EVOLUTIONARY DISTANCE PREDICTS RECURRENCE AFTER LIVER TRANSPLANTATION IN MULTIFOCAL HEPATOCELLULAR CARCINOMA

Background Liver transplantation (LTx) is a potentially curative treatment option for hepatocellular carcinoma (HCC) in cirrhosis. However, patients, where HCC is already a systemic disease, LTx may be individually harmful and has a negative impact on donor organ usage. Thus, there is a need for improved selection criteria beyond nodule morphology to select patients with a favorable outcome for LTx in multifocal HCC. Evolutionary distance measured from genome-wide single nucleotide polymorphism (SNP) data between tumor nodules and the cirrhotic liver may be a prognostic marker of survival after liver transplantation for multifocal HCC. Methods In a retrospective multicenter study, clinical data and formalin fixed paraffin embedded (FFPE) specimens of the liver and 2 tumor nodules were obtained from explants of 30 patients in the discovery and 180 patients in the replication cohort. DNA was extracted from FFPE specimens followed by genome wide SNP genotyping. Results Genotype quality criteria allowed for analysis of 8 patients in the discovery and 17 patients in the replication set. DNA concentrations of a total of 25 patients fulfilled the quality criteria and were included in the analysis. Both, in the discovery (p=0.04) and in the replication datasets (p=0.01), evolutionary distance was associated with the risk of recurrence of HCC after transplantation (combined p=0.0002). In a univariate analysis, evolutionary distance (p=7.4×10-6) and microvascular invasion (p=1.31×10-5) were significantly associated with survival in a Cox regression analysis. Conclusions Evolutionary distance allows for the determination of a high-risk group of recurrence, if preoperative liver biopsy is considered. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. *N.H., M.B. and A.H. contributed equally to the study and the manuscript §C.S., F.B. and J.H. contributed equally to the study and the manuscript and assume equal responsibility for senior authorship Corresponding author: #to whom correspondence should be addressed: Clemens Schafmayer, MD, Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel Campus, Christian-Albrechts-University Kiel, Arnold-Heller-Str. 3, 24105 Kiel / Germany, Tel.: +49 (0) 431 500-20411, Fax: +49 (0) 431 500-20404. Email: Clemens.Schafmayer@uksh.de AUTHORSHIP PAGE Authorship: a. Substantial contributions to the conception or design of the work. b. Acquisition, analysis, or interpretation of data for the work. c. Drafting the work or revising it critically for important intellectual content. d. Final approval of the version to be published. e. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Nils Heits a, b, c, d, e Mario Brosch a, b, c, d, e Alexander Herrmann a, b, c, d, e Robin Behrens b, d, e Christoph Röcken b, d, e Harald Schrem b, d, e Alexander Kaltenborn b, d, e Jürgen Klempnauer b, d, e Hans-Heinrich Kreipe b, d, e Benedikt Reichert b, d, e Christina Lenschow b, d, e Christian Wilms b, d, e Thomas Vogel b, d, e Heiner Wolters b, d, e Eva Wardelmann b, d, e Daniel Seehofer b, d, e Stephan Buch b, d, e Sebastian Zeissig b, d, e Sven Pannach b, d, e Nathanael Raschzok b, d, e Manfred Dietel b, d, e Witigo von Schoenfels b, d, e Sebastian Hinz b, d, e Andreas Teufel b, d, e Matthias Evert b, d, e Andre Franke b, d, e Thomas Becker b, d, e Felix Braun a, b, c, d, e Jochen Hampe a, b, c, d, e Clemens Schafmayer a, b, c, d, e Disclosure: The authors declare no conflicts of interest. Funding: This work was supported by institutional funds from the Medical Faculties of the Christian-Albrechts University Kiel and the Technical University Dresden. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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