AID/APOBEC-network reconstruction identifies pathways associated with survival in ovarian cancer
Svoboda M, Meshcheryakova A, Heinze G, Jaritz M, Pils D, Castillo-Tong DC, Hager G, Thalhammer T, Jensen-Jarolim E, Birner P, Braicu I, Sehouli J, Lambrechts S, Vergote I, Mahner S, Zimmermann P, Zeillinger R and Mechtcheriakova D. (2016). BMC Genomics, 17, 643. DOI: 10.1186/s12864-016-3001-y
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Accumulated knowledge on dysregulated cellular checkpoints associated with cancer development and systematic studies using genomic analysis tools have suggested many new classes of cancer-causing and/or cancer-promoting genes. The discovery of AID/APOBEC gene family members with their potential multifaceted contribution to malignant transformation gave a fundamental impact. In humans, the AID/APOBEC family consists of eleven molecules including AID (activation-induced cytidine deaminase, gene name: AICDA) and APOBECs (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) with the remarkable ability to edit DNA or RNA through cytosine deamination and thus providing tools to introduce DNA or RNA alterations/damages. Under physiological conditions, AID and APOBECs belong to the key players in adaptive and innate immunity.
Given that under pathological circumstances AID and APOBECs’ aberrant expression/activity and/or aberrant mechanisms of recruitment to target(s) and/or aberrant processing of the resulting mismatches might take place, their oncogenicity and impact to the development and/or progression of cancer have been proposed. In the current study we assessed the contribution of the AID/APOBEC family and their associated genes to the pathobiology of ovarian cancer based on the reprogramming of tumor cells and/or stroma and/or 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. 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 results propose for a consideration of potential novel biomarkers and/or targets and therapeutic regiments, although with a strong indication for necessity to stratify the patient population prior to drug application. Among them are APOBEC3G, AID, ID3, IL-6, IFNalpha and novel IFN-related mimetics. This study additionally suggest to consolidate the acquired knowledge and research efforts in the fields of virology and cancer research around AID/APOBECs expression and functionality as well as drug targeting and drugs in development. Furthermore, the study yielded an innovative analysis algorithm, named by us as MuSiCO/from Multigene Signature to Patient-Orientated Clinical Outcome. MuSiCO can be applied further for any biologically relevant signature and any type of diseased tissue.
Link to MSBP/Molecular Systems Biology and Pathophysiology Group