title: AID/APOBEC-network reconstruction identifies pathways associated with survival in ovarian cancer.
abstract: Building up of pathway-/disease-relevant signatures provides a persuasive tool for understanding the functional relevance of gene alterations and gene network associations in multifactorial human diseases. Ovarian cancer is a highly complex heterogeneous malignancy in respect of tumor anatomy, tumor microenvironment including pro-/antitumor immunity and inflammation; still, it is generally treated as single disease. Thus, further approaches to investigate novel aspects of ovarian cancer pathogenesis aiming to provide a personalized strategy to clinical decision making are of high priority. Herein we assessed the contribution of the AID/APOBEC family and their associated genes given the remarkable ability of AID and APOBECs to edit DNA/RNA, and as such, providing tools for genetic and epigenetic alterations potentially leading to reprogramming of tumor cells, stroma and immune cells.
  
  
  
  We structured the study by three consecutive analytical modules, which include the multigene-based expression profiling in a cohort of patients with primary serous ovarian cancer using a self-created AID/APOBEC-associated gene signature, building up of multivariable survival models with high predictive accuracy and nomination of top-ranked candidate/target genes according to their prognostic impact, and systems biology-based reconstruction of the AID/APOBEC-driven disease-relevant mechanisms using transcriptomics data from ovarian cancer samples. We demonstrated that inclusion of the AID/APOBEC signature-based variables significantly improves the clinicopathological variables-based survival prognostication allowing significant patient stratification. Furthermore, several of the profiling-derived variables such as ID3, PTPRC/CD45, AID, APOBEC3G, and ID2 exceed the prognostic impact of some clinicopathological variables. We next extended the signature-/modeling-based knowledge by extracting top genes co-regulated with target molecules in ovarian cancer tissues and dissected potential networks/pathways/regulators contributing to pathomechanisms. We thereby revealed that the AID/APOBEC-related network in ovarian cancer is particularly associated with remodeling/fibrotic pathways, altered immune response, and autoimmune disorders with inflammatory background.
  
  
  
  The herein study is, to our knowledge, the first one linking expression of entire AID/APOBECs and interacting genes with clinical outcome with respect to survival of cancer patients. Overall, data propose a novel AID/APOBEC-derived survival model for patient risk assessment and reconstitute mapping to molecular pathways. The established study algorithm can be applied further for any biologically relevant signature and any type of diseased tissue.
authors.affiliation: Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Svoboda
authors.affiliation: Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Meshcheryakova
authors.affiliation: Section for Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University Vienna, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Heinze
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Jaritz
authors.affiliation: Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pils
authors.affiliation: Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Dan Cacsire
authors.initials: DC
authors.lastname: Castillo-Tong
authors.affiliation: Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Hager
authors.affiliation: Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Theresia
authors.initials: T
authors.lastname: Thalhammer
authors.affiliation: Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.|Comparative Medicine, Messerli Research Institute of the Veterinary University of Vienna, Medical University of Vienna and University of Vienna, Vienna, Austria.
authors.forename: Erika
authors.initials: E
authors.lastname: Jensen-Jarolim
authors.affiliation: Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Birner
authors.affiliation: Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ioana
authors.initials: I
authors.lastname: Braicu
authors.affiliation: Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.affiliation: Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Universitaire Ziekenhuizen Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Sandrina
authors.initials: S
authors.lastname: Lambrechts
authors.affiliation: Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Universitaire Ziekenhuizen Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
authors.affiliation: Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Mahner
authors.affiliation: Nebion AG, Zürich, Switzerland.
authors.forename: Philip
authors.initials: P
authors.lastname: Zimmermann
authors.affiliation: Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeillinger
authors.affiliation: Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria. diana.mechtcheriakova@meduniwien.ac.at.
authors.forename: Diana
authors.identifier: 0000-0002-8737-3592
authors.initials: D
authors.lastname: Mechtcheriakova
mesh_terms: D000071478:APOBEC Deaminases / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D019295:Computational Biology / Q000379:methods; D066264:Datasets as Topic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D005810:Multigene Family; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D011379:Prognosis; D016016:Proportional Hazards Models; D015398:Signal Transduction
chemical_list: D000071478:APOBEC Deaminases
keywords: Integrated analysis of disease-relevant pathways; Multigene signature; Multivariable survival models; Primary serous ovarian carcinoma; Prognostic effect; The AID/APOBEC family