Cellular responses induced by surgical procedure or ischemia-reperfusion injury (IRI) may severely alter transcriptome profiles and complicate molecular diagnostics. To investigate this effect, we characterized such pre-analytical effects in 143 non-malignant liver samples obtained from 30 patients at different time points of ischemia during surgery from two individual cohorts treated either with the Pringle manoeuvre or total vascular exclusion. Transcriptomics profiles were analyzed by Affymetrix microarrays and expression of selected mRNAs was validated by RT-PCR. We found 179 mutually deregulated genes which point to elevated cytokine signaling with NFκB as a dominant pathway in ischemia responses. In contrast to ischemia, reperfusion induced pro-apoptotic and pro-inflammatory cascades involving TNF, NFκB and MAPK pathways. FOS and JUN were down-regulated in steatosis compared to their up-regulation in normal livers. Surprisingly, molecular signatures of underlying primary and secondary cancers were present in non-tumor tissue. The reported inter-patient variability might reflect differences in individual stress responses and impact of underlying disease conditions. Furthermore, we provide a set of 230 pre-analytically highly robust genes identified from histologically normal livers (<2% covariation across both cohorts) that might serve as reference genes and could be particularly suited for future diagnostic applications.

BioXpedia A S 8200 Aarhus Denmark

Department of Medical Oncology Erasmus MC Cancer Institute and Cancer Genomics Netherlands Erasmus University Medical Center 3015CN Rotterdam the Netherlands

Department of Surgical Oncology Erasmus MC Cancer Institute Erasmus University Medical Center 3015CN Rotterdam the Netherlands

Diagnostic and Research Institute of Pathology Medical University of Graz 8010 Graz Austria

Division of General Surgery Department of Surgery Medical University of Graz 8010 Graz Austria

Division of General Surgery Department of Surgery Medical University of Graz 8010 Graz Austria; Department of Orthopedics and Trauma Surgery Medical University of Graz 8010 Graz Austria

Laboratory of Gene Expression Institute of Biotechnology CAS 252 50 Vestec Czech Republic

Pathology Department Erasmus University Medical Center 3015CN Rotterdam the Netherlands

TATAA Biocenter AB 411 03 Göteborg Sweden

Technische Universität München 81675 München Germany

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