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 data between tumor nodules and the cirrhotic liver may be a prognostic marker of survival after LTx for multifocal HCC.
In a retrospective multicenter study, clinical data and formalin-fixed paraffin-embedded 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 formalin-fixed paraffin-embedded specimens followed by genome wide single-nucleotide polymorphism genotyping.
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 data sets (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.
Evolutionary distance allows for the determination of a high-risk group of recurrence if preoperative liver biopsy is considered.
1 Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
2 Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
3 Institute for Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
4 Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
5 Core Facility Quality Management and Health Technology Assessment in Transplantation, Integrated Research Treatment Center-Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.
6 Department of Trauma and Orthopaedic Surgery, Federal Armed Forces Hospital Westerstede, Germany.
7 Institute of Pathology, Hannover Medical School, Hannover, Germany.
8 Department of General Surgery and Visceral Surgery, University Hospital of Muenster, Muenster, Germany.
9 Clinic for Transplantation Medicine, University Hospital of Muenster, Muenster, Germany.
10 Department for Visceral and General Surgery, St. Josefs Hospital Dortmund-Hoerde, Germany.
11 Department of Pathology, University Hospital of Muenster, Muenster, Germany.
12 Department of General, Visceral, and Transplantation Surgery, Charité, Campus Virchow Klinikum, Berlin, Germany.
13 Institute of Pathology, Charité University Hospital, Berlin, Germany.
14 Department of Medicine, University Hospital Regensburg, Regensburg, Germany.
15 Institute of Pathology, University of Regensburg, Regensburg, Germany.
16 Institute for Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Received 4 January 2018. Revision received 1 June 2018.
Accepted 7 June 2018.
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.
The authors declare no conflicts of interest.
This work was supported by institutional funds from the Medical Faculties of the Christian-Albrechts University Kiel and the Technical University Dresden.
N.H., M.B., A.H., F.B., J.H., C.S. made substantial contributions to the conception or design of the work. N.H., M.B., A.H. R.B., C.R., H.S., A.K., J.K., H-H.K., B.R., C.L., C.W., T.V., H.W., E.W., D.S., S.B., S.Z., S.P., N.R., M.D., W.S., S.H., A.T., M.E., A.F., T.B., F.B., J.H., C.S. participated in the acquisition, analysis, or interpretation of data for the work. N.H., M.B., F.B., J.H., C.S. participated in the drafting the work or revising it critically for important intellectual content. N.H., M.B., A.H. R.B., C.R., H.S., A.K., J.K., H-H.K., B.R., C.L., C.W., T.V., H.W., E.W., D.S., S.B., S.Z., S.P., N.R., M.D., W.S., S.H., A.T., M.E., A.F., T.B., F.B., J.H., C.S. gave the final approval of the version to be published. N.H., M.B., A.H. R.B., C.R., H.S., A.K., J.K., H-H.K., B.R., C.L., C.W., T.V., H.W., E.W., D.S., S.B., S.Z., S.P., N.R., M.D., W.S., S.H., A.T., M.E., A.F., T.B., F.B., J.H., C.S. made an 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.
Correspondence: 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. (Clemens.Schafmayer@uksh.de).
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