical research communications.

[84]  J. Bromberg,et al.  Targeting the interleukin-6/Jak/stat pathway in human malignancies. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[85]  Jie Cao,et al.  Up-regulation of bone marrow stromal protein 2 (BST2) in breast cancer with bone metastasis , 2009, BMC Cancer.

[86]  C. Sonnenschein,et al.  The aging of the 2000 and 2011 Hallmarks of Cancer reviews: A critique , 2013, Journal of Biosciences.

[87]  Zhaojing Meng,et al.  Targeted mass spectrometry approaches for protein biomarker verification. , 2011, Journal of proteomics.

[88]  C. Meijer,et al.  Loss of transporter protein, encoded by the TAP-1 gene, is highly correlated with loss of HLA expression in cervical carcinomas , 1994, The Journal of experimental medicine.

[89]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[90]  M. Ratain,et al.  Biomarkers in Phase I Oncology Trials: Signal, Noise, or Expensive Distraction? , 2007, Clinical Cancer Research.

[91]  Taka-Aki Sato,et al.  Differential Expression of Ribosomal Proteins in Human Normal and Neoplastic Colorectum , 2003, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[92]  Paul Tempst,et al.  Pathway-based biomarker search by high-throughput proteomics profiling of secretomes. , 2009, Journal of proteome research.

[93]  Vladimir Brusic,et al.  Proteome informatics for cancer research: From molecules to clinic , 2007, Proteomics.

[94]  M. Imieliński,et al.  Integrated Proteomic, Transcriptomic, and Biological Network Analysis of Breast Carcinoma Reveals Molecular Features of Tumorigenesis and Clinical Relapse* , 2012, Molecular & Cellular Proteomics.

[95]  T. Stamey,et al.  Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. , 1988, The New England journal of medicine.

[96]  S. Loi,et al.  Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer. , 2013, Cancer treatment reviews.

[97]  E. Marcotte,et al.  Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation , 2007, Nature Biotechnology.

[98]  R. Weinberg,et al.  Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits , 2009, Nature Reviews Cancer.

[99]  P. Pandolfi,et al.  A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language? , 2011, Cell.

[100]  P. van der Bruggen,et al.  T cell defined tumor antigens. , 1997, Current opinion in immunology.

[101]  P. Hogg,et al.  Phosphoglycerate kinase acts in tumour angiogenesis as a disulphide reductase , 2000, Nature.

[102]  S. Gottesman,et al.  Posttranslational quality control: folding, refolding, and degrading proteins. , 1999, Science.

[103]  W. Birchmeier,et al.  Wnt signaling in stem and cancer stem cells. , 2013, Current opinion in cell biology.

[104]  The UniProt Consortium,et al.  Update on activities at the Universal Protein Resource (UniProt) in 2013 , 2012, Nucleic Acids Res..

[105]  Nathalie Vigneron,et al.  Database of T cell-defined human tumor antigens: the 2013 update. , 2013, Cancer immunity.

[106]  R. Moon,et al.  WNT signalling pathways as therapeutic targets in cancer , 2012, Nature Reviews Cancer.

[107]  L. Zelek,et al.  Phase II study of pemetrexed in breast cancer patients pretreated with anthracyclines. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[108]  James D Brooks,et al.  Translational genomics: the challenge of developing cancer biomarkers. , 2012, Genome research.

[109]  T. Nilsen,et al.  Expansion of the eukaryotic proteome by alternative splicing , 2010, Nature.

[110]  M. S. Ledesma,et al.  Massachusetts General Hospital - Harvard Medical School , 2010 .

[111]  Paola Bonizzoni,et al.  ASPicDB: a database of annotated transcript and protein variants generated by alternative splicing , 2010, Nucleic Acids Res..

[112]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[113]  O. Burrone,et al.  Molecular cloning and characterization of a transmembrane surface antigen in human cells. , 1996, European journal of biochemistry.

[114]  Albert Koong,et al.  Impaired interferon signaling is a common immune defect in human cancer , 2009, Proceedings of the National Academy of Sciences.

[115]  R. Bast,et al.  A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. , 1983, The New England journal of medicine.

[116]  榎本 明美,et al.  What's going on 婦人科癌 Gene expression signature with independent prognostic significance in epithelial ovarian cancer. Spentzos D, Levine DA, Ramoni MF, Joseph M, Gu X, Boyd J, Libermann TA, Cannistra SA. J Clin Oncol. 2004; 22: 4700-10. PMID: 15505275--上皮性卵巣癌における遺伝子発現特性は、独立した予後因子である , 2005 .

[117]  Peter A. Jones,et al.  Epigenetics in cancer. , 2010, Carcinogenesis.

[118]  W. Zou.  Regulatory T cells, tumour immunity and immunotherapy , 2006, Nature Reviews Immunology.

[119]  Aleix Prat Aparicio.  Comprehensive molecular portraits of human breast tumours , 2012 .

[120]  Hua Yu,et al.  STATs in cancer inflammation and immunity: a leading role for STAT3 , 2009, Nature Reviews Cancer.

[121]  J. Becker,et al.  The Immune System Strikes Back: Cellular Immune Responses against Indoleamine 2,3-dioxygenase , 2009, PloS one.

[122]  Mads Hald Andersen,et al.  Therapeutic Cancer Vaccines in Combination with Conventional Therapy , 2010, Journal of biomedicine & biotechnology.

[123]  D. Kell.  BMC Medical Genomics , 2008 .

[124]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[125]  Masaaki Ito,et al.  Two Proliferation-Related Proteins, TYMS and PGK1, Could Be New Cytotoxic T Lymphocyte-Directed Tumor-Associated Antigens of HLA-A2+ Colon Cancer , 2004, Clinical Cancer Research.

[126]  Damian Szklarczyk,et al.  STRING v9.1: protein-protein interaction networks, with increased coverage and integration , 2012, Nucleic Acids Res..

[127]  S Ferrone,et al.  HLA class I antigen downregulation in human cancers: T-cell immunotherapy revives an old story. , 1999, Molecular medicine today.